Alpha adrenergic modulation on effects of norepinephrine transporter inhibitor reboxetine in five-choice serial reaction time task

The study examined the effects of a norepinephrine transporter (NET) inhibitor reboxetine (RBX) on an attentional performance test. Adult SD rats trained with five-choice serial reaction time task (5-CSRTT) were administered with RBX (0, 3.0 and 10 mg/kg) in the testing day. Alpha-1 adrenergic receptor antagonist PRA and alpha-2 adrenergic receptor antagonist RX821002 were used to clarify the RBX effect. Results revealed that rat received RBX at 10 mg/kg had an increase in the percentage of the correct response and decreases in the numbers of premature response. Alpha-1 adrenergic receptor antagonist Prazosin (PRA) at 0.1 mg/kg reversed the RBX augmented correct responding rate. However, alpha-2 adrenergic receptor antagonist RX821002 at 0.05 and 0.1 mg/kg dose dependently reversed the RBX reduced impulsive responding. Our results suggested that RBX as a norepinephrine transporter inhibitor can be beneficial in both attentional accuracy and response control and alpha-1 and alpha-2 adrenergic receptors might be involved differently

Ameliorated chest drain wound closure in patients undergoing uniportal thoracoscopic pulmonary resection

BackgroundAlthough uniportal video-assisted thoracoscopic surgery (VATS) has been performed for a wide array of thoracic diseases, unsightliness and poor wound healing often occur, particularly when a chest drain is placed postoperatively. Different chest drain wound closure (CWC) methods have been introduced with the benefits of cosmesis and patient satisfaction. We aimed to describe our improved CWC technique in this setting and assess its efficacy.MethodsA total of consecutive 334 patients undergoing uniportal VATS pulmonary resection with single chest drain placement were investigated from 2016 to 2021. The techniques for CWC were classified into the conventional method (35 patients, group A), continuous suture with removal-free stitches (122 patients, group B), and continuous suture with removal-free barbed suture plus topical skin adhesives (177 patients, group C). Perioperative data and complications related to CWC were analyzed.ResultsGroup C had a significantly shorter operative time, postoperative hospital stay, and chest tube days than groups A and B (all p < 0.01). In terms of chest tube-related complications, there were no statistically significant differences in post-removal pneumothorax, subcutaneous emphysema, incisional effusion leakage, wound dehiscence, or infection. Overall, significant differences in scar scale scores were observed between the groups, where the ameliorated group C was superior to the conventional group A (p < 0.01).ConclusionThe improved CWC technique using continuous sutures with removal-free barbed sutures and topical skin adhesives is simple, safe, and effective. This may be a favorable CWC strategy when performing uniportal VATS, with enhanced patient satisfaction

Computational modeling with forward and reverse engineering links signaling network and genomic regulatory responses: NF-κB signaling-induced gene expression responses in inflammation

<p>Abstract</p> <p>Background</p> <p>Signal transduction is the major mechanism through which cells transmit external stimuli to evoke intracellular biochemical responses. Diverse cellular stimuli create a wide variety of transcription factor activities through signal transduction pathways, resulting in different gene expression patterns. Understanding the relationship between external stimuli and the corresponding cellular responses, as well as the subsequent effects on downstream genes, is a major challenge in systems biology. Thus, a systematic approach is needed to integrate experimental data and theoretical hypotheses to identify the physiological consequences of environmental stimuli.</p> <p>Results</p> <p>We proposed a systematic approach that combines forward and reverse engineering to link the signal transduction cascade with the gene responses. To demonstrate the feasibility of our strategy, we focused on linking the NF-κB signaling pathway with the inflammatory gene regulatory responses because NF-κB has long been recognized to play a crucial role in inflammation. We first utilized forward engineering (Hybrid Functional Petri Nets) to construct the NF-κB signaling pathway and reverse engineering (Network Components Analysis) to build a gene regulatory network (GRN). Then, we demonstrated that the corresponding IKK profiles can be identified in the GRN and are consistent with the experimental validation of the IKK kinase assay. We found that the time-lapse gene expression of several cytokines and chemokines (TNF-α, IL-1, IL-6, CXCL1, CXCL2 and CCL3) is concordant with the NF-κB activity profile, and these genes have stronger influence strength within the GRN. Such regulatory effects have highlighted the crucial roles of NF-κB signaling in the acute inflammatory response and enhance our understanding of the systemic inflammatory response syndrome.</p> <p>Conclusion</p> <p>We successfully identified and distinguished the corresponding signaling profiles among three microarray datasets with different stimuli strengths. In our model, the crucial genes of the NF-κB regulatory network were also identified to reflect the biological consequences of inflammation. With the experimental validation, our strategy is thus an effective solution to decipher cross-talk effects when attempting to integrate new kinetic parameters from other signal transduction pathways. The strategy also provides new insight for systems biology modeling to link any signal transduction pathways with the responses of downstream genes of interest.</p

Mitochondrial oxidative phosphorylation complex regulates NLRP3 inflammasome activation and predicts patient survival in nasopharyngeal carcinoma

© 2020 Chung et al. We previously reported that tumor inflammasomes play a key role in tumor control and act as favorable prognostic markers in nasopharyngeal carcinoma (NPC). Activated inflammasomes frequently form distinguishable specks and govern the cellular secretion of IL-1β. However, we know little about the biological and biochemical differences between cells with and without apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC) speck formation. In this study, we used proteomic iTRAQ analysis to analyze the proteomes of NPC cells that differ in their ASC speck formation upon cisplatin treatment. We identified proteins that were differentially over-expressed in cells with specks, and found that they fell into two Gene ontology (GO) pathways: mitochondrial oxidative phosphorylation (OxPhos) and ubiquinone metabolism. We observed up-regulation of various components of the OxPhos machinery (including NDUFB3, NDUFB8 and ATP5B), and subsequently found that these changes lead to mitochondrial ROS (mtROS) production, which promotes the formation and activation of NLRP3 inflammasomes and subsequent pyroptosis. In NPC patients, better local recurrence-free survival was significantly associated with high-level expression of NDUFB8 (p = 0.037) and ATP5B (p = 0.029), as examined using immunohistochemistry. However, there were no significant associations between the expression of NDUFB8 and ATP5B with overall survival of NPC patients. Together, our results demonstrate that up-regulated mitochondrial OxPhos components are strongly associated with NLRP3 inflammasome activation in NPC. Our findings further suggest that high-level expression of OxPhos components could be markers for local recurrence and/or promising therapeutic targets in patients with NPC

Cbl negatively regulates nlrp3 inflammasome activation through glut1-dependent glycolysis inhibition

Activation of the nod-like receptor 3 (NLRP3) inflammasomes is crucial for immune defense, but improper and excessive activation causes inflammatory diseases. We previously reported that Cbl plays a pivotal role in suppressing NLRP3 inflammasome activation by inhibiting Pyk2-mediated apoptosis-associated speck-like protein containing a CARD (ASC) oligomerization. Here, we showed that Cbl dampened NLRP3 inflammasome activation by inhibiting glycolysis, as demonstrated with Cbl knockout cells and treatment with the Cbl inhibitor hydrocotarnine. We revealed that the inhibition of Cbl promoted caspase-1 cleavage and interleukin (IL)-1β secretion through a glycolysis-dependent mechanism. Inhibiting Cbl increased cellular glucose uptake, glycolytic capacity, and mitochondrial oxidative phosphorylation capacity. Upon NLRP3 inflammasome activation, inhibiting Cbl increased glycolysis-dependent activation of mitochondrial respiration and increased the production of reactive oxygen species, which contributes to NLRP3 inflammasome activation and IL-1β secretion. Mechanistically, inhibiting Cbl increased surface expression of glucose transporter 1 (GLUT1) protein through post-transcriptional regulation, which increased cellular glucose uptake and consequently raised glycolytic capacity, and in turn enhanced NLRP3 inflammasome activation. Together, our findings provide new insights into the role of Cbl in NLRP3 inflammasome regulation through GLUT1 downregulation. We also show that a novel Cbl inhibitor, hydrocortanine, increased NLRP3 inflammasome activity via its effect on glycolysis

Acute Paraparesis Caused by a Giant Cell Tumor of the Thoracic Spine

AbstractGiant cell tumor (GCT) is a benign but locally aggressive skeletal neoplasm of young adults. GCT located in the spine is relatively rare and may need a combination of surgical and adjunctive therapies. Here we present a patient who had intermittent thoracic back pain for two weeks and experienced an acute episode of decreased muscle power of both lower limbs. Magnetic resonance (MR) imaging examinations of the thoracic spine revealed that the patient had severe spinal canal compression caused by pathological fracture due to a tumor within the seventh thoracic vertebra. She underwent an emergent surgical intervention for total removal of the tumor and spinal reconstruction with autologous rib grafts and instruments. Postoperatively, the patient made an uneventful recovery of muscle power of bilateral lower limbs. She subsequently received adjuvant radiotherapy. In a follow-up period of 36 months, the patient had no clinical or radiological evidence of tumor recurrence. Even though spinal location for GCT is a rare event, it should be included in the differential diagnosis in patients with osteolytic lesions or pathological fractures of the vertebra, especially in young female patients sustaining no trauma who had a clinical history of persistent low back pain

Design and performance of an ultrahigh vacuum spectroscopic-imaging scanning tunneling microscope with a hybrid vibration isolation system

A spectroscopic imaging-scanning tunneling microscope (SI-STM) allows the atomic scale visualization of surface electronic and magnetic structure of novel quantum materials with high energy resolution. To achieve the optimal performance, low vibration facility is required. Here, we describe the design and the performance of an ultrahigh vacuum STM system supported by a hybrid vibration isolation system that consists of a pneumatic passive and a piezoelectric active vibration isolation stages. The STM system is equipped with a 1K pot cryogenic insert and a 9 Tesla superconducting magnet, capable of continuous SI-STM measurements for 7 days. A field ion microscopy system is installed for in situ STM tip treatment. We present the detailed vibrational noise analysis of the hybrid vibration isolation system and demonstrate the performance of our STM system by taking high resolution spectroscopic maps and topographic images on several quantum materials. Our results establish a new strategy to achieve an effective vibration isolation system for high-resolution STM and other scanning probe microscopy to investigate the nanoscale quantum phenomena

Inflammatory Marker but Not Adipokine Predicts Mortality among Long-Term Hemodialysis Patients

Aims: chronic inflammation contributes significantly to the morbidity and mortality of chronic hemodialysis patients. A recent research has shown that adipokines were associated with inflammation in these patients. We aim to investigate whether biomarkers of inflammation, adipokines, and clinical features can predict the outcome of hemodialysis patients. Materials and methods: we enrolled 181 hemodialysis patients (men: 97, mean age: 56.3±13.6) and analyzed predictors of long-term outcomes. Results: during the 3-year followup period, 41 patients died; the main causes of death were infection and cardiovascular disease. Elevated serum levels of hsCRP and albumin and advanced age were highly associated with death (all P<.001). Leptin and adiponectin levels were not significantly different between deceased patients and survivors. Cox-regression analysis indicated that age, diabetes, albumin level, and hsCRP were independent factors predicting mortality. Conclusion: the presence of underlying disease, advanced age, and markers of chronic inflammation is strongly related to survival rate in long-term hemodialysis patients

Obliquity pacing of the western Pacific Intertropical Convergence Zone over the past 282,000 years

The Intertropical Convergence Zone (ITCZ) encompasses the heaviest rain belt on the Earth. Few direct long-term records, especially in the Pacific, limit our understanding of long-term natural variability for predicting future ITCZ migration. Here we present a tropical precipitation record from the Southern Hemisphere covering the past 282,000 years, inferred from a marine sedimentary sequence collected off the eastern coast of Papua New Guinea. Unlike the precession paradigm expressed in its East Asian counterpart, our record shows that the western Pacific ITCZ migration was influenced by combined precession and obliquity changes. The obliquity forcing could be primarily delivered by a cross-hemispherical thermal/pressure contrast, resulting from the asymmetric continental configuration between Asia and Australia in a coupled East Asian-Australian circulation system. Our finding suggests that the obliquity forcing may play a more important role in global hydroclimate cycles than previously thought