The role of the indoleamine 2,3-dioxygenase gene in preventing ovarian transplant rejection in rats.

Indoleamine 2, 3-dioxygenase (IDO) plays important roles in maternal immune tolerance. Female Sprague Dawley rats (9-11 weeks old) were randomly divided into an autoplastic transplantation group (n = 75) and an allograft transplantation group (n = 300) further divided into subgroups of ovarian transplantation, allograft ovarian transplantation, allograft ovarian transplantation with cyclosporine A treatment, allograft ovarian transplantation and transfection with IDO-expressing lentiviruses, and allograft ovarian transplantation and transfection with control lentiviruses. IDO was successfully transfected intothe transplanted ovarian tissue. The survival rate, success rate of ovarian transplantation, period until estrous cycle restoration, and estrogen levels of rats that received IDO-expressing lentiviruseswere significantly different from those of rats that underwent allograft transplantation and with control transfection (all P < 0.05), but not significantly different from those of rats that received autoplastic transplantation (all P > 0.05). The number of ovarian follicles in the transplanted ovarian tissue of rats that received IDO-expressing lentiviruses was also significantly higher. The expression level of IDO protein detected by immunohistochemistry and western blotting was especially high in ovaries that had received IDO-containing lentiviruses. Naturally pregnant rats were found in each group postoperatively. These results indicate that IDO-expressing lentiviruses were successfully transfected into transplanted ovarian tissues of rats and that IDO was stably expressed within a certain time. These findings suggest that the expression level of IDO protein is associated with an enhanced success rate of ovarian tissue transplantation and a short restoration period of endocrine function.

Elevated circulating BMP9 aggravates pulmonary angiogenesis in hepatopulmonary syndrome rats through ALK1-Endoglin-Smad1/5/9 signalling.

BACKGROUND: Bone morphogenetic protein 9 (BMP9) is a hepatokine that plays a pivotal role in the progression of liver diseases. Moreover, an increasing number of studies have shown that BMP9 is associated with hepatopulmonary syndrome (HPS), but its role in HPS is unclear. Here, we evaluated the influence of CBDL on BMP9 expression and investigated potential mechanisms of BMP9 signalling in HPS. METHODS: We profiled the circulating BMP9 levels in common bile duct ligation-induced HPS rat model, and then investigated the effects and mechanisms of HPS rat serum on pulmonary vascular endothelial dysfunction in rat model, as well as in primarily cultured rat pulmonary microvascular endothelial cells. RESULTS: Our data revealed that circulating BMP9 levels were significantly increased in the HPS rats compared to control group. Besides, the elevated BMP9 in HPS rat serum was not only crucial for promoting endothelial cell proliferation and tube formation through the activin receptor-like kinase1 (ALK1)-Endoglin-Smad1/5/9 pathway, but also important for accumulation of monocytes. Treatments with ALK1-Fc or silencing ALK1 expression to inhibit the BMP9 signalling pathway effectively eliminated these effects. In agreement with these observations, increased circulating BMP9 was associated with an increase in lung vessel density and accumulation of pro-angiogenic monocytes in the microvasculature in HPS rats. CONCLUSIONS: This study provided evidence that elevated circulating BMP9, secreted from the liver, promote pulmonary angiogenesis in HPS rats via ALK1-Endoglin-Smad1/5/9 pathway. In addition, BMP9-regulated pathways are also involved in accumulation of pro-angiogenic monocytes in the pulmonary microvasculature in HPS rats.

Suppression of DNMT1 combined with ATM or ATR inhibitor as a therapeutic combination of acute myeloid leukemia.

The potential treatment option of targeting DNA methyltransferase 1 (DNMT1) has been explored, but further investigation is required to assess the efficacy of combination therapy in acute myeloid leukemia (AML). In this study, bioinformatics and online databases were utilized to select the combined therapeutic targets. The potential kinases associated with DNMT1-related genes in AML were analyzed using the Cancer Genome Atlas (TCGA) database and X2K Appyter (Expression2Kinases) database. In-vitro evaluations were conducted to assess the synergistic effects between DNMT1 and ATR/ATM in five AML cell lines (MOLM-16, NB-4, HEL 92.1.7, HEL, EOL-1). In our study, ATR and ATM are primarily the kinases associated with DNMT1-related genes in AML. We observed a significant upregulation of DNMT1, ATR, and ATM expression in AML tissues and cell lines. The five AML cell lines demonstrated sensitivity to monotherapy with GSK-368, AZD-1390, or AZD-6738 (EC50 value ranges from 5.461 to 7.349 nM, 5.821 to 10.120 nM, and 7.618 to 10.100 nM, respectively). A considerable synergistic effect was observed in AML cell lines when combining GSK-368 and AZD-1390, GSK-368 and AZD-6738, or AZD-1390 and AZD-6738, resulting in induced cell apoptosis and inhibited cell growth. DNMT1, ATM, and ATR possess potential as therapeutic targets for AML. Both individual targeting and combination targeting of these molecules have been confirmed as promising therapeutic approaches for AML.

Chemotherapy-related symptoms in children with leukemia: application of latent profile analysis and network analysis.

PURPOSE: Children with leukemia may experience a range of chemotherapy-related symptoms. Identifying subgroups and their distinct characteristics of symptoms may improve symptom management. We aimed to identify subgroups and their distinct characteristics of chemotherapy-related symptoms in children with leukemia. METHODS: A cross-sectional survey was conducted among 500 children with leukemia, who completed questionnaires that assessed their demographic and clinical characteristics, as well as the Memorial Symptom Assessment Scale. Latent profile analysis was conducted to identify subgroups of symptoms. Additionally, multiple regression analysis and network analysis were utilized to reveal the characteristics of each subgroup. RESULTS: Four subgroups were identified: "Profile 1: low symptom burden subgroup" (26.2%), "Profile 2: moderate symptom burden subgroup in transitional period" (14.8%), "Profile 3: moderate psychological symptom burden subgroup" (35.6%), and "Profile 4: high symptom burden subgroup" (23.4%). Multiple logistic regression analysis indicated that lower primary caregiver's education level, lower family monthly income, self-paid medical expenses, induction remission period, and consolidation enhancement period were associated with more severe symptoms of subgroups. Network analysis further revealed that nausea was the core symptom in Profiles 1 and 2, while the core symptom in Profile 3 was "I don't look like myself." Additionally, worrying was the core symptom in Profile 4. CONCLUSION: There exists heterogeneity in chemotherapy-related symptoms. Four subgroups and their corresponding characteristics of children with varying symptom severity were identified. Identifying these subgroups will facilitate personalized care, maximize intervention effectiveness, and alleviate symptom burden.

Immunomodulation in allergic rhinitis: Insights from Th2 cells and NLRP3/IL-18 pathway.

Allergic rhinitis (AR) is characterized by nasal symptoms such as rubbing and sneezing, often triggered by allergen exposure. The purpose of this study is to dissect the roles of NLRP3-mediated immune modulation and macrophage pyroptosis in modulating T cell differentiation within the context of ovalbumin (OVA)-induced AR in mice. OVA-induced AR was established in mice, evaluating nasal symptoms, macrophage infiltration, cytokine levels, and T cell differentiation. Manipulations using NLRP3-/-, ASC-/- mice, clodronate liposome treatment, and NLRP3 inhibitor MCC950 were performed to assess their impact on AR symptoms and immune responses. Following OVA stimulation, increased nasal symptoms were observed in the OVA group along with augmented GATA3 expression and elevated IL-4 and IL-1b levels, indicative of Th2 polarization and cellular pyroptosis involvement. NLRP3-/- and ASC-/- mice exhibited reduced CD3+ T cells post OVA induction, implicating cellular pyroptosis in AR. Macrophage depletion led to decreased IgE levels, highlighting their involvement in allergic responses. Further investigations revealed enhanced macrophage pyroptosis, influencing Th1/Th2 differentiation in AR models. IL-18 released through NLRP3-mediated pyroptosis induced Th2 differentiation, distinct from IL-1b. Additionally, MCC950 effectively mitigated AR symptoms by modulating Th2 responses and reducing macrophage infiltration. This comprehensive study unravels the pivotal role of NLRP3-mediated immune modulation and macrophage pyroptosis in Th1/Th2 balance regulation in OVA-induced AR. Targeting NLRP3 pathways with MCC950 emerged as a promising strategy to alleviate AR symptoms, providing insights for potential therapeutic interventions in AR management.

Recent progress of iron-based nanomaterials in gene delivery and tumor gene therapy.

Gene therapy aims to modify or manipulate gene expression and change the biological characteristics of living cells to achieve the purpose of treating diseases. The safe, efficient, and stable expression of exogenous genes in cells is crucial for the success of gene therapy, which is closely related to the vectors used in gene therapy. Currently, gene therapy vectors are mainly divided into two categories: viral vectors and non-viral vectors. Viral vectors are widely used due to the advantages of persistent and stable expression, high transfection efficiency, but they also have certain issues such as infectivity, high immunological rejection, randomness of insertion mutation, carcinogenicity, and limited vector capacity. Non-viral vectors have the advantages of non-infectivity, controllable chemical structure, and unlimited vector capacity, but the transfection efficiency is low. With the rapid development of nanotechnology, the unique physicochemical properties of nanomaterials have attracted increasing attention in the field of drug and gene delivery. Among many nanomaterials, iron-based nanomaterials have attracted much attention due to their superior physicochemical properties, such as Fenton reaction, magnetic resonance imaging, magnetothermal therapy, photothermal therapy, gene delivery, magnetically-assisted drug delivery, cell and tissue targeting, and so on. In this paper, the research progress of iron-based nanomaterials in gene delivery and tumor gene therapy is reviewed, and the future application direction of iron-based nanomaterials is further prospected.

Real-time non-invasive hemoglobin prediction using deep learning-enabled smartphone imaging.

BACKGROUND: Accurate measurement of hemoglobin concentration is essential for various medical scenarios, including preoperative evaluations and determining blood loss. Traditional invasive methods are inconvenient and not suitable for rapid, point-of-care testing. Moreover, current models, due to their complex parameters, are not well-suited for mobile medical settings, which limits the ability to conduct frequent and rapid testing. This study aims to introduce a novel, compact, and efficient system that leverages deep learning and smartphone technology to accurately estimate hemoglobin levels, thereby facilitating rapid and accessible medical assessments. METHODS: The study employed a smartphone application to capture images of the eye, which were subsequently analyzed by a deep neural network trained on data from invasive blood test data. Specifically, the EGE-Unet model was utilized for eyelid segmentation, while the DHA(C3AE) model was employed for hemoglobin level prediction. The performance of the EGE-Unet was evaluated using statistical metrics including mean intersection over union (MIOU), F1 Score, accuracy, specificity, and sensitivity. The DHA(C3AE) model's performance was assessed using mean absolute error (MAE), mean-square error (MSE), root mean square error (RMSE), and R^2. RESULTS: The EGE-Unet model demonstrated robust performance in eyelid segmentation, achieving an MIOU of 0.78, an F1 Score of 0.87, an accuracy of 0.97, a specificity of 0.98, and a sensitivity of 0.86. The DHA(C3AE) model for hemoglobin level prediction yielded promising outcomes with an MAE of 1.34, an MSE of 2.85, an RMSE of 1.69, and an R^2 of 0.34. The overall size of the model is modest at 1.08 M, with a computational complexity of 0.12 FLOPs (G). CONCLUSIONS: This system presents a groundbreaking approach that eliminates the need for supplementary devices, providing a cost-effective, swift, and accurate method for healthcare professionals to enhance treatment planning and improve patient care in perioperative environments. The proposed system has the potential to enable frequent and rapid testing of hemoglobin levels, which can be particularly beneficial in mobile medical settings. TRIAL REGISTRATION: The clinical trial was registered on the Chinese Clinical Trial Registry (No. ChiCTR2100044138) on 20/02/2021.

The NG2-glia is a potential target to maintain the integrity of neurovascular unit after acute ischemic stroke.

The neurovascular unit (NVU) plays a critical role in health and disease. In the current review, we discuss the critical role of a class of neural/glial antigen 2 (NG2)-expressing glial cells (NG2-glia) in regulating NVU after acute ischemic stroke (AIS). We first introduce the role of NG2-glia in the formation of NVU during development as well as aging-induced damage to NVU and accompanying NG2-glia change. We then discuss the reciprocal interactions between NG2-glia and the other component cells of NVU, emphasizing the factors that could influence NG2-glia. Damage to the NVU integrity is the pathological basis of edema and hemorrhagic transformation, the most dreaded complication after AIS. The role of NG2-glia in AIS-induced NVU damage and the effect of NG2-glia transplantation on AIS-induced NVU damage are summarized. We next discuss the role of NG2-glia and the effect of NG2-glia transplantation in oligodendrogenesis and white matter repair as well as angiogenesis which is associated with the outcome of the patients after AIS. Finally, we review the current strategies to promote NG2-glia proliferation and differentiation and propose to use the dental pulp stem cells (DPSC)-derived exosome as a promising strategy to reduce AIS-induced injury and promote repair through maintaining the integrity of NVU by regulating endogenous NG2-glia proliferation and differentiation.

Radiological predictive factors of transmural intestinal necrosis in acute mesenteric ischemia: systematic review and meta-analysis.

OBJECTIVE: Transmural intestinal necrosis (TIN) is related to high mortality in patients with acute mesenteric ischemia (AMI). Radiological predictive factors of TIN in AMI remains controversial. This study aimed to identify the CT-based predictive factors of TIN in AMI. METHODS: EMBASE and PUBMED were searched for publications predicting TIN using radiological features. Quality Assessment of Diagnostic Accuracy Studies-2 was used to assess the methodological quality of individual studies. Data were presented in terms of diagnostic odds ratio (DOR), sensitivity, specificity, and 95% confidence interval (CI). The random-effects models were used for the meta-analysis. RESULTS: Eleven studies including 1037 cases with AMI were considered. The meta-analysis showed that bowel wall thinning (DOR = 13.10; 95% CI: 3.71, 46.25), decreased or absent bowel wall enhancement (DOR = 5.77; 95% CI: 2.95, 11.30), bowel dilation (DOR = 3.23; 95% CI: 2.03, 5.15), pneumatosis intestinalis (DOR = 5.78; 95% CI: 2.24, 14.95), porto-mesenteric venous gas (DOR = 5.36; 95% CI: 2.14, 13.40), and arterial occlusive AMI (DOR = 2.66; 95% CI: 1.53, 4.63) were risk factors for predicting TIN. Bowel wall thinning and porto-mesenteric venous gas displayed high specificity to diagnose TIN (98%, 95%, respectively). The subgroup analysis showed that decreased or absent bowel wall enhancement (DOR = 8.23; 95% CI: 4.67, 14.51) and bowel dilation (DOR = 3.14; 95% CI: 1.55, 6.39) were predictors of TIN in venous occlusive AMI, which were not related to TIN in arterial-origin AMI. CONCLUSIONS: For predicting TIN, there are specific radiological features. The radiological predictors of TIN may differ according to the various causes of AMI. Future primary studies should further evaluate the relationships between radiological signs and TIN based on different etiologies. KEY POINTS: • Bowel wall thinning, decreased or absent bowel wall enhancement, bowel dilation, pneumatosis intestinalis, porto-mesenteric venous gas, and arterial occlusive AMI were risk factors for predicting TIN. • Decreased or absent bowel wall enhancement and bowel dilation were predictors of TIN in venous occlusive AMI, which were not related to TIN in arterial-origin AMI.

Prognostic value of contrast staining on dual-energy CT after endovascular therapy in acute ischemic stroke: a meta-analysis.

BACKGROUND: Contrast staining (CS) on dual-energy CT (DECT) is common after endovascular therapy (EVT) in acute ischemic stroke (AIS). We performed a meta-analysis to investigate the prognostic significance of CS detected by DECT after EVT in AIS. METHOD: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Web of Science and Scopus databases were searched from inception to July 2023 for publications on the prognostic significance of CS on DECT after EVT in patients with AIS. Prognostic outcomes were hemorrhage transformation (HT) and poor functional outcome (modified Rankin Scale [mRS] Score of 3-6 at the 90-day follow-up). Data are presented as odds ratios (OR) and 95% confidence intervals (CI). RESULTS: Eleven studies including 1123 cases of AIS were included. Pooled results indicated a higher risk of HT in patients with CS than in those without CS (OR = 2.22; 95% CI 1.41-3.51, P = 0.001; I2 = 45.4%). No association between CS and symptomatic HT was observed (OR = 2.10; 95% CI 0.64-6.95, P = 0.223; I2 = 67.3%). Moreover, there was also higher odds of poor functional outcome in patients with CS than in those without CS (OR = 2.76; 95% CI 1.53-4.97, P = 0.001; I2 = 44.9%). CONCLUSIONS: The presence of contrast staining on DECT after EVT is associated with a higher risk of hemorrhage transformation and poor functional outcome. However, further high-quality studies with standardized processes are required to confirm these results.

Nicotine pretreatment alleviates MK-801-induced behavioral and cognitive deficits in mice by regulating Pdlim5/CRTC1 in the PFC.

Increasing evidence shows that smoking-obtained nicotine is indicated to improve cognition and mitigate certain symptoms of schizophrenia. In this study, we investigated whether chronic nicotine treatment alleviated MK-801-induced schizophrenia-like symptoms and cognitive impairment in mice. Mice were injected with MK-801 (0.2 mg/kg, i.p.), and the behavioral deficits were assessed using prepulse inhibition (PPI) and T-maze tests. We showed that MK-801 caused cognitive impairment accompanied by increased expression of PDZ and LIM domain 5 (Pdlim5), an adaptor protein that is critically associated with schizophrenia, in the prefrontal cortex (PFC). Pretreatment with nicotine (0.2 mg · kg-1 · d-1, s.c., for 2 weeks) significantly ameliorated MK-801-induced schizophrenia-like symptoms and cognitive impairment by reversing the increased Pdlim5 expression levels in the PFC. In addition, pretreatment with nicotine prevented the MK-801-induced decrease in CREB-regulated transcription coactivator 1 (CRTC1), a coactivator of CREB that plays an important role in cognition. Furthermore, MK-801 neither induced schizophrenia-like behaviors nor decreased CRTC1 levels in the PFC of Pdlim5-/- mice. Overexpression of Pdlim5 in the PFC through intra-PFC infusion of an adreno-associated virus AAV-Pdlim5 induced significant schizophrenia-like symptoms and cognitive impairment. In conclusion, chronic nicotine treatment alleviates schizophrenia-induced memory deficits in mice by regulating Pdlim5 and CRTC1 expression in the PFC.

Clinical value of serum soluble receptor for advanced glycation end products in evaluating the condition of patients with bronchial asthma.

Objective: This study focused on the clinical value of serum soluble receptor for advanced glycation end products (sRAGE) levels in evaluating the severity of bronchial asthma (BA). Methods: Serum sRAGE expression was measured by using enzyme-linked immunosorbent assay, eosinophils (EOS) count was measured by using an automatic blood cell counter, and forced expiratory volume in 1 second (FEV1) was measured by pulmonary function analyzer in 120 patients with BA, 40 patients with non-BA pulmonary disease, and 40 healthy controls. Receiver operating characteristic curves were used to analyze the clinical value of sRAGE expression levels, EOS counts, and FEV1 level to assess the severity of illness in the patients with BA. Results: Compared with the healthy controls and the patients without BA, the patients with BA had the lowest serum sRAGE expression level (47.36 ± 6.3 ng/L versus 75.3 ± 6.3 ng/L versus 67.5 ± 5.06 ng/L; p < 0.05), the highest EOS count (231.2 ± 18.3 106/L versus 175.9 ± 15.6 106/L versus 197.8 ± 19.6 106/L; p < 0.05), and the lowest FEV1 level (1.19 ± 0.15 L versus 1.57 ± 0.2 L versus 1.3 ± 0.17 L; p < 0.05). Correlation analysis revealed that the serum sRAGE expression levels were notably negatively correlated with the EOS counts (r value of -0.471, p < 0.05) but significantly positively linked to FEV1 levels (r value of 0.362, p < 0.05). Serum sRAGE expression levels could help in accurately diagnosing patients with severe BA (area under the receiver operating characteristic curve (AUC) = 0.904), whereas prediction in the patients with mild BA was achieved by EOS counts (AUC = 0.857). Conclusion: The serum sRAGE level has potential value in diagnosing the severity of BA, which is conducive to identifying patients with severe BA and guiding in development of new therapeutic strategies.

Immature permanent incisors with complicated crown fractures treated with partial pulpotomy using white mineral trioxide aggregate and IRoot BP plus-a retrospective long-term study.

BACKGROUND/AIMS: Calcium silicate cements have been widely used for pulpotomies in immature permanent teeth with complicated crown fractures due to their superior properties. However, few studies have evaluated the long-term outcomes of white mineral trioxide aggregate (WMTA) and iRoot BP Plus for partial pulpotomies. The aim of this study was to investigate the long-term clinical and radiographic outcomes of WMTA and iRoot BP Plus for partial pulpotomies in immature permanent incisors with complicated crown fractures. MATERIALS AND METHODS: Children who had partial pulpotomies of immature permanent incisors with complicated crown fractures using WMTA or iRoot BP Plus as capping agents were enrolled. Eighty immature permanent incisors in 68 children (aged 8-13 years) were included. They were divided into two groups (WMTA and iRoot BP Plus) according to the capping agents. Clinical and radiographic information was collected during a 5-year follow-up period. Study data were analyzed using Chi-square tests or Fisher exact tests. RESULTS: The clinical and radiographic success rates in the WMTA (n = 36) and iRoot BP Plus groups (n = 44) were 94.4% versus 97.7% and 88.9% versus 97.7%, respectively (both p < .05). The average observation period was 74.5 ± 13.2 months and 61.9 ± 1.6 months in the WMTA and iRoot BP Plus groups, respectively (p < .01). Five cases presented with periapical radiolucencies. The WMTA group had four cases of pulp canal calcification (11.1%), while the iRoot BP Plus group had two cases (4.6%). There was crown discolouration in all cases in the WMTA group, but none in the iRoot BP Plus group. CONCLUSION: Both WMTA and iRoot BP Plus had favorable outcomes in promoting physiological development and maintaining the basic functions of immature permanent incisors with complicated crown fractures. As a partial pulpotomy material, iRoot BP Plus may be more suitable for the esthetic zone than WMTA.

A retrospective study of iRoot BP Plus pulpotomy compared with Vitapex pulpectomy for irreversible pulpitis of primary molars with the presence of coronal pulp tissue.

BACKGROUND: Pulpotomy has been successfully performed in immature and mature permanent teeth with irreversible pulpitis but rarely in primary teeth. AIM: To evaluate the outcomes of iRoot BP Plus pulpotomy and Vitapex pulpectomy in primary molars with irreversible pulpitis. DESIGN: We selected 130 primary molars of 99 patients, aged 3-7 years, diagnosed with irreversible pulpitis with coronal pulp tissue and treated with iRoot BP Plus pulpotomy or Vitapex pulpectomy (median follow-up period: 18 months). They were divided into the pulpotomy (n = 88) and pulpectomy (n = 42) groups according to treatment procedure. The pulpotomy group was further divided into asymptomatic (n = 46) and symptomatic (n = 42) subgroups according to preoperative symptoms. The chi-squared test and Cox regression were performed to analyze the outcomes. RESULTS: Clinical and radiographic success rates were significantly higher in the pulpotomy group (98.9% and 95.5%) than in the pulpectomy group (88.1% and 54.8%) and did not differ significantly between asymptomatic and symptomatic pulpotomy subgroups. CONCLUSION: Irreversible pulpitis of primary molars with coronal pulp tissue can be successfully treated with iRoot BP Plus pulpotomy. Early intraradicular resorption of materials is the main adverse outcome of Vitapex pulpectomy.

Compact vertical grating coupler with an achromatic in-plane metalens on a 220-nm silicon-on-insulator platform.

We proposed a new type of vertical grating couplers (VGCs) with a compact footprint on the 220-nm silicon-on-insulator platform. The overall size of the device containing the L-shaped coupling grating and the taper with achromatic in-plane metalens is only 45 × 15 µm2, and the measured coupling efficiency at 1550 nm is -5.2 dB with a 1 dB bandwidth of 38 nm, around 1.6 dB higher than the VGC without metalens. The incidence angle mismatch has a 1 dB bandwidth of roughly 4°, whereas the displacement mismatch along the x-/y- axis has a bandwidth of around 3/4 µm. Furthermore, we experimentally show that such a design is compatible with VGCs operating in the S, C, and L bands.

Programmable low-threshold optical nonlinear activation functions for photonic neural networks.

We experimentally demonstrate two types of programmable, low-threshold, optically controlled nonlinear activation functions, which are challenging to realize in photonic neural networks (PNNs). These devices rely on on-chip integrated Ge-Si photoelectric detectors and silicon electro-optical switches, and they generate rectified linear unit (ReLU) or sigmoid functions with arbitrary slopes without additional electrical processing. Both devices function at an extremely low threshold of 0.2 mW. The embedding of these nonlinear activation functions into convolutional neural networks facilitates the attainment of high inference accuracies of up to 95% when applied to Modified National Institute of Standards and Technology (MNIST) handwritten digit-classification tasks. The devices are suitable for low-power PNNs with an arbitrary number of propagation layers in photonic-computing chips.

Mechanisms underlying synergism between circularized tumor necrosis factor-related apoptosis inducing ligand and bortezomib in bortezomib-sensitive or -resistant myeloma cells.

Mechanisms underlying interactions between a novel, clinically relevant circularized tumor necrosis factor-related apoptosis inducing ligand (TRAIL) agonist, circularly permuted TRAIL (CPT) have been examined in multiple myeloma (MM) cells sensitive or resistant to bortezomib (BTZ). Various MM cell lines for example, U266, including those resistant to bortezomib-resistant U266 cells were exposed to low nanomolar concentrations of bortezomib ± CPT and apoptosis monitored. Circularly permuted TRAIL and bortezomib synergistically induced apoptosis in both BTZ-naïve and -resistant cells. The regimen up-regulated DR4 receptor internalization in MM cells, known to modulate both NF-κB and extrinsic apoptotic pathways. CPT/BTZ disrupted the non-canonical NF-κB pathway, reflected by tumor necrosis factor (TNF) receptor associated factors 3 (TRAF3) up-regulation, NF-κB inducing kinase down-regulation, diminished p52 and p50 processing, and B-cell lymphoma-extra large (BCL-XL) down-regulation, but failed to inactivate the canonical NF-κB pathway, reflected by unchanged or increased expression of phospho-p65. The regimen also sharply increased extrinsic apoptotic pathway activation. Cells exhibiting TRAF3 knock-down, dominant-negative Fas-associated protein with death domain, knock-down of caspase-8, BCL-2/BCL-XL, or exposure to a caspase-9 inhibitor displayed markedly reduced CPT/BTZ sensitivity. Concordant results were observed in bortezomib-resistant cells. The regimen was also active in the presence of stromal cells and was relatively sparing toward normal CD34+ hematopoietic cells. Finally, ex vivo results revealed synergism in primary MM primary cells, including those BTZ, and the CPT/BTZ regimen significantly decreased tumor growth in a patient-derived MM xenograft model. These results indicate that the CPT/BTZ regimen acts via the non-canonical NF-κB as well as intrinsic/extrinsic apoptotic pathways to induce cell death in MM cells, and may represent an effective strategy in the setting of bortezomib resistance.

Modulation of α7nAchR by Melatonin Alleviates Ischemia and Reperfusion-Compromised Integrity of Blood-Brain Barrier Through Inhibiting HMGB1-Mediated Microglia Activation and CRTC1-Mediated Neuronal Loss.

The only food and drug administration (FDA)-approved drug currently available for the treatment of acute ischemic stroke is tissue plasminogen activator (tPA), yet the therapeutic benefits of this drug are partially outweighed by the increased risk of hemorrhagic transformation (HT). Analysis of the NIH trial has shown that cigarette smoking protected tPA-treated patients from HT; however, the underlying mechanism is not clear. Nicotinic acetylcholine receptors (nAChR) has shown anti-inflammatory effect and modulation nAChR could be a strategy to reduce ischemia/reperfusion-induced blood-brain barrier (BBB) damage. Since melatonin could regulate the expression of α7nAchR and melatonin's neuroprotective effect against ischemic injury is mediated via α7nAChR modulation, here, we aim to test the hypothesis that melatonin reduces ischemia and reperfusion (I/R)-induced BBB damage through modulation of α7nACh receptor (α7nAChR). Mice were subjected to 1.5 h ischemia and 24 h reperfusion and at the onset of reperfusion, mice received intraperitoneal administration (i.p.) of either drug or saline. Mice were randomly assigned into five groups: Saline; α7nAChR agonist PNU282987; Melatonin; Melatonin+Methyllycaconitine (MLA, α7nAChR antagonist), and MLA group. BBB permeability was assessed by detecting the extravasation of Evan's blue and IgG. Our results showed that I/R significantly increased BBB permeability accompanied by occludin degradation, microglia activation, and high mobility group box 1 (HMGB1) release from the neuron. In addition, I/R significantly induced neuronal loss accompanied by the decrease of CREB-regulated transcriptional coactivator 1 (CRTC1) and p-CREB expression. Melatonin treatment significantly inhibited the above changes through modulating α7nAChR. Taken together, these results demonstrate that melatonin provides a protective effect on ischemia/reperfusion-induced BBB damage, at least in part, depending on the modulation of α7nAChR.

miR-1290 promotes IL-8-mediated vascular endothelial cell adhesion by targeting GSK-3ß.

BACKGROUND: MicroRNA-1290 (miR-1290) has been reported to be involved in many diseases and play a key role during the development process. However, the role of miR-1290 in atherosclerosis (AS) is still unclear. METHODS AND RESULTS: The current study showed that the expressions of miR-1290 were high in serum of patients with hyperlipidemia. The functional role of miR-1290 were then investigated in human umbilical vein endothelial cells (HUVECs). Here, we found that miR-1290 expressions were notably enhanced in HUVECs mediated by IL-8. miR-1290 inhibitor repressed monocytic THP-1 cells adhesion to HUVECs by regulating ICAM-1 and VCAM-1, inhibited proliferation through regulating cyclinD1 and PCNA, and inhibited inflammatory response by regulating IL-1ß. Mechanistically, we verified that miR-1290 mimic was able to directly target the 3'-UTR of GSK-3ß mRNA using luciferase reporter assay. Knockdown of GSK-3ß (si-GSK-3ß) promoted HUVECs adhesion and the expression of IL-1ß, and partially restore the depression effect of miR-1290 inhibitor on HUVECs adhesion and inflammation. In contrast, si-GSK-3ß inhibited the proliferation of HUVECs and the expression of cyclinD1 and PCNA. CONCLUSIONS: In summary, our study revealed that miR-1290 promotes IL-8-mediated the adhesion of HUVECs by targeting GSK-3ß. However, GSK-3ß is not the target protein for miR-1290 to regulate the proliferation of HUVECs. Our findings may provide potential target in atherosclerosis treatment.

Intracavitary electrocardiography for femorally inserted central catheter tip location in adult patients.

BACKGROUND: In this study, the intracavitary electrocardiogram (ECG) P-wave and QRS-wave changes during femorally inserted central catheter (FICC) placement in adults were observed with the aim of reducing malposition occurrence. The observed method provides venous access in patients who have limited upper limb venous catheterization potential and require medium-term and long-term infusions. METHODS: A retrospective analysis of 34 adult patients who underwent FICC placement was conducted. After body surface measurements were taken, all patients were connected to an ECG during catheter placement, and the P-wave and QRS-wave changes were observed. Next, the catheter tip position was confirmed with an abdominal X-ray, and an analysis of the changes occurring during the procedure was conducted. RESULTS: In the 34 patients included in the present study, the catheter tips were located below the diaphragm level in the inferior vena cava. Of the patients, 18 showed negative P waves, biphasic P waves, and positive high-amplitude P waves with increasing the insertion depth. In 16 patients, no P-wave characteristic changes were observed during catheterization, and an abdominal X-ray confirmed that the catheter tip was positioned below the level of the first lumbar vertebra. CONCLUSION: Negative P waves, biphasic P waves, and positive high-amplitude P waves appeared during FICC placement in adults. Catheter withdrawal until the P wave reverted to normal indicated that a tip position close to the inferior vena cava above the diaphragm level was ideal.