Clinical value of FAT1 mutations to indicate the immune response in colorectal cancer patients.

Immunotherapy is currently approved for CRC whose tumors have high MSI-H. To find additional biomarkers for immunotherapy in CRC, targeted sequencing was performed on tumor tissues from a discovery cohort of 161 CRC patients. Validation cohorts from the cBioPortal were also used for survival and tumor cell infiltration analyses. The FAT1-mutated CRC group often co-occurred with MSI events and displayed a higher tumor mutational burden compared to the FAT1 wild-type CRC. Overall survival was higher in patients with FAT1 mutations than in patients with wild type FAT1. The altered PI3K-AKT pathway and immune pathways were enriched in the FAT1-mutated CRC. A higher infiltration rate of immune cells including CD4+ T cells, CD8+ T cells, macrophages M1 and regulatory T cells were also observed in the colorectal tumors with FAT1 mutation compared to tumors with wild type FAT1. The results showed that CRC patients with FAT1 mutations exhibited an immunotherapy-favorable profile.

Intestinal Autotransplantation for Locally Advanced or Locally Recurrent Colon Cancer Invading SMA.

OBJECTIVE: To examine the outcomes of intestinal autotransplantation (IATx) in patients with locally advanced or recurrent colon cancer (LACC or LRCC) invading the superior mesenteric artery (SMA). BACKGROUND: SMA Involvement in LACC or LRCC is deemed unresectable and is associated with a poor prognosis. Combined extended resections of multiple organs together with SMA, followed by IATx may offer favorable clinical outcomes. However, data on its safety and efficacy are scarce. DESIGN: This retrospective cohort study included patients undergoing IATx between May 2018 and December 2022 in intestinal transplant programs at two university-affiliated hospitals in China. Patients with LACC or LRCC concomitantly with SMA contact of more than 180° were included. Patients with a locoregional peritoneal, pelvic, or distal metastasis were excluded. RESULTS: Ten patients underwent either IATx combined with pancreaticoduodenectomy (n=8) or IATx alone (n=2). Eight patients (80%) were male, and the median age was 55 years (range, 32 - 71 y). The Kaplan-Meier estimates for recurrence-free survival and overall survival at 3 years after IATx were 68% and 80%, respectively. No perioperative deaths occurred. All ten patients experienced postoperative complications including Clavien-Dindo grade I (n=1), grade II (n=4), grade IIIa (n=1), grade IIIb (n=3) and grade IVa (n=1), which comprised acute venous thromboses, upper gastrointestinal hemorrhage, anastomotic leak, gastropareses and significant pleural effusions. With an average follow-up of 23.9 months, eight patients (80%) were currently alive without evidence of disease. CONCLUSION: Extended resection for LACC or LRCC invading SMA can be performed safely and is associated with prolonged survival.

Successful combined auxiliary partial liver and intestinal transplantation in two highly sensitized, cross-match positive patients.

INTRODUCTION: Sensitization to human leukocyte antigen (HLA) creates an immunological barrier to intestinal transplantation (ITx). Current desensitization therapies are limited and ineffective in the most highly sensitized patients. A co-transplanted whole liver transplant can protect a kidney, heart, or intestinal allograft from antibody-mediated injury. Whether an auxiliary partial liver allograft provides effective protection for highly sensitized intestinal transplant recipients is unknown. METHODS: Two patients with strong HLA donor-specific antibody at high titer against their deceased donors underwent combined auxiliary partial liver and ITx across a positive cross-match. The left lateral lobes from the combined-graft recipients and the right liver lobes from the deceased donors were transplanted as a domino procedure to other four patients. RESULTS: Two combined-graft recipients have had an uneventful postoperative course without major complications at a 12- and 24-month follow-up, respectively. Intestinal graft function has been excellent with no evidence of humoral or cellular rejection. While a positive cross-match turned negative, titers of donor-specific HLA antibodies gradually declined over time after transplant. The left liver lobes procured from the combined-graft recipients were successfully transplanted into two pediatric patients (age 1.9, 2.4 years) and the right lobes from two deceased donors were successfully transplanted into two adult patients. All transplant procedures went well, without post-operative complications related to the splitting technique. CONCLUSION: Our results indicate that an auxiliary liver transplant can effectively protect a co-transplanted intestinal allograft against rejection and suggest that this combined procedure may serve as a useful therapeutic adjunct for a highly sensitized intestinal transplant candidate.

Identification and characterization of tryptophan-kynurenine pathway-related genes involving lamprey (Lampetra japonica) innate immunity.

The tryptophan-kynurenine (TRP-KYN) pathway is involved in several biological functions, including immunosuppression, inflammatory response, and tumor suppression. Six TRP-KYN pathway-related genes, tryptophan 2,3-dioxygenase (TDO), indoleamine 2,3-dioxygenase 2 (IDO2), aminoadipate aminotransferase (AADAT), glutamate oxaloacetate transaminase 2 (GOT2), kynurenine monooxygenase (KMO), and kynureninase (KYNU) have been identified and cloned from the jawless vertebrate lamprey (Lampetra japonica) to gain insights into their evolution and characterization. Expression distribution showed that the key gene Lj-TDO was highly expressed in the oral gland. Real-time quantitative PCR showed that TRP-KYN pathway-related genes were significantly overexpressed after multi-stimulation. RNA interference showed that Lj-IDO2 knockdown regulated the expression of inflammatory factors. In conclusion, our study successfully clarified the ancestral features and functions of the TRP-KYN pathway, while providing valuable insights into the involvement of this pathway in the immune responses of a jawless vertebrate.

Short- and long-term complications after living donor ileal resection.

Intestinal transplantation from deceased donors is the established procedure for patients with irreversible intestinal failure. However, a living-donor intestinal transplant has not been routinely performed yet because of undefined surgical risks to the donor. In this report, we reviewed our experience with living-donor ileal resection from May 1999 to December 2021. A total of 40 living-donor ileal resections were performed for 40 intestinal transplant recipients. Clinical data were prospectively collected and analyzed for postoperative complications after ileal procurement. None of the donors experienced life-threatening complications or mortality. Six (15%) of 40 donors experienced minor operative complications. Transit intestinal graft inadequacy including weight loss, diarrhea, and vitamin B12 deficiency was common early following surgery, but was manageable and disappeared in most cases within a year. All donors had significant reductions in total plasma cholesterol and low-density lipoprotein cholesterol concentrations after donation as compared with the baseline levels. With an average follow-up of 67.8 months, bilateral kidney stones occurred in one donor and gallstones in the other. All the donors have regained their normal capacity for work. Living-donor ileal resection is associated with minimal short- and long-term morbidity and remains an attractive alternative for potential recipients when suitable deceased donors are unavailable.

Elucidation of the Transport Mechanism of Puerarin and Gastrodin and Their Interaction on the Absorption in a Caco-2 Cell Monolayer Model.

Puerarin (PUR) and gastrodin (GAS) are often used in combined way for treating diseases caused by microcirculation disorders. The current study aimed to investigate the absorption and transportation mechanism of PUR and GAS and their interaction via Caco-2 monolayer cell model. In this work, the concentration in Caco-2 cell of PUR and GAS was determined by HPLC method. The bidirectional transport of PUR and GAS and the inhibition of drug efflux including verapamil and cyclosporine on the transport of these two components were studied. The mutual influence between PUR and GAS, especially the effect of the latter on the former of the bidirectional transport were also investigated. The transport of 50 µg·mL-1 PUR in Caco-2 cells has no obvious directionality. While the transport of 100 and 200 µg·mL-1 PUR presents a strong directionality, and this directionality can be inhibited by verapamil and cyclosporine. When PUR and GAS were used in combination, GAS could increase the absorption of PUR while PUR had no obvious influence on GAS. Therefore, the compatibility of PUR and GAS is reasonable, and GAS can promote the transmembrane transport of PUR, the effect of which is similar to that of verapamil.

Melatonin attenuates repeated mild traumatic brain injury-induced cognitive deficits by inhibiting astrocyte reactivation.

Melatonin has been well documented for its neuroprotective role through inhibiting oxidative stress against traumatic brain injury (TBI). However, the specific role of melatonin and the exact effects on cell responses (neurons, astrocytes, and microglia) in different brain regions are unclear. Here, we subjected mice to closed head injury, to establish a repeated mild TBI model and detect neuronal activity and glial responses in cognition-related brain regions after melatonin administration. Melatonin only showed cognitive enhancement if administered during early pathological stages, but not in late (chronic) stages. Additionally, we observed a significant increase in neuronal activity and inhibition of astrocyte reactivation in medial prefrontal cortex and hippocampus, but not in other cognitive deficit related brain regions. Furthermore, by activating astrocytes in these brain regions, we found neuronal activity upregulation and cognitive improvement following melatonin treatment. Therefore, we concluded that melatonin administration during the early stages of TBI is necessary to inhibit astrocyte reactivation and to promote cognitive function. Our results provide evidence for use of melatonin for cognitive improvement after TBIs.

Magnolol, a natural aldehyde dehydrogenase-2 agonist, inhibits the proliferation and collagen synthesis of cardiac fibroblasts.

Inhibiting myocardial fibrosis can help prevent cardiovascular diseases, including heart failure. Magnolol (Mag), a natural component of Magnoliae officinalis, has been reported to inhibit fibrosis. However, the mechanism of Mag activity and its effects on myocardial fibrosis remain unclear. Here, we investigated the involvement of ALDH2, an endogenous protective agent against myocardial fibrosis, in the Mag-mediated inhibition of cardiac fibroblast proliferation and collagen synthesis. We found that Mag significantly inhibited cardiac fibroblast proliferation and collagen synthesis, based on the results of MTT, EdU and western blot assays. Moreover, molecular docking, molecular dynamics simulation and surface plasmon resonance (SPR) assays showed that Mag could bind directly and stably to ALDH2. Further analysis of the mechanism of these effects indicated that treatment with Mag dose-dependently enhanced ALDH2 activity without altering protein expression. Mag could enhance the activity of recombinant human ALDH2 proteins with a half-maximal effective concentration of 5.79 × 10-5 M. In addition, ALDH2 activation via Alda-1 inhibited cardiac fibroblast proliferation and collagen synthesis, while ALDH2 inhibition via daidzin partially blocked the suppressive effects of Mag. In summary, Mag may act as a natural ALDH2 agonist and inhibit cardiac fibroblast proliferation and collagen synthesis.

Experimental Investigation of the Role of DC Voltage in the Wettability Alteration in Tight Sandstones.

The usage of direct current (DC) voltage has enormous potential for oil fields due to the effect of wettability alteration. However, the unclear mechanism of the wettability alteration has limited the application of this technology to oil fields. In this study, chemical and physical methods including contact angle tests, Fourier-transform infrared spectroscopy (FTIR) measurements, and atomic force microscope (AFM) experiments were combined to investigate the wettability alteration mechanism for tight sandstones subjected to DC voltage treatment. From the view of a chemical factor, FTIR results show that DC voltage decreases the number of Si-O-Si, C-O-C, C-O, and COOH groups, while it also increases the number of C═O and OH groups. The changes in molecular groups further improve the water-wetting property of tight sandstones. On the other hand, in a physical way, AFM results indicate that DC voltage improves the roughness of the rock surface. At the same time, the wetting state transfers from the Cassie-Baxter to the Wenzel. This increases the contact area of the solid-liquid interface. The augment of roughness and the transfer of the wetting state improve the water-wetting property of tight sandstones. By comparing the influences of both chemical and physical factors on wettability, it is concluded that although roughness indeed affects the wettability, chemical factors play a dominant role in determining the wettability. Achievements in this study can help researchers and engineers better understand the mechanism of wettability alteration and further accelerate the development of tight sandstones with DC voltage-related technology.

Effect of Hawthorn Leaf Flavonoids in Dehydroepiandrosterone-Induced Polycystic Ovary Syndrome in Rats.

OBJECTIVE: To evaluate the potential beneficial effects of hawthorn leaf flavonoids (HLF) against polycystic ovary syndrome (PCOS) in a rat model of disease and elucidate the underlying molecular mechanism. METHODS: The PCOS model was established by subcutaneous injection of dehydroepiandrosterone (DHEA, 60 mg/kg/day) for 21 consecutive days. HLF (200 mg/kg/day) were orally administered simultaneously or after the injection. The body weight was regularly monitored and recorded. The ovaries were weighed and histologically examined via hematoxylin and eosin staining. The number of follicular cysts was counted under a light microscope. The serous hormones were measured using enzyme-linked immunosorbent assay kits. Insulin resistance (IR) was calculated as HOMA-IR = fasting insulin (µU/L) × fasting glucose (mM)/22.5. The estrous cycle was determined by vaginal smear. The relative expression of tumor necrosis factor-α and interleukin-6 was measured by real-time polymerase chain reaction. The superoxide dismutase activity and malondialdehyde content was determined using commercially available kits. RESULTS: DHEA induced a significant increase of body weight, ovary weight, number of follicular cysts, serous hormones, IR, inflammatory cytokines, and oxidative stress, and it also impaired the estrous cycle. Oral administration of HLF greatly alleviated these complications. Little toxicity of HLF was observed in our rat model. CONCLUSION: HLF manifest protective effects against PCOS progression in the animal model, which may hold great promise for future clinical applications.

The down-regulation of neuroligin-2 and the correlative clinical significance of serum GABA over-expression in Hirschsprung's disease.

The goal of this study was to investigate the expression level of neuroligin-2 in different colon tissue segments of children with Hirschsprung's disease (HSCR) and the correlative clinical significance of serum Gamma-Aminobutyric Acid (serum GABA) in HSCR. Neuroligin-2 was assessed by Immunohistochemistry staining method on routine paraffin section from different colon tissue segments of HSCR (ganglionic colonic segment, transitional colonic segment and aganglionic colonic segment). Western-blot analysis and real-time fluorescence quantitative PCR(qRT-PCR) were applied to compare and evaluate the expression levels of neuroligin-2 from three segments of HSCR, and we used Enzyme-linked Immunosorbent Assay (ELISA) method to detect and compare the serum GABA between HSCR and non-HSCR. Immunohistochemistry staining demonstrated that intensive neuroligin-2 staining was detected in the ganglion cells in the ganglionic colonic and transitional colonic segments from the HSCR children; however, neuroligin-2 staining was down-regulated significantly in the aganglionic colonic segments. The expression levels of neuroligin-2 mRNA and protein in the aganglionic colonic segment were decreased compared to the ganglionic colonic segment and transitional colonic segment (P < 0.05). And the level of serum GABA was significantly higher in HSCR than that in non-HSCR. The expression of neuroligin-2 varies from different segments of HSCR. The down-regulation of neuroligin-2 in aganglionic colonic segments may be correlated with the excessive intestine contraction and further result in HSCR. The over-expression of serum GABA may be considered as a new diagnostic method of HSCR.

Expression of neurexin and neuroligin in the enteric nervous system and their down-regulated expression levels in Hirschsprung disease.

To investigate the expression levels of neurexins and neuroligins in the enteric nervous system (ENS) in Hirschsprung Disease (HSCR). Longitudinal muscles with adherent mesenteric plexus were obtained by dissection of the fresh gut wall of mice, guinea pigs, and humans. Double labeling of neurexin I and Hu (a neuron marker), neuroligin 1 and Hu, neurexin I and synaptophysin (a presynaptic marker), and neuroligin 1 and PSD95 (a postsynaptic marker) was performed by immunofluorescence staining. Images were merged to determine the relative localizations of the proteins. Expression levels of neurexin and neuroligin in different segments of the ENS in HSCR were investigated by immunohistochemistry. Neurexin and neuroligin were detected in the mesenteric plexus of mice, guinea pigs, and humans with HSCR. Neurexin was located in the presynapse, whereas neuroligin was located in the postsynapse. Expression levels of neurexin and neuroligin were significant in the ganglionic colonic segment of HSCR, moderate in the transitional segment, and negative in the aganglionic colonic segment. The expressions of neurexin and neuroligin in the transitional segments were significantly down-regulated compared with the levels in the normal segments (P < 0.05). Expression levels of neurexin and neuroligin in ENS are significantly down-regulated in HSCR, which may be involved in the pathogenesis of HSCR.

Effect of green tea on reward learning in healthy individuals: a randomized, double-blind, placebo-controlled pilot study.

BACKGROUND: Both clinical and preclinical studies revealed that regular intake of green tea reduced the prevalence of depressive symptoms, as well as produced antidepressant-like effects in rodents. Evidence proposed that disturbed reward learning has been associated with the development of anhedonia, a core symptom of depression. However, the relationship between green tea and reward learning is poorly investigated. Our goal was to test whether chronic treatment with green tea in healthy subjects affects the process of reward learning and subsequently regulates the depressive symptoms. METHODS: Seventy-four healthy subjects participated in a double-blind, randomized placebo-controlled study with oral administration of green tea or placebo for 5weeks. We used the monetary incentive delay task to evaluate the reward learning by measurement of the response to reward trial or no-reward trial. We compared the reaction time of reward responsiveness between green tea and placebo treatment. Furthermore, we selected Montgomery-Asberg depression rating scale (MADRS) and 17-item Hamilton Rating Scale for Depression (HRSD-17) to estimate the depressive symptoms in these two groups. RESULTS: The results showed chronic treatment of green tea increased reward learning compared with placebo by decreasing the reaction time in monetary incentive delay task. Moreover, participants treated with green tea showed reduced scores measured in MADRS and HRSD-17 compared with participants treated with placebo. CONCLUSIONS: Our findings reveal that chronic green tea increased the reward learning and prevented the depressive symptoms. These results also raised the possibility that supplementary administration of green tea might reverse the development of depression through normalization of the reward function.

Fecal microbiota transplantation repairs intestinal permeability and regulates the expression of 5-HT to influence alcohol-induced depression-like behaviors in C57BL/6J mice.

The epidemic of alcohol abuse affects millions of people worldwide. Relevant evidence supports the notion that the gut microbiota (GM) plays a crucial role in central nervous system (CNS) function, and its composition undergoes changes following alcohol consumption. Therefore, the purpose of this study was to investigate the effect of reconstructing the gut microbiota by fecal microbiota transplantation (FMT) on alcohol dependence. Here, we established an alcohol dependence model with C57BL/6J mice and proved that FMT treatment improved anxiety-like behavior and alcohol-seeking behavior in alcohol-dependent mice. Additionally, we found that the expression of the intestinal intercellular tight junction structure proteins ZO-1 and occludin was significantly increased after FMT. FMT repaired intestinal permeability in alcohol-dependent mice and decreased the levels of lipopolysaccharide (LPS) and proinflammatory factors. Moreover, the serotonin (5-hydroxytryptamine, 5-HT) content was significantly increased in alcohol-dependent mouse intestinal and brain tissues after receiving the fecal microbiome from healthy mice. 16S rRNA sequencing demonstrated that FMT markedly reshaped the composition of the gut microbiota and elicited changes in the intestinal barrier and 5-HT levels. Collectively, our results revealed that FMT has a palliative effect on alcohol dependence and explored the underlying mechanisms, which provides new strategies for the treatment of alcohol dependence.

Combined ultrasound and low temperature pretreatment improve the content of anthocyanins, phenols and volatile substance of Merlot red wine.

Ultrasound combined with low temperature treatment is a new food processing technology. In this study, low temperature, three ultrasound power levels, and their combinations were adopted in the must before fermentation to study their effects on Merlot red wine. The results showed that ultrasound combined with low temperature pretreatment increased the total and monomer contents of anthocyanins and phenols, affected the color of the wine, and significantly increased its antioxidant capacity. In particular, 240 W of ultrasound combined with low temperature pretreatment reduced the bad odors (caprylic acid, benzaldehyde, and 1-ethanol content) and improved the flower and fruit aroma (1-octanol and phenethyl acetate), as well as the aftertaste, thus improving the quality of the wine. Ultrasound combined with low temperature pretreatment positively affected the quality of Merlot red wine.

Underlying mechanism of aconitum lizhong acting on experimental hypothermia with indigestion in rats: role of ghrelin.

This study is aimed to investigate the Aconitum Lizhong pill (ALZ) pharmacological actions on hypothermia with indigestion, especially the ghrelin roles. The littermate-matched rats were randomly divided into four groups. Control did sham operation or standard diet, Model carried out interscapular brown adipose (IBA) removal with standard diet, Fat-diet did IBA removal with fat-diet, and ALZ did IBA removal and fat-diet with 4.536 g/kg/d ALZ. The potency of adaptive thermogenesis, ghrelin levels in plasma or gastric mucosa, thyroid hormones and metabolite in sera, expression of ghrelin mRNA, and protein in gastric mucous membrane were determined. ALZ relieved the hypothermia processes with indigestion, via inhibiting ghrelin expression and increasing ghrelin secretion; the dynamics from the therapy is supported with the energy changes as less body weight loss, less plasma lipid decrease, more plasma T(3) or T(4) increase with TSH decrease, and more compensation of thermogenic AUC decrease. Ghrelin played key roles in the actions of ALZ on the hypothermia with indigestion. The pharmacological mechanisms of ALZ involved the homeostasis of ghrelin expression and secretion.

Use of computed tomographic reconstruction to establish the ideal entry point for pedicle screws in idiopathic scoliosis.

OBJECTIVE: To determine the ideal entry point for individual pedicle screw in the surgical treatment of idiopathic scoliosis using computed tomographic (CT) three-dimensional (3D) reconstruction. METHODS: Twenty patients with moderate or severe idiopathic scoliosis from two groups received surgical treatment using "Free Hand technique" and "Assisted Free Hand technique". Computed tomographic scanning with 3D reconstruction of the thoracic and lumbar spine was conducted to determine the entry point and to evaluate the placement accuracy. RESULTS: The accuracy of placement was 88.2% in convexity and 84.5% in concavity for the "Free Hand" group, and 94.1% in convexity and 94% in concavity for the "Assisted Free Hand" group. Evidence showed that "Assisted Free Hand" group had higher accuracy when screws were placed in the thoracic spine (P = 0.02), while no obvious difference was seen in the lumbar spine placement (P = 0.47). CONCLUSIONS: We conclude that in the surgical treatment of severe scoliosis, individual screw placement guided by entry points determined by CT reconstruction can result in improved accuracy and ease of the procedure.

[Effectiveness analysis of metatarsal mortise and tenon shortening osteotomy in treatment of macrodactyly in children].

Objective: To investigate the application and effectiveness of metatarsal mortise and tenon shortening osteotomy in the treatment of macrodactyly in children. Methods: The clinical data of 17 children with macrodactyly (18 feet and 27 toes) admitted between January 2018 and January 2020 were retrospectively analyzed. There were 12 males (12 feet and 18 toes) and 5 females (6 feet and 9 toes); the age ranged from 1 to 13 years, with a median age of 5 years. All children were treated with metatarsal mortise and tenon shortening osteotomy. Ten cases of single-segment metatarsals were shortened, 7 cases of 2-segment metatarsals, and 1 case of 3-segment metatarsals; involved 1 foot of single toe, 9 feet of 2 toes, 3 feet of 3 toes, 3 feet of 4 toes, and 2 feet of 5 toes. Five cases had lameness, and 1 case had limited walking with the big toes of both feet, and there was no obvious pain in all children. X-ray films showed that the involved phalanges were thickened and increased in 18 feet, and the deformity of the distal segment was heavier than that of the proximal segment in 13 feet, and the two were similar in 5 feet. The length of metatarsal shortening was 0.7-2.5 cm, with an average of 1.2 cm. The clinical healing of shortened metatarsal fractures in children was observed after operation, and the occurrence of related complications was recorded. Results: All 17 children were followed up 6-22 months, with an average of 14 months. All incisions healed by first intention. The osteotomy ends of 27 toes were clinically healed after operation, and the healing time was 4-8 weeks. No nonunion, fracture displacement, malunion, epiphyseal plate premature closure, and needle tract infection occurred. Conclusion: Metatarsal mortise and tenon shortening osteotomy is a good osteotomy method. It can improve the stability of the osteotomy end and increase the contact surface of the osteotomy end, which is conducive to the healing of the osteotomy end and is suitable for the treatment of macrodactyly.

Design of LDMOS Device Modeling Method Based on Neural Network.

The rapid development of power semiconductor devices is helping to realize a low-carbon society and provide a better life for everyone. Power semiconductors not only are used in many large-scale industrial control fields such as power transmission and control in power grids, rail transit traction systems, and defense weapons and equipment, but also play a vital role in daily equipment such as home appliances, medical electronics, and electronic communications; all devices such as power steering in cars, battery chargers, cell phones, and microwave ovens utilize power electronics. This research mainly focuses on the high-voltage LDMOS device model and its implementation. Based on the in-depth study of the structure and physical mechanism of high-voltage LDMOS devices, with the help of BSIM4 core model, which is now very mature and widely used in industry, the drift region of high-voltage LDMOS is mainly modeled, and the drift region of LDMOS is modeled as a variable resistance controlled by voltage. Finally, Verilog-A language and neural network method are used to establish a compact model of LDMOS. The improved model is applied to LDMOS and can better fit the output characteristics with self-heating effect.

Plasticity of neuronal excitability and synaptic balance in the anterior nucleus of paraventricular thalamus after nerve injury.

The anterior nucleus of the paraventricular thalamus (aPVT) integrates various synaptic inputs and conveys information to the downstream brain regions for arousal and pain regulation. Recent studies have indicated that the PVT plays a crucial role in the regulation of chronic pain, but the plasticity mechanism of neuronal excitability and synaptic inputs for aPVT neurons in neuropathic pain remains unclear. Here, we report that spinal nerve ligation (SNL) significantly increased the neuronal excitability and reset the excitatory/inhibitory (E/I) synaptic inputs ratio of aPVT neurons in mice. SNL significantly increased the membrane input resistance, firing frequency, and the half-width of action potential. Additionally, SNL enlarged the area of afterdepolarization and prolonged the rebound low-threshold spike following a hyperpolarized current injection. Further results indicate that an inwardly rectifying current density was decreased in SNL animals. SNL also decreased the amplitude, but not the frequency of spontaneous excitatory postsynaptic currents (sEPSCs), nor the amplitude or frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) of aPVT neurons. Moreover, SNL disrupted the E/I synaptic ratio, caused a decrease in weighted tau and half-width of averaged sIPSCs, but did not change these physiological properties of averaged sEPSCs. Finally, pharmacological activation of the GABAA receptor at aPVT could effective relieve SNL-induced mechanical allodynia in mice. These results reveal the plasticity of intrinsic neuronal excitability and E/I synaptic balance in the aPVT neurons after nerve injury and it may play an important role in the development of pain sensitization.