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Abstract The evolution process of regional space between coastal and interior areas is a direct manifestation of the theory of regional economic development imbalance. Previous research has neglected the impacts of population, and economic factor flows on the balance of regional development between coastal and interior areas. By constructing global coastal-interior regional population-economic panel data and a threshold effect model, this study explored regional development imbalance on the largest scale between global coastal and interior areas. The results indicated that the global population is unevenly distributed across coastal and interior areas. Global coastal areas (accounting for 18.43% of the world’s landmass) are occupied by ~52.8% of the global population; meanwhile, ~23% of the global population is concentrated in the ‘near region’ subtropical zone extending from 10° to 30° north and south in latitude. The economic pattern between global coastal and interior areas has become more balanced, and the per capita GDP gap between the two sub-regions has decreased from 2.08 times to 1.78 times during the study period (2000 to 2018). Nevertheless, the evolutionary process of population factors lags behind that of economic factors. Apart from Africa, the development gap of intercontinental coastal and interior areas has been converging to varying degrees. Adjusting regional per capita income levels and population-economic density can promote balanced development between coastal and interior areas both globally and across continents. These findings may contribute to the implementation of effective policies for spatial balance and sustainable development in coastal and interior areas across multiple spatial scales. This study extends the theoretical research on uneven regional growth and provides a foundation for further research to achieve the goals of the UN 2030 Agenda for Sustainable Development.

[Introduction] The widespread adoption of electric vehicles (EVs) enhances environmental sustainability during travel, yet it simultaneously elevates strain on the mains supply. To assess the impact of EV charging on the power grid, a specialized charging load calculation method is developed for large EV cluster on the basis of the Monte Carlo method. [Method] In this approach, EVs were categorized into six groups based on their usage: private EVs, electric buses, electric taxis, online ride-hailing EVs, official EVs, and logistics EVs. Typical battery performance parameters for each group were identified, and probability models were established to characterize the variability in their travel and charging patterns. By integrating group scale forecasts, daily charging schedules for each group were simulated through random sampling. Subsequently, the daily charging load for each group was calculated, culminating in the total charging load for the EV cluster through an aggregation method. [Result] The EV cluster in a southern province in 2030 was taken as the simulation case. [Conclusion] The case analysis reveals that the proposed approach can provide the daily charging load of various EV groups and the entire EV cluster. Furthermore, among all types of EVs, electric buses have the highest peak charging load at 4 639.5 MW, followed by that of private EVs (not higher than 70% of the electric buses' peak load), and electric taxis have the lowest peak charging load. The charging peak of the entire EV cluster occurs between 19:00 and 23:00 at night, and the peak load can reach 10.0927 GW.

Abstract It is still a huge challenge to introduce effective crack‐healing ability into energetic composites with a high oxidizer content. In this article, a poly(urea‐urethane) energetic elastomer was prepared by the polycondensation reaction of glycidyl azido polymer (GAP), isophorone diisocyanate (IPDI), and 2‐aminophenyl disulfide (2‐APD). In the poly(urea‐urethane) elastomer structure, the hybrid dynamic lock, including multilevel H‐bonds and disulfide bonds, not only provides abundant dynamic interactions and promotes chain diffusion, but also enhances physical crosslinking density. Such a unique design fabricated the energetic elastomer with robust tensile strength (0.72 MPa), high stretchability (1631%), and outstanding toughness (8.95 MJ/m3) in the field of energetic polymers. Meanwhile, this energetic elastomer exhibited high self‐healing efficiency (98.4% at 60 °C) and heat release (Q = 1750.46 J/g). Experimental and theoretical results adequately explain the self‐healing mechanism, particularly the role of azido units. The high‐solid content (80 wt%) energetic composites based on the energetic elastomer presented outstanding micro‐defect self‐healing (97.8%) and recycling without loss of mechanical performance. The development of smart energetic composites with excellent self‐healing and recyclable ability provides a meaningful way for a wide range of applications in the field of energetic materials.

This paper studies how to integrate the smart charging of large-scale electric vehicles (EVs) into the generation and storage expansion planning (GSEP), while analyzing the impact of smart charging on the GSEP of a real power system in south China. For this purpose, a random simulation-based method is first developed to provide the tractable formulations of the adjustable charging load and reserve provision from EVs. This method avoids the unrealistic assumption that EVs drive and charge every day, which often exists in prior relevant approaches. Based on the random simulation, this paper proposes a novel GSEP optimization model which incorporates the weekly adjustable charging load of EVs. In the proposed model, the total charging load of EVs can be co-optimized with the investment and operational decisions of various generation and storage units. This GSEP model is applied to a provincial power system in south China. The numerical results show that the implementation of smart charging can significantly alter the decisions of GSEP. As the participation rate of smart charging improves from 0% to 90%, there is an additional 1,800 MW installation in wind and solar power, while the need to build new batteries is noticeably reduced; also, depending on the level of EV uptake, the annualized total system cost decreases by 5.11%–7.57%, and the curtailment of wind and solar power is reduced by 10.34%–19.64%. Besides, numerical tests reveal that the traditional assumption that EVs drive and charge every day can mislead the evaluation of adjustable charging load and overestimate the daily charging power peak by averagely 24.72%.

Abstract Background Acute kidney injury (AKI), characterized by necroptosis and activation of MAPK pathway, causes sudden declines in renal function. To date, efficacious treatments are lacking. JianPiYiShen Formula (JPYSF) has a protective effect on the kidneys. The aim of this study is to explore the mechanism of JPYSF in cisplatin-induced AKI. Methods Male C57/BL6J mice were divided into control group, cisplatin group and cisplatin + JPYSF group. Before establishing the model, the cisplatin + JPYSF group was administered JPYSF (18.35 g/kg/day) by gavage for 5 consecutive days. A single intraperitoneal injection of cisplatin (20 mg/kg) was used to establish AKI model. Measurement of renal function and H&E staining were performed to assess renal damage. WB, PCR, TUNEL staining and immunohistochemistry were used to detect related indicators of mitochondrial function, oxidative stress, necroptosis, inflammation and MAPK pathway. And one-way analysis of variance was used to compare group differences. Results Compared with the cisplatin group, JPYSF can attenuate AKI, reflected by the decrease in Scr and BUN levels, the improvement of renal tubular injury, and the downregulation of NGAL and KIM1. Cisplatin can induce mitochondrial dysfunction and oxidative stress, triggering necroptosis. In this study, JPYSF improved mitochondrial dysfunction to enhance oxidative stress, as manifested by upregulation of OPA1, PGC-1α, SOD and CAT, and downregulation of DRP1 and MFF. Then JPYSF showed a significant protective effect in necroptosis, as embodied by reduced number of TUNEL-positive cells, decreased the gene expression of RIPK3 and MLKL, as well as downregulation the proteins expression of P-RIPK1, P-RIPK3, and P-MLKL. Moreover, necroptosis can aggravate inflammation. JPYSF ameliorated inflammation by improving inflammatory and anti-inflammatory indexes, including downregulation of TNF-α, IL-6, MCP-1 and LY6G, and upregulation of IL-10. In addition, JPYSF also inhibited MAPK pathway to improve necroptosis by decreasing the expression of P-JNK and P-ERK. Conclusion Our data showed that JPYSF prevents cisplatin-induced AKI by improving necroptosis through MAPK pathway, which is related to the improvement of mitochondrial dysfunction, oxidative stress, and inflammation.

In northern China, the combined heat and power (CHP) units account for a large proportion of the local generation capacity. However, the inherent heat-power coupling of CHP units poses a large barrier for wind power accommodation. To facilitate the local wind integration, the key is to improve the flexibility of the CHP system, and there are two types of feasible methods. One is the addition of heat storage tanks and electric boilers into the CHP system, and this method has been considered in the scheduling of the CHP system, such as the unit commitment (UC) optimization. The other type of method is the flexibility retrofit of CHP units, including the two-stage bypass modification and low-pressure cylinder removal (LPCR). However, prior research has not attempted to integrate the flexibility retrofit into the UC scheduling. To fill this gap, this paper proposes a novel UC model incorporating the bypass and LPCR retrofit of CHP units. In this model, the constraints on the safe operation region, fuel cost, reserve provision, ramping and mode switching of different types of CHP units are thoroughly described. Cases studies are conducted on a test system. Simulation results show that the proposed UC model is capable of utilizing the bypass and LPCR retrofit to facilitate wind accommodation, with the wind curtailment reduced by 81.94% and 20.45% under the bypass and LPCR retrofit, respectively.

Abstract Background The RNA‐binding motif single‐stranded interacting protein 3 (RBMS3) is a constituent of the RNA‐binding motif (RBM) protein family, which assumes a pivotal role in governing cellular biogenesis processes such as the cell cycle and apoptosis. Despite an abundance of studies elucidating RBMS3's divergent roles in the genesis and advancement of various tumors, its involvement in colon cancer remains enigmatic. Methods The present investigation employed data analysis from TCGA and GTEx to unveil that RBMS3 expression demonstrated a diminished presence in colon cancer tissues when juxtaposed with normal colon tissues. The effect of RBMS3 and LIM zinc finger domain 1 (LIMS1) on colon cancer was substantiated via animal models and cellular experiments. The connection between RBMS3 and LIM zinc finger domain 1 (LIMS1) was verified by molecular biology methods. Results The study conclusively ascertained that augmenting RBMS3 expression quells the proliferation, migration, and invasion of colon cancer cells. Furthermore, the inquiry unveiled a plausible mechanism through which RBMS3 impacts the expression of LIMS1 by modulating its mRNA stability. The investigation ascertained that RBMS3 inhibits the progression of colon cancer by regulating LIMS1. The inhibitory function of LIMS1 and RBMS3 is closely intertwined in colon cancer, with knocking down LIMS1 being able to rescue the inhibitory effect of RBMS3 overexpression on the functionality of colon cancer cell Conclusions The discernments delineate RBMS3 as a novel suppressor of cancer via LIMS1, thereby bestowing fresh therapeutic possibilities and illuminating the intricacies of colon cancer.

Abstract It is well established that nighttime light brightness value, which is measured from satellites, correlates with economic prosperity across the globe. Researchers have diverged over whether economic factors cluster in coastal areas or move to interior areas. By using nighttime light data and applying the random forest algorithm to measure the proportion of global “near regions” GDP, it was seen that global GDP decreased from 67.25% in 2000 to 63.02% in 2018. This research reveals that under the continuous promotion of economic globalization, there is still a spatial imbalance of economic development between global “near regions” and “far regions”; however, economic factors are gradually shifting to interior areas and forming a “coastal remoteness” evolution pattern. Within the intercontinental range, there are obvious differences in the evolution patterns and spatial structure of economic development between the sub-regions. The reduction of overseas transportation costs and diseconomies of scale are the primary reasons for the evolution of “coastal remoteness” in global economic development. Our findings can facilitate future policymaking and the management of global coastal and interior areas, as well as establish new horizons for relevant research topics within the context of land and marine-coordinated development.

A clinical case of a 19-year-old male patient with pharmacoresistant seizures occurring following parieto-occipital tumor-resection at age 6 is described. Seizure surgery work-up included prolonged video EEG monitoring and head CT without contrast. Seizure focus was localized to the left temporal lobe, and we felt that the patient was an excellent candidate for seizure surgery. The patient underwent a left frontotemporal craniotomy for removal of the seizure focus with intraoperative electrocorticography (ECoG) conducted pre and post resection. ECoG recordings pre- and post-resection confirmed resolution of seizure generation. Imaging obtained immediately postoperatively showed complete resection of the residual tumor with no evidence of recurrence in follow-ups. A year after the surgery the patient is seizure-free but remains on seizure medication. With the patient's consent the excised epileptogenic tissue was used for ex-vivo research studies. The microelectrode recordings confirmed epileptiform activity in the excised tissue incubated in excitatory artificial cerebrospinal fluid. The epileptiform activity in the epileptogenic tissue was suppressed by addition of KRM–II–81, a novel α2/3 subtype preferring GABAA receptor (GABAAR) potentiator with previously demonstrated antiepileptic efficacy in multiple animal models of epilepsy and with reduced potential for CNS side-effects compared to classical benzodiazepine GABAAR potentiators. These findings support the proposition that KRM–II–81 might reduce seizure burden in pharmacoresistant patients.

The impact of 0.1–10 MeV neutron-induced single-event upsets (NSEUs) on terrestrial SER (soft error rate) prediction is analyzed for several broad spectrum neutron sources based on 0.1–200 MeV NSEU energetic-dependent cross-sectional data of a 40 nm SRAM. The results show that for test facilities with abundant

Stroke is the most common cause of acquired epilepsy, but treatment for preventing the development of post-stroke epilepsy is still unavailable. Since stroke results in neuronal damage and death as well as initial loss of activity in the affected brain region, homeostatic plasticity may be trigged and contribute to an increase in network hyperexcitability that underlies epileptogenesis. Correspondingly, enhancing brain activity may inhibit hyperexcitability from enhanced homeostatic plasticity and prevent post-stroke epileptogenesis. To test these hypotheses, we first used in vivo two-photon and mesoscopic imaging of activity of cortical pyramidal neurons in Thy1-GCaMP6 transgenic mice to determine longitudinal changes in excitatory activity after a photothrombotic ischemic stroke. At 3-days post-stroke, there was a significant loss of neuronal activity in the peri-injury area as indicated by reductions in the frequency of calcium spikes and percentage of active neurons, which recovered to baseline level at day 7, supporting a homeostatic activity regulation of the surviving neurons in the peri-injury area. We further used optogenetic stimulation to specifically stimulate activity of pyramidal neurons in the peri-injury area of Thy-1 channelrhodopsin transgenic mice from day 5 to day 15 after stroke. Using pentylenetetrazole test to evaluate seizure susceptibility, we showed that stroke mice are more susceptible to Racine stage V seizures (time latency 54.3 ± 12.9 min) compared to sham mice (107.1 ± 13.6 min), but optogenetic stimulation reversed the increase in seizure susceptibility (114.0 ± 9.2 min) in mice with stroke. Similarly, administration of D-cycloserine, a partial N-methyl-d-aspartate (NMDA) receptor agonist that can mildly enhance neuronal activity without causing post-stroke seizure, from day 5 to day 15 after a stroke significantly reversed the increase in seizure susceptibility. The treatment also resulted in an increased survival of glutamic acid decarboxylase 67 (GAD67) positive interneurons and a reduced activation of glial fibrillary acidic protein (GFAP) positive reactive astrocytes. Thus, this study supports the involvement of homeostatic activity regulation in the development of post-stroke hyperexcitability and potential application of activity enhancement as a novel strategy to prevent post-stroke late-onset seizure and epilepsy through regulating cortical homeostatic plasticity.

Aircraft icing has historically been a critical cause of airplane crashes. The electro-impulse de-icing system has a wide range of applications in aircraft de-icing due to its lightweight design, low energy consumption, high efficiency, and other advantages. However, there has been little study into accurate wing electric-impulse de-icing simulation methods and the parameters impacting de-icing efficacy. Based on the damage mechanics principle and considering the influence mechanisms of interface debonding and ice fracture on ice shedding, this paper establishes a more accurate numerical model of wing electric-impulse de-icing using the Cohesive Zone Model (CZM). It simulates the process of electric-impulse de-icing at the leading edge of the NACA 0012 wing. The numerical results are compared to the experimental results, revealing that the constructed wing electro-impulse de-icing numerical model is superior. Lastly, the effects of varying ice–skin interface shear adhesion strengths, doubler loading positions, and impulse sequences on de-icing effectiveness were studied. The de-icing rate is a quantitative description of the electro-impulse’s de-icing action, defined in the numerical model as the ratio of cohesive element deletions to the total elements at the ice–skin interface. The findings reveal that varying shear adhesion strengths at the ice–skin interface significantly impact the de-icing effect. The de-icing rate steadily falls with increasing shear adhesion strength, from 66% to 56%. When two, four, and seven impulses were applied to doubler two, the de-icing rates were 59%, 71%, and 71%, respectively, significantly increasing the de-icing efficiency compared to when impulses were applied to doubler one. Doubler one and two impulse responses are overlaid differently depending on the impulse sequences, resulting in varying de-icing rates. When the impulse sequence is 20 ms, the superposition results are optimal, and the de-icing rate reaches 100%. These studies can guide the development and implementation of a wing electric-impulse de-icing system.

Yiwei decoction (YWD) is a formula of traditional Chinese medicine (TCM) that is clinically effective for the prevention and treatment of gastric cancer recurrence and metastasis. According to the theory of TCM, YWD tonifies the body and strengthens the body’s resistance to gastric cancer recurrence and metastasis potentially via the immune regulation of the spleen. The aims of the present study were to investigate whether YWD-treated spleen-derived exosomes in rats inhibit the proliferation of tumor cells, to elucidate the anticancer effects of YWD, and to provide evidence supporting the use of YWD as a new clinical treatment for gastric cancer. Spleen-derived exosomes were obtained by ultracentrifugation and identified by transmission electron microscopy, nanoparticle tracking analysis, and western blot analysis. The location of the exosomes in tumor cells was then determined by immunofluorescence staining. After tumor cells were treated with different concentrations of exosomes, the effect of exosomes on cell proliferation was determined by cell counting kit 8 (CCK8) and colony formation assays. Tumor cell apoptosis was detected by flow cytometry. Particle analysis and western blot analysis identified the material extracted from spleen tissue supernatant as exosomes. Immunofluorescence staining showed that spleen-derived exosomes were taken up by HGC-27 cells, and the CCK8 assay confirmed that the relative tumor inhibition rate of YWD-treated spleen-derived exosomes in the 30 μg/mL reached 70.78% compared to control exosomes in the 30 μg/mL (p < 0.05). Compared to control exosomes in the 30 μg/mL, the colony formation assay indicated that YWD-treated spleen-derived exosomes in the 30 μg/mL colonies have decreased by 99.03% (p < 0.01). Moreover, flow cytometry analysis showed that treatment with YWD-treated exosomes in the 30 μg/mL increased the apoptosis rate to 43.27%, which was significantly higher than that of the control group in the 30 μg/mL (25.91%) (p < 0.05). In conclusion, spleen-derived exosomes from YWD-treated animals inhibit the proliferation of HGC-27 cells via inducing apoptosis, suggesting that spleen-derived exosomes are involved in mediating the antitumor effect of YWD. These results demonstrated a novel exosome-mediated anticancer effect of YWD as a TCM formula, thereby supporting the use of YWD-treated exosomes as a new approach for the clinical treatment of gastric cancer.

Background: Cisplatin is an effective anti-tumor drug. However, its usage is constrained by side effects such as nephron toxicity. Cisplatin-induced acute kidney injury (AKI) appears in approximately 20%–30% of cases. Hence, finding an effective protective strategy is necessary. San-Huang decoction (SHD) is a Chinese herbal decoction with good efficacy in treating chronic kidney disease (CKD). Nevertheless, the mechanism of SHD on AKI remains unclear. Consequently, we proposed to explore the potential mechanism of SHD against cisplatin-induced AKI.Methods: Active compounds, core target proteins, and associated signaling pathways of SHD were predicted through network pharmacology. Then confirmed by molecular docking. In vivo experiment, Cisplatin + SHD group was treated with SHD (6.5 g/kg/day) for 6 days before building the model. An AKI model was established with a single intraperitoneal injection of cisplatin at 20 mg/kg. After 72 h of cisplatin injection, all mice were sacrificed to collect blood and kidney tissues for verification of network pharmacology analysis.Results: We found that calycosin, rhein, and ginsenoside Rh2 may be SHD’s primary active compounds in treating cisplatin-induced AKI, and AKT, TNF-α, IL-6, IL-1β, caspase-3, and MMP9 are the core target proteins. The relationship between the compound and target protein was further confirmed by molecular docking. The Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses predicted that SHD has an anti-inflammatory role through the TNF and IL-17 signaling pathway. Moreover, Western blot and immunohistochemistry validated the potential molecular mechanisms of SHD, predicted from network pharmacology analysis. The mechanism of cisplatin-induced AKI involves apoptosis and inflammation. In apoptosis, Caspase-3, caspase-8, caspase-9, and Bax proteins were down-regulated, while Bcl-2 was up-regulated by SHD. The differential expression of MMP protein is involved in the pathological process of AKI. MMP9 protects from glomerular tubule damage. MMP9 and PI3K/AKT anti-apoptosis pathway were up-regulated by SHD. In addition, we discovered that SHD alleviated AKI by inhibiting the NF-κB signaling pathway.Conclusion: SHD plays a critical role in anti-inflammation and anti-apoptosis via inhibiting the NF-κB signaling pathway and activating PI3K/AKT anti-apoptosis pathway, indicating that SHD is a candidate herbal drug for further investigation in treating cisplatin-induced AKI.

IntroductionAutism spectrum disorder (ASD) is a group of neurodevelopmental disorders mainly representing impaired social communication. The etiology of ASD includes genetic and environmental risk factors. Rodent models containing ASD risk gene mutations or environmental risk factors, such as exposure to maternal inflammation, show abnormal behavior. Although zebrafish conserves many important brain structures of humans and has sophisticated and fine behaviors in social interaction, it is unknown whether the social behaviors of their offspring would be impaired due to exposure to maternal inflammation.MethodsWe exposed zebrafish to maternal immune activation (MIA) by injection with polyinosinic:polycytidylic acid [poly(I:C)], and screened their behaviors through social behavioral tests such as social preference and shoaling behavior tests. We compared phenotypes resulted from different ways of poly(I:C) exposure. RNA sequencing was performed to explore the differential expression genes (DEGs). Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and protein–protein interaction (PPI) network analysis was performed with the detected DEGs to find the concentrated pathways. Finally, we knocked out the fatty acid-binding protein 2 (fabp2), a key node of the concentrated PPI network, to find its rescues on the altered social behavior.ResultsWe reported here that MIA offspring born to mothers injected with poly(I:C) exhibited impaired social approach and social cohesion that mimicked human ASD phenotypes. Both maternal exposure and direct embryo exposure to poly(I:C) resulted in activations of the innate immune system through toll-like receptors 3 and 4. RNA-sequencing results from MIA brain tissues illustrated that the numbers of overexpressed genes were significantly more than that of underexpressed genes. GO and KEGG analyses found that MIA-induced DEGs were mainly concentrated in complement and coagulation cascade pathways. PPI network analyses suggested that villin-1 (vil1) pathway might play a key role in MIA-induced ASD. Knockout of fabp2 in F0 zebrafish rescued the social behavior deficits in MIA offspring.ConclusionsOverall, our work established an ASD model with assessable behavior phenotype in zebrafish and provided key insights into environmental risk factor in ASD etiology and the influence of fabp2 gene on ASD-like behavior.

In the field of agricultural machinery, various empirical field tests are performed to measure the tillage force for precision tillage. However, the field test performance is costly and time-consuming, and there are many constraints on weather and field soil conditions; the utilization of simulation studies is required to overcome these shortcomings. As a result, the SPH method and the coupled FEM-SPH method are used in this paper to investigate the mouldboard plough–soil interaction. In this paper, the finite element software LS-DYNA was used to build the SPH model and the FEM-SPH coupling model of soil cutting, as well as to investigate the change in cutting resistance during the soil cutting process. The simulation results are compared with those of the experiments, and the curves of the simulation and experiment are in good agreement, which verifies the reliability of the model. The validated simulation model was used to investigate the effects of the cutting speed, depth of cut, inclination angle, and lifting angle of the mouldboard plough on cutting resistance. The simulation studies show that the SPH model takes 5 h and 2 min to compute, while the FEM-SPH coupled model takes 38 min; obviously, the computational efficiency of the FEM-SPH coupled model is higher. The relative errors between the SPH model and the experiment are 2.17% and 3.65%, respectively. The relative errors between the FEM-SPH coupled model and the experiment are 5.96% and 10.67%, respectively. Obviously, the SPH model has a higher computational accuracy. The average cutting resistances predicted by the SPH model and the FEM-SPH coupled model, respectively, were 349.48 N and 306.25 N; these resistances are useful for precision tillage. The cutting resistance increases with the increase in cutting speed and is quadratic; the cutting resistance increases with the increase in cutting depth and is quadratic; the horizontal cutting resistance and the combined cutting resistance increase with the increase in inclination angle, while the vertical cutting resistance remains essentially constant with the increase in inclination angle; the horizontal cutting resistance and combined cutting resistance increase as the lifting angle increases, while the vertical cutting resistance decreases as the lifting angle increases.

Understanding the reorganization of neural circuits spared after spinal cord injury in the motor cortex and spinal cord would provide insights for developing therapeutics. Using optogenetic mapping, we demonstrated a transhemispheric recruitment of neural circuits in the contralateral cortical M1/M2 area to improve the impaired forelimb function after a cervical 5 right-sided hemisection in mice, a model mimicking the human Brown-Séquard syndrome. This cortical reorganization can be elicited by a selective cortical optogenetic neuromodulation paradigm. Areas of whisker, jaw, and neck, together with the rostral forelimb area, on the motor cortex ipsilateral to the lesion were engaged to control the ipsilesional forelimb in both stimulation and nonstimulation groups 8 weeks following injury. However, significant functional benefits were only seen in the stimulation group. Using anterograde tracing, we further revealed a robust sprouting of the intact corticospinal tract in the spinal cord of those animals receiving optogenetic stimulation. The intraspinal corticospinal axonal sprouting correlated with the forelimb functional recovery. Thus, specific neuromodulation of the cortical neural circuits induced massive neural reorganization both in the motor cortex and spinal cord, constructing an alternative motor pathway in restoring impaired forelimb function.

Abstract Objective Sudden unexpected death in epilepsy (SUDEP) is the cause of premature death of 50% patients with chronic refractory epilepsy. Respiratory failure during seizures is regarded as an important mechanism of SUDEP. Previous studies have shown that abnormal serotonergic neurotransmission is involved in the pathogenesis of seizure‐induced respiratory failure, while enhancing serotonergic neurotransmission in the brainstem suppresses it. Because peripheral inflammation is known to enhance serotonergic neuron activation and 5‐HT synthesis and release, we investigated the effect of intraperitoneal lipopolysaccharide (LPS)‐induced inflammation on the S‐IRA susceptibility during audiogenic seizures in DBA/1 mice. Methods After DBA/1 mice were primed by exposing to sound stimulation for three consecutive days, they were tested for seizure severity and seizure‐induced respiratory arrest (S‐IRA) induced by sound stimulation under different conditions. We determined the dose and time course of the effects of intraperitoneal administration of LPS on audiogenic seizures and S‐IRA. The effects of blocking TLR4 or RAGE receptors and blocking 5‐HT receptors on the LPS‐induced effect on S‐IRA were investigated. Statistical significance was evaluated using the Kruskal‐Wallis test. Results Intraperitoneal injection of LPS significantly had dose‐dependent effects in reducing the incidence of S‐IRA as well as seizure severity in DBA/1 mice. The protective effect of LPS on S‐IRA peaked at 8‐12 hours after LPS injection and was related to both reducing seizure severity and enhancing autoresuscitation. Blocking TLR4 or RAGE receptor with TAK‐242 or FPS‐ZM1, respectively, prior to LPS injection attenuated its effects on S‐IRA and seizure severity. Injection of a nonselective 5‐HT receptor antagonist, cyproheptadine, or a 5‐HT3 receptor antagonist, ondansetron, was effective in blocking LPS‐induced effect on S‐IRA. Immunostaining results showed a significant increase in c‐Fos‐positive serotonergic neurons in the dorsal raphe. Significance This is the first study that demonstrates the effect of intraperitoneal LPS injection‐induced inflammation on reducing S‐IRA susceptibility and provides additional evidence supporting the serotonin hypothesis on SUDEP. Our study suggests that inflammation may enhance brainstem 5‐HT neurotransmission to promote autoresuscitation during seizure and prevent SUDEP.

Summary: Background: The efficacy and mechanisms of acupuncture for Crohn's disease (CD) are not well understood. We investigated its effects on symptoms, intestinal microbiota, and circulating inflammatory markers in CD patients. Methods: This 48-week, randomized, sham controlled, parallel-group clinical trial was performed at a tertiary outpatient clinic in China. From April 2015 to November 2019, 66 patients (mean age 40·4, 62·1% were male, all were Han Chinese) with mild to moderate active CD and unresponsive to drug treatment were enrolled and randomly assigned equally to an acupuncture group or a sham group. The treatment group received 3 sessions of acupuncture plus moxibustion per week for 12 weeks and a follow-up of 36 weeks. Clinicaltrials.gov: NCT02559037. Findings: At week 12, the clinical remission rate (the primary outcome) and clinical response rate of acupuncture group were significantly higher than that of sham group, with a difference of 42·4% (95% CI: 20·1%-64·0%) and 45·5% (95% CI: 24·0%-66·9%), respectively, both of which maintained at week 48. The acupuncture group had significantly lower CD activity index and C-reactive protein level at week 12, which maintained at 36-week follow-up. The CD endoscopic index of severity, histopathological score, and recurrence rate at week 48 were significantly lower in acupuncture group. The number of operational taxonomic unit of intestinal microbiota and relative abundance of Faecalibacterium prausnitzii and Roseburia faecis were increased. Plasma diamine oxidase, lipopolysaccharide, and Th1/Th17 related cytokines were decreased in 12-week after acupuncture. Interpretation: Acupuncture was effective in inducing and maintaining remission in patients with active CD, which was associated with increased abundance of intestinal anti-inflammatory bacteria, enhanced intestinal barrier, and regulation of circulating Th1/Th17-related cytokines. Funding: National Key Basic Research Program of China (2015CB554500 and 2009CB522900), Shanghai Rising-Star Program (19QA1408100).

Background: Moxibustion is increasingly used for treatment of irritable bowel syndrome (IBS). This study investigated the long-term effects of moxibustion for IBS with diarrhea (IBS-D). Methods: Patients with IBS-D were assigned to receive moxibustion or sham moxibustion (52 each, 3× per week, 6 weeks) and were followed up to 24 weeks. The acupoints were bilateral ST25 and ST36, body surface temperatures at acupoints were 43°C ± 1°C and 37°C ± 1°C for the moxibustion and sham groups, respectively. Primary outcome was changes in IBS Adequate Relief (IBS-AR) from baseline to 6 weeks. Secondary outcomes included the following: IBS symptom severity scale (IBS-SSS), Bristol stool form scale (BSS), IBS quality of life (IBS-QOL), and Hospital Anxiety and Depression Scale (HADS). Results: Based on an intention-to-treat analysis, the rate of IBS-AR in the moxibustion group was significantly higher than the sham group at 6 weeks (76.9% versus 42.3%; p 50 points in IBS-SSS of the treatment group was significantly higher than that of the sham ( p

Effects of total ionizing dose (TID) on the transient radiation upset sensitivity of commercial static random access memories (SRAMs) were investigated. Commercial SRAMs of three technology nodes were irradiated with Co-60 gamma rays for total dose effects and with pulsed x rays generated using a “Chen-Guang” accelerator for doserate effects. It is shown that TID irradiation and the memory pattern written to the memory array during TID irradiation can substantially affect the transient radiation upset sensitivity of all the SRAMs. First, the memory pattern written to the memory array during TID irradiation is more sensitive to pulsed x rays for all SRAMs. Second, the variation in transient radiation upset sensitivity with total dose has different tendencies for different SRAMs, but the static power current increased with the increase in total dose for all SRAMs. The increase in static power current with total dose and the increasing sensitivity of the memory pattern during TID irradiation are caused by the increasing TID induced leakage current, which results in an asymmetric noise margin of individual memory cells.

The coalbed methane (CBM) resource in the southern Qinshui Basin, North China, is abundant. Proper understanding of the geological control factors on CBM enrichment in Anze Block of southern Qinshui Basin is critical to design efficient CBM development plan in this area. Field and laboratory data including well logging, well testing, hydraulic fracturing, and groundwater chemical analysis of were used to evaluate the characteristics of the hydrodynamic and geostress, and then, the combined effect of hydrodynamic and geostress field on CBM enrichment was analyzed. The results show that the total dissolved solids (TDS) of groundwater in the west is generally lower than that in other areas in the block, and the primary formation water is NaHCO3-type. The geostress field shows a σH>σv>σh dominated geostress type in this area, and the western block has a lower value than the eastern block. The strong hydrodynamic field with low TDS also has a lower gas content while the weak hydrodynamic field with high TDS has a higher gas content. Both the TDS value and the horizontal stress differences are positively related to the gas content, indicating that inactive hydrodynamics and large horizontal stress difference of coal reservoir is favorable for CBM preservation.

Clinical and animal studies have shown that acupuncture may benefit controlling neuropathic pain. However, the underlying molecular mechanisms are poorly understood. In a well-established mouse unilateral tibial nerve injury (TNI) model, we confirmed the efficacy of electroacupuncture (EA) in reducing mechanical allodynia and measured methylation and hydroxy-methylation levels in the primary somatosensory cortex (S1) and anterior cingulate cortex (ACC), two cortical regions critically involved in pain processing. TNI resulted in increased DNA methylation of both the contra- and ipsilateral S1, while EA only reduced contralateral S1 methylation. RNA sequencing of the S1 and ACC identified differentially expressed genes related to energy metabolism, inflammation, synapse function, and neural plasticity and repair. One week of daily EA decreased or increased the majority of up- or downregulated genes, respectively, in both cortical regions. Validations of two greatly regulated genes with immunofluorescent staining revealed an increased expression of gephyrin in the ipsilateral S1 after TNI was decreased by EA; while TNI-induced increases in Tomm20, a biomarker of mitochondria, in the contralateral ACC were further enhanced after EA. We concluded that neuropathic pain is associated with differential epigenetic regulations of gene expression in the ACC and S1 and that the analgesic effect of EA may involve regulating cortical gene expression.

Tumor cells not only show a vigorous metabolic state, but also reflect the disease progression and prognosis from their metabolites. To judge the progress and prognosis of ovarian cancer is generally based on the formation of ascites, or whether there is ascites recurrence during chemotherapy after ovarian cancer surgery. To explore the relationship between the production of ascites and ovarian cancer tissue, metabolomics was used to screen differential metabolites in this study. The significant markers leading to ascites formation and chemoresistance were screened by analyzing their correlation with the formation of ascites in ovarian cancer and the clinical indicators of patients, and then provided a theoretical basis. The results revealed that nine differential metabolites were screened out from 37 ovarian cancer tissues and their ascites, among which seven differential metabolites were screened from 22 self-paired samples. Sebacic acid and 20-COOH-leukotriene E4 were negatively correlated with the high expression of serum CA125. Carnosine was positively correlated with the high expression of serum uric acid. Hexadecanoic acid was negatively correlated with the high expression of serum γ-GGT and HBDH. 20a,22b-Dihydroxycholesterol was positively correlated with serum alkaline phosphatase and γ-GGT. In the chemotherapy-sensitive and chemotherapy-resistant ovarian cancer tissues, the differential metabolite dihydrothymine was significantly reduced in the chemotherapy-resistant group. In the ascites supernatant of the drug-resistant group, the differential metabolites, 1,25-dihydroxyvitamins D3-26, 23-lactonel and hexadecanoic acid were also significantly reduced. The results indicated that the nine differential metabolites could reflect the prognosis and the extent of liver and kidney damage in patients with ovarian cancer. Three differential metabolites with low expression in the drug-resistant group were proposed as new markers of chemotherapy efficacy in ovarian cancer patients with ascites.

Many cases of acute pain can be resolved with few side effects. However, some cases of acute pain may persist beyond the time required for tissue injury recovery and transit to chronic pain, which is hard to treat. The mechanisms underlying pain transition are not entirely understood, and treatment strategies are lacking. In this study, the hyperalgesic priming model was established on rats to study pain transition by injection of carrageenan (Car) and prostaglandin E2 (PGE2). The expression levels of protein kinase C epsilon (PKCε) and transient receptor potential vanilloid 1 (TRPV1) in the L4–L6 dorsal root ganglion (DRG) were investigated. Electroacupuncture (EA) is a form of acupuncture in which a small electric current is passed between a pair of acupuncture needles. EA was administrated, and its effect on hyperalgesia and PKCε and TRPV1 expression was investigated. The PKCε–TRPV1 signaling pathway in DRG was implicated in the pain transition. EA increased the pain threshold of model animals and regulated the high expression of PKCε and TRPV1. Moreover, EA also regulated hyperalgesia and high TRPV1 expression induced by selective PKCε activation. We also found that EA partly increased chronic pain threshold, even though it was only administered between the Car and PGE2 injections. These findings suggested that EA could prevent the transition from acute to chronic pain by inhibiting the PKCε and TRPV1 expression in the peripheral nervous system.

Abstract Background Fatigue is one of the primary symptoms in lung cancer, with a prevalence of 88.0% in survivors of cancer, and an even higher prevalence post resection surgery. Effective fatigue control after lung cancer surgery is important for patient recovery and quality of life. Some studies have shown that acupuncture might be effective in treating cancer-related fatigue; however, randomized controlled trials (RCTs) of suitable sample size are limited. Method/design This is a multi-center, patient-blinded RCT. A total of 320 eligible patients will be recruited in four centers and randomly assigned to either the acupuncture group or the sham acupuncture group in a 1:1 ratio. Treatment will be given twice per week for 12 sessions. Treatment will be given at acupoints GV20, GV29, CV12, CV6, CV4, and bilateral LI4, LR3, SP6, ST36. The primary outcome will be assessed using the Chinese version of The Brief Fatigue Inventory. The secondary outcomes will be measured using The European Organization for Research and The Treatment of Cancer Quality of Life Questionnaire, and the Hamilton Rating Scale for Depression. The primary outcome will be assessed at all main points (baseline, the 3rd week, the 6th week, and at follow up time points) and the secondary outcomes will be assessed at baseline and the 6th week. Intention-to-treat analysis will be used in this RCT. Discussion This trial protocol provides an example of the clinical application acupuncture treatment in the management of lung cancer-related fatigue. If the acupuncture treatment protocol confirms that acupuncture is an effective and safe option for lung cancer-related fatigue, it can be adopted as a standardized treatment. Trial registration Chinese Clinical Trial Registry, ChiCTR1900022831. Registered on 27 April 2019. URL: http://www.chictr.org.cn/showproj.aspx?proj=37823

Abstract Hyperexcitability of the neural network often occurs after brain injuries or degeneration and is a key pathophysiological feature in certain neurological diseases such as epilepsy, neuropathic pain, and tinnitus. Although the standard approach of pharmacological treatments is to directly suppress the hyperexcitability through reducing excitation or enhancing inhibition, different techniques for stimulating brain activity are often used to treat refractory neurological conditions. However, it is unclear why stimulating brain activity would be effective for controlling hyperexcitability. Recent studies suggest that the pathogenesis in these disorders exhibits a transition from an initial activity loss after acute injury or progressive neurodegeneration to subsequent development of hyperexcitability. This process mimics homeostatic activity regulation and may contribute to developing network hyperexcitability that underlies neurological symptoms. This hypothesis also predicts that stimulating brain activity should be effective in reducing hyperexcitability due to homeostatic activity regulation and in relieving symptoms. Here we review current evidence of homeostatic plasticity in the development of hyperexcitability in some neurological diseases and the effects of brain stimulation. The homeostatic plasticity hypothesis may provide new insights into the pathophysiology of neurological diseases and may guide the use of brain stimulation techniques for treating them.

Abstract Background Ovarian cancer is often accompanied by the production of ascites, and patients with repeated ascites are associated with chemotherapy resistance. The previous study confirmed that the ovarian cancer patients who developed ascites after chemotherapy had elevated autophagy levels in the ascites and precipitated cells, which was positively correlated with MDR1 expression in the blood of patients. Methods In order to explore the correlation between autophagy and chemoresistant, we searched TCGA and GEO database to analyze the correlation between LC3B and MDR1, and identified the targeting miRNA of LC3B. It was verified by dual luciferase that miR-204 can target LC3B. The ovarian cancer cell line and the BALB/c nude mice tumor-bearing model were selected for in vitro and in vivo verification. In vitro studies confirmed that ovarian cancer cells were more sensitive to cisplatin by inhibiting LC3B. Results Overexpression of miR-204 reduced the expression of LC3B, Atg7, and MDR1, and promoted apoptosis. In vivo studies have also confirmed that reducing the level of autophagy in ovarian cancer cells increases the sensitivity to cisplatin. Conclusions It suggests that miR-204 can be used as a tumor suppressor gene and LC3B expression level can be used as a potential molecular marker to guide the diagnosis and treatment of patients with ovarian cancer.

Hyperexcitability of neural network is a key neurophysiological mechanism in several neurological disorders including epilepsy, neuropathic pain, and tinnitus. Although standard paradigm of pharmacological management of them is to suppress this hyperexcitability, such as having been exemplified by the use of certain antiepileptic drugs, their frequent refractoriness to drug treatment suggests likely different pathophysiological mechanism. Because the pathogenesis in these disorders exhibits a transition from an initial activity loss after injury or sensory deprivation to subsequent hyperexcitability and paroxysmal discharges, this process can be regarded as a process of functional compensation similar to homeostatic plasticity regulation, in which a set level of activity in neural network is maintained after injury-induced activity loss through enhanced network excitability. Enhancing brain activity, such as cortical stimulation that is found to be effective in relieving symptoms of these disorders, may reduce such hyperexcitability through homeostatic plasticity mechanism. Here we review current evidence of homeostatic plasticity in the mechanism of acquired epilepsy, neuropathic pain, and tinnitus and the effects and mechanism of cortical stimulation. Establishing a role of homeostatic plasticity in these disorders may provide a theoretical basis on their pathogenesis as well as guide the development and application of therapeutic approaches through electrically or pharmacologically stimulating brain activity for treating these disorders.

Particulate matter (PM) is a carrier of many substances. Microorganisms are vital constituents contained in PM, and their varieties and concentrations are closely connected to human health and animal production. This study aimed to investigate the distribution characteristics of bioaerosols inside a pig house and in the respiratory tract of pigs. Environmental indices inside a nursery pig house were monitored in winter, including temperature, relative humidity, total suspended particulate (TSP), PM10, PM2.5, NH3, CO2, CO and NO. The concentrations of airborne culturable bacteria, fungi and Escherichia coli were detected. Then, 16S rRNA sequencing technology was applied to identify different-sized bioaerosols and bacteria in the respiratory tract of piglets. The results showed that the concentration of airborne culturable bacteria inside the pig house was significantly higher than that outside, and no significant difference was found among culturable fungi and Escherichia coli. The 16S rRNA results showed that the bacterial aerosols presented high similarity to the bacteria in the respiratory tract of piglets. The airborne bacterial aerosols within the size range of 1.1–3.3 µm showed high similarity to the bacteria in the lower respiratory tract (bronchus and lung) of piglets. In addition, four potential pathogenic bacterial genera (Escherichia-Shigella, Streptococcus, Acinetobacter, Pseudomonas) were identified both in the bacterial aerosols and the respiratory tract of piglets. These results will provide a significant scientific basis for exploring the potential risk of aerosols from animal houses to human and animal health.

The hypoxic microenvironment is beneficial to the metastasis but not to the proliferation of cancer cells. However, the mechanisms regarding to hypoxia differentially regulating cancer metastasis and proliferation are largely unknown. In this study, we revealed that hypoxia induced the expression of LIN28A at mRNA level but segregated LIN28A mRNAs in the P-bodies and thus inhibits the production of LIN28A protein. This unexpected finding suggests that there may be non-coding role for LIN28A mRNA in the progression of colon cancer. We further showed that the non-coding LIN28A mRNA promotes the metastasis but not proliferation of colon cancer cells in vitro and in vivo. Mechanistically, we revealed that methionyl aminopeptidase 2 (METAP2) is one of the up-regulated metastasis regulators upon over-expression of non-coding LIN28A identified by mass spectrum, and confirmed that it is non-coding LIN28A mRNA instead of LIN28A protein promotes the expression of METAP2. Moreover, we demonstrated that knockdown of DICER abolished the promotional effects of non-coding LIN28A on the metastasis and METAP2 expression. Conclusively, we showed that hypoxia induces the production of LIN28A mRNAs but segregated them into the P-bodies together with miRNAs targeting both LIN28A and METAP2, and then promotes the metastasis by positively regulating the expression of METAP2. This study uncovered a distinctive role of hypoxia in manipulating the metastasis and proliferation by differently regulating the expression of LIN28A at mRNA and protein level.

Mild traumatic brain injury (mTBI), or concussion, is reported to interfere with cerebral blood flow and microcirculation in patients, but our current understanding is quite limited and the results are often controversial. Here we used longitudinal in vivo two-photon imaging to investigate dynamic changes in cerebral vessels and velocities of red blood cells (RBC) following mTBI. Closed-head mTBI induced using a controlled cortical impact device resulted in a significant reduction of dwell time in a Rotarod test but no significant change in water maze test. Cerebral blood vessels were repeatedly imaged through a thinned skull window at baseline, 0.5, 1, 6 h, and 1 day following mTBI. In both arterioles and capillaries, their diameters and RBC velocities were significantly decreased at 0.5, 1, and 6 h after injury, and recovered in 1 day post-mTBI. In contrast, decreases in the diameter and RBC velocity of venules occurred only in 0.5–1 h after mTBI. We also observed formation and clearance of transient microthrombi in capillaries within 1 h post-mTBI. We concluded that in vivo two-photon imaging is useful for studying earlier alteration of vascular dynamics after mTBI and that mTBI induced reduction of cerebral blood flow, vasospasm, and formation of microthrombi in the acute stage following injury. These changes may contribute to early brain functional deficits of mTBI.

Abstract Background The pathogenesis of irritable bowel syndrome (IBS) is closely related to intestinal dysbacteriosis and can be controlled by moxibustion treatment. However, the mechanism underlying the therapeutic value of moxibustion in IBS treatment remains unknown. Methods An IBS rat model was established by colorectal distention (CRD) stimulus and mustard oil clyster. Sixty-five male rats were randomly divided into six groups: normal, IBS model, moxibustion, electroacupuncture (EA), Bifid-triple Viable Capsule (BTVC) and Pinaverium Bromide (PB) groups. The moxibustion group was treated with mild moxibustion at the bilateral Tianshu (ST25) and Shangjuxu (ST37) for 10 min/day for 7 days, the EA group was given EA at ST25 and ST37 once daily for 7 days, while the BTVC group and PB groups received Bifid-triple Viable Capsule and Pinaverium Bromide solution (at the proportion of 1:0.018) respectively by gavage once daily for 7 days. After the treatment, abdominal withdrawal reflex (AWR) scores were determined based on CRD stimulus, gut microbiota profiling was conducted by 16S rRNA high-throughput sequencing. Results Irritable bowel syndrome model rats had significantly increased AWR scores at all intensities (20, 40, 60 and 80 mmHg) compared with the normal group. Moxibustion treatment significantly reduced AWR scores compared with the IBS model group at all intensities. Across all groups the most abundant phyla were Bacteroidetes and Firmicutes followed by Proteobacteria and Candidatus Saccharibacteria. At genus level IBS model rats had a higher abundance of Prevotella, Bacteroides and Clostridium XI and a lower abundance of Lactobacillus and Clostridium XIVa compared with normal rats. These changes in microbiota profiles could however be reversed by moxibustion treatment. Alpha diversity was decreased in IBS model rats compared with normal rats, yet significantly increased in moxibustion- and PB-treated rats compared with IBS rats. Conclusion Our findings suggest that moxibustion treats IBS by modulating the gut microbiota.

Background/Aims: Colorectal cancer (CRC) is mainly caused by chromosomal instability (CIN) and microsatellite instability (MSI). The RAS and RAF genes are essential components of the CIN pathway, and several studies have found that RAS and RAF mutations are associated with MSI status in CRC. Here, we examined these three factors in CRC in Northeast China and aimed to reveal new details of the relationship between these mutations and MSI status. Methods: This study involved 290 patients with CRC who had RAS or RAF gene mutation detected using fluorescence-based allele-specific polymerase chain reaction or Sanger sequencing. The majority of the identified patients were found to harbor MSI (MSI status). Accurate molecular detection was carried out using formalin-fixed paraffin-embedded tissue or blood samples. Results: The rates of RAS and RAF mutations were 58.5% and 4.1%, respectively. The prevalence of RAS mutation in CRC was clearly higher and that of RAF mutation was lower in Northeast China compared with previously reported cohorts in other locations. High MSI level (MSI-H status) was more complex, at around 10%. This was consistent with previous data from China. However, compared with data reported from other continents, MSI-H was higher than that of Japan or South Korea in Asia, and lower than that of Europe or the United States. Conclusion: RAS/RAF mutations and MSI status in CRC are closely associated with tumor location and ethnicity. Further studies investigating the relationship between these three factors can help in the development of treatment strategies for patients with CRC.

Abstract Background The clinical treatment of ovarian cancer with ascites is problematic. The main reasons for treatment failure are the susceptibility to intraperitoneal metastasis and chemotherapeutic drug resistance. The purpose and significance of this study is to evaluate which marker might evaluate treatment efficacy and improve the cure rate. Results This study compared a no chemotherapy group with a chemotherapy group regarding the determination of carbohydrate antigen 125 and human epididymis protein 4 in ovarian cancer ascitic supernatants and cross-analyzed routine serum carbohydrate antigen 125 levels. The level of human epididymis protein 4 in the ascites of the chemotherapy group was significantly lower than that of the no chemotherapy group (p

Abstract Background It has been widely accepted that hepatitis B virus X protein (HBx) plays an important role in hepatocellular carcinoma (HCC). This study aimed to explore the function of long non-coding RNAs (lncRNAs) in the epithelial-mesenchymal transition (EMT) induced by HBx. Methods The association between HBx and EMT markers was detected using immunohistochemistry in HCC tissues. The effect of HBx on HCC EMT was assessed through morphological analysis, transwell assay, metastatic in vivo study and detection of EMT markers. LncRNA microarray was used to screen the differently expressed lncRNAs. Small interfering RNA and Western blot were used to analyse the function and mechanism of the locked lncRNA. Results HBx was negatively correlated with the epithelial marker E-cadherin but positively correlated with the mesenchymal marker vimentin in HCC tissues. HBx induced the mesenchymal phenotype and improved the metastatic ability of HCC cells. Meanwhile, HBx down-regulated E-cadherin, whereas it up-regulated vimentin. In HCC cells, HBx altered the expression of 2002 lncRNAs by more than 2-fold. One of them was ZEB2-AS1. Inhibition of ZEB2-AS1 can compensate for the EMT phenotype and reverse the expression of EMT markers regulated by HBx. Additionally, HBx affected the Wnt signalling pathway. Conclusions HBx promotes HCC cell metastasis by inducing EMT, which is at least partly mediated by lncRNAs.

The physical reason behind the much more rapid short-term annealing progress in the presence of electrons in P-type silicon irradiated by pulse neutrons is investigated. Continuum equations coupled with defect reactions are used for the numerical simulation on the temporary evolutions of defects at different electron injection ratios. It is indicated that electron injections can significantly accelerate the creations of boron and carbon interstitials, but may have little influence on the creation of the vacancy-oxygen complex. The calculations on the relative concentrations of interstitials and vacancies in different charge states via the electron injection ratio show that more and more interstitials in the doubly positive charge state change into neutral ones, and neutral vacancies are always dominant with an increase in the electron concentration. The thermal diffusion coefficient of neutral interstitials is much larger than the ones of interstitials in other charge states. As a consequence, normal ionization enhanced diffusion for interstitials in the presence of electrons can significantly accelerate the short-term annealing progress in P-type silicon. Ionization enhanced diffusion coefficients for interstitials due to athermal diffusion are further estimated using the Bourgoin mechanism, and results indicate that the diffusion coefficients of positively charged interstitials are improved by several orders of magnitude when compared to their corresponding thermal diffusion coefficients. However, the production of boron and carbon interstitials is only accelerated by about one order of magnitude, which would be ascribed into such large thermal diffusion coefficients of neutral interstitials.

Background/Aims: Plasma gelsolin (pGSN) is an actin-binding protein that plays a critical role in the pathogenesis of rheumatoid arthritis. However, whether pGSN is involved in other immunological diseases remains unknown. This study focused on the relationship between pGSN and immunoglobulin A (IgA) nephropathy (IgAN). Methods: Two hundred patients with IgAN, 200 patients each with several other types of nephropathy and healthy controls (HCs) who underwent kidney biopsies between 2000 and 2014 were enrolled in the study. The Oxford classification system was used to predict the risk of disease progression. Serum and renal tissue were used to detect pGSN, and the correlations between pGSN and IgA, galactose-deficient IgA1 (Gd-IgA1), transforming growth factor beta1 (TGF-β1), fibronectin (FN) content, clinical symptoms, and kidney function were analyzed. Results: We found that the pGSN levels were significantly decreased in sera from IgAN patients compared to sera from patients with other forms of glomerular nephritis and HCs. Furthermore, the serum pGSN levels were negatively correlated with the serum IgA1, FN, and TGF-β1 levels, and positively correlated with the estimated glomerular filtration rate. Conversely, the glomerular pGSN content was significantly elevated in the IgAN patients and was positively correlated with TGF-β1 and FN levels. In renal tissue, the pGSN levels were significantly higher in IgAN patients with M1 and S1 compared to patients with M0 and S0 (p in vitro. pGSN also promoted integrin α2β1 expression in HMCs and enhanced the integrin α2β1-pGSN interaction. Conclusion: Our study suggested that pGSN may play an important role in the development of IgAN by promoting the proliferation of mesangial cells and that serum and glomerular pGSN levels may be new markers for predicting IgAN progression and prognosis.

White spot lesions (WSLs) can develop quickly and compromise the successful outcome of the orthodontic treatment. Orthodontic bonding cement with the capability to prevent or mitigate WSLs could be beneficial, especially for patients with high risk of caries. This study explored novel mono- and di-imidazolium-based polymerizable antibacterial monomers and evaluated orthodontic cement compositions comprising such novel monomers. Their antibacterial potentials, mechanical properties, and shear bond strength (SBS) to bovine enamel were investigated. Statistical tests were applied to SBS and mechanical tests (one-way ANOVA and Tukey’s test). For antibacterial resins C (ABR-C) and E (ABR-E), their minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) against cariogenic Streptococcus mutans bacterial strain UA159 were found to be 4 μg/mL and 8 μg /mL, respectively. The loss of dry mass from completely demineralized dentin beams in buffer solutions pre-dipped into ABR-C and ABR-E resins is much less than that in control buffer (artificial saliva) only. For unfilled resins comprising up to 12 wt % ABR-C, no significant decreases in flexural strength or modulus were observed. For experimental cements incorporating 1–4 wt % ABR-C, there was no drastic compromise to the SBS to enamel except for 3 wt % ABR-C. Furthermore, their SBS was all comparable to the commercially available orthodontic cements. The ISO-22196 antimicrobial test against S. aureus showed significant levels of antibacterial effects—up to over 5 logs of microorganism reduction exhibited by ABR-C-containing experimental cements. The imidazolium-based polymerizable monomers could be utilized to functionalize orthodontic bonding cement with steady antibacterial activity and develop a potential strategy to counteract WSLs.

OBJECTIVES/GOALS: Our goal is to develop a non-invasive stimulation technique using magneto-electric nanoparticles (MENs) for inducing and enhancing neuronal activity with high spatial and temporal resolutions and minimal toxicity, which can potentially be used as a more effective approach to brain stimulation. METHODS/STUDY POPULATION: MENs compose of core-shell structures that are attracted to strong external magnetic field (~5000 Gauss) but produces electric currents with weaker magnetic field (~450 Gauss). MENs were IV treated into mice and drawn to the brain cortex with a strong magnetic field. We then stimulate MENs with a weaker magnetic field via electro magnet. With two photon calcium imaging, we investigated both the temporal and spatial effects of MENs on neuronal activity both in vivo and in vitro. We performed mesoscopic whole brain calcium imaging on awake animal to assess the MENs effects. Furthermore, we investigated the temporal profile of MENs in the vasculatures post-treatment and its toxicities to CNS. RESULTS/ANTICIPATED RESULTS: MENs were successfully localized to target cortical regions within 30 minutes of magnetic application. After wirelessly applying ~450 G magnetic field between 10-20 Hz, we observed a dramatic increase of calcium signals (i.e. neuronal excitability) both in vitro cultured neurons and in vivo treated animals. Whole brain imaging of awake mice showed a focal increase in calcium signals at the area where MENs localized and the signals spread to regions further away. We also found MENs stimulatory effects lasted up to 24 hours post treatment. MEN stimulation increases c-Fos expression but resulted in no inflammatory changes, up to one week, by assessing microglial or astrocytes activations. DISCUSSION/SIGNIFICANCE OF IMPACT: Our study shows, through controlling the applied magnetic field, MENs can be focally delivered to specific cortical regions with high efficacy and wirelessly activated neurons with high spatial and temporal resolution. This method shows promising potential to be a new non-invasive brain modulation approach disease studies and treatments.

Acupuncture and moxibustion have been shown to be effective in treating Crohn’s disease (CD), but their therapeutic mechanisms remain unclear. Here we compared brain responses to either electro-acupuncture or moxibustion treatment in CD patients experiencing remission. A total of 65 patients were randomly divided into an electro-acupuncture group (n = 32) or a moxibustion group (n = 33), and treated for 12 weeks. Eighteen patients in the electro-acupuncture group and 20 patients in the moxibustion group underwent resting-state functional magnetic resonance imaging at baseline and after treatment. Seed-based analysis was used to compare the resting-state functional connectivity (rsFC) between bilateral hippocampus and other brain regions before and after the treatments, as well as between the two groups. The CD activity index (CDAI) and inflammatory bowel disease questionnaire (IBDQ) were used to evaluate disease severity and patient quality of life. Electro-acupuncture and moxibustion both significantly reduced CDAI values and increased IBDQ scores. In the electro-acupuncture group, the rsFC values between bilateral hippocampus and anterior middle cingulate cortex (MCC) and insula were significantly increased, and the changes were negatively correlated with the CDAI scores. In the moxibustion group, the rsFC values between bilateral hippocampus and precuneus as well as inferior parietal lobe (IPC) were significantly elevated, and the changes were negatively correlated with the CDAI scores. We conclude that the therapeutic effects of electro-acupuncture and moxibustion on CD may involve the differently modulating brain homeostatic afferent processing network and default mode network (DMN), respectively.

In the past few decades, apoptosis has been regarded as the only form of programmed cell death. However, the traditional view has been challenged by the identification of several forms of regulated necrosis, including necroptosis. Necroptosis is typified by a necrotic cell death morphology and is controlled by RIP1, RIP3, and mixed lineage kinase domain–like protein. The physiological role of necroptosis is to serve as a “fail-safe” form of cell death for cells that fail to undergo apoptosis during embryonic development and disease defense. Currently, established studies have indicated that necroptosis is involved in cancer initiation and progression. Although elevated necroptosis contributes to cancer cell death, extensive cell death also increases the risk of proliferation and metastasis of the surviving cells by inducing the generation reactive oxygen species, activation of inflammation, and suppression of the immune response. Thus, questions regarding the overall impact of necroptosis on cancer remain open. In this review, we introduce the basic knowledge regarding necroptosis, summarize its dual effects on cancer progression, and analyze its advantages and disadvantages in clinical applications.

Transgenic mice that express channelrhodopsin-2 or its variants provide a powerful tool for optogenetic study of the nervous system. Previous studies have established that introducing such exogenous genes usually does not alter anatomical, electrophysiological, and behavioral properties of neurons in these mice. However, in a line of Thy1-ChR2-YFP transgenic mice (line 9, Jackson lab), we found that short-latency motor evoked potentials (MEPs) induced by transcranial magnetic stimulation had a longer latency and much lower amplitude than that of wild type mice. MEPs evoked by transcranial electrical stimulation also had a much higher threshold in ChR2 mice, although similar amplitudes could be evoked in both wild and ChR2 mice at maximal stimulation. In contrast, long-latency MEPs evoked by electrically stimulating the motor cortex were similar in amplitude and latency between wild type and ChR2 mice. Whole-cell patch clamp recordings from layer V pyramidal neurons of the motor cortex in ChR2 mice revealed no significant differences in intrinsic membrane properties and action potential firing in response to current injection. These data suggest that corticospinal tract is not accountable for the observed abnormality. Motor behavioral assessments including BMS score, rotarod, and grid-walking test showed no significant differences between the two groups. Because short-latency MEPs are known to involve brainstem reticulospinal tract, while long-latency MEPs mainly involve primary motor cortex and dorsal corticospinal tract, we conclude that this line of ChR2 transgenic mice has normal function of motor cortex and dorsal corticospinal tract, but reduced excitability and responsiveness of reticulospinal tracts. This abnormality needs to be taken into account when using these mice for related optogenetic study.

Posttraumatic epilepsy (PTE) usually develops in a small percentage of patients of traumatic brain injury after a varying latent period. Modeling this chronic neurological condition in rodents is time consuming and inefficient, which constitutes a significant obstacle in studying its mechanism and discovering novel therapeutics for its prevention and treatment. Partially isolated neocortex, or undercut, is known to induce cortical hyperexcitability and epileptiform activity in vitro, and has been used extensively for studying the neurophysiological mechanism of posttraumatic epileptogenesis. However, whether the undercut lesion in rodents causes chronic epileptic seizures has not been systematically characterized. Here we used a miniature telemetry system to continuously monitor electroencephalography (EEG) in adult C57BL mice for up to 3 months after undercut surgery. We found that 50% of animals developed spontaneous seizures between 16-50 days after injury. The mean seizure duration was 8.9±3.6 seconds, and the average seizure frequency was 0.17±0.17 times per day. There was no progression in seizure frequency and duration over the recording period. Video monitoring revealed behavioral arrests and clonic limb movement during seizure attacks. A pentylenetetrazol (PTZ) test further showed increased seizure susceptibility in the undercut mice. We conclude that undercut lesion in mice is a model of chronic PTE that involves spontaneous epileptic seizures.

OBJECTIVE:To characterize the significance of correlated autoantibodies in systemic lupus erythematosus (SLE) and its complication lupus nephritis (LN) in a large cohort of patients. METHODS:Clinical data were statistically analyzed in 1699 SLE patients with or without nephritis who were diagnosed and treated during 2002-2013 in the northeast region of China. Reactivity to a list of 16 autoantibodies was detected by the serum test Euroline ANA profile (IgG). Serum titers of the anti-nucleosome autoantibodies were measured by ELISA assays. Kidney biopsies were examined by pathologists. Immune complex deposition was identified by immunohistochemistry stain. RESULTS:Simultaneous positivity of anti-dsDNA, -nucleosome and -histone antibodies (3-pos) was prevalent in SLE patients with LN compared to Non-renal SLE patients (41% vs 11%, p< 0.001). Significant correlations were found between any two of the above three anti-nucleosome antibodies in LN patients. In comparison to non-3-pos cohorts, 3-pos patients with LN had significantly higher serum levels of the three antibodies and more active disease; was associated with type IV disease; suffered from more severe renal damages; received more intensive treatment and had worse disease outcome. The serum levels of these three autoantibodies in 3-pos LN patients were significantly decreased when they underwent clinical recovery. CONCLUSIONS:Simultaneous reactivity to anti-dsDNA, -nucleosome and -histone antibodies by Euroline ANA profile (IgG) may indicate severe nephropathy in patients with SLE.

Astrocytes form extensive intercellular networks through gap junctions to support both biochemical and electrical coupling between adjacent cells. ATP-sensitive K(+) (K(ATP)) channels couple cell metabolic state to membrane excitability and are enriched in glial cells. Activation of astrocytic mitochondrial K(ATP) (mitoK(ATP)) channel regulates certain astrocytic functions. However, less is known about its impact on electrical coupling between directly coupled astrocytes ex vivo. By using dual patch clamp recording, we found that activation of mitoK(ATP) channel increased the electrical coupling ratio in brain slices. The electrical coupling ratio started to increase 3 min after exposure to Diazoxide, a mitoK(ATP) channel activator, peaked at 5 min, and maintained its level with little adaptation until the end of the 10-min treatment. Blocking the mitoK(ATP) channel with 5-hydroxydecanoate, inhibited electrical coupling immediately, and by 10-min, the ratio dropped by 71% of the initial level. Activation of mitoK(ATP) channel also decreased the latency time of the transjunctional currents by 50%. The increase in the coupling ratio resulting from the activation of the mitoK(ATP) channel in a single astrocyte was further potentiated by the concurrent inhibiting of the channel on the recipient astrocyte. Furthermore, Meclofenamic acid, a gap-junction inhibitor which completely blocked the tracer coupling, hardly reversed the impact of mitoK(ATP) channel's activation on electrical coupling (by 7%). The level of mitochondrial Connexin43, a gap junctional subunit, significantly increased by 70% in astrocytes after 10-min Diazoxide treatment. Phospho-ERK signals were detected in Connexin43 immunoprecipitates in the Diazoxide-treated astrocytes, but not untreated control samples. Finally, inhibiting ERK could attenuate the effects of Diazoxide on electrical coupling by 61%. These findings demonstrate that activation of astrocytic mitoK(ATP) channel upregulates electrical coupling between hippocampal astrocytes ex vivo. In addition, this effect is mainly via up-regulation of the Connexin43-constituted gap junction coupling by an ERK-dependent mechanism in the mitochondria.

Despite advances in wound closure techniques and devices, there is still a critical need for new methods of enhancing the healing process to achieve optimal outcomes. Recently, stem cell therapy has emerged as a new approach to accelerate wound healing. Adipose-derived stem cells (ASCs) hold great promise for wound healing, because they are multipotential stem cells capable of differentiation into various cell lineages and secretion of angiogenic growth factors. The aim of this study was to evaluate the benefit of ASCs on wound healing and then investigate the probable mechanisms. ASCs characterized by flow cytometry were successfully isolated and cultured. An excisional wound healing model in rat was used to determine the effects of locally administered ASCs. The gross and histological results showed that ASCs significantly accelerated wound closure in normal and diabetic rat, including increased epithelialization and granulation tissue deposition. Furthermore, we applied GFP-labeled ASCs on wounds to determine whether ASCs could differentiate along multiple lineages of tissue regeneration in the specific microenvironment. Immunofluorescent analysis indicated that GFP-expressing ASCs were costained with pan-cytokeratin and CD31, respectively, indicating spontaneous site-specific differentiation into epithelial and endothelial lineages. These data suggest that ASCs not only contribute to cutaneous regeneration, but also participate in new vessels formation. Moreover, ASCs were found to secret angiogenic cytokines in vitro and in vivo, including VEGF, HGF, and FGF2, which increase neovascularization and enhance wound healing in injured tissues. In conclusion, our results demonstrate that ASC therapy could accelerate wound healing through differentiation and vasculogenesis and might represent a novel therapeutic approach in cutaneous wounds.