Scalable Approach to Molecular Motor-Polymer Conjugates for Light-Driven Artificial Muscles.

The integration of molecular machines and motors into materials represents a promising avenue for creating dynamic and functional molecular systems, with potential applications in soft robotics or reconfigurable biomaterials. However, the development of truly scalable and controllable approaches for incorporating molecular motors into polymeric matrices has remained a challenge. Here, it is shown that light-driven molecular motors with sensitive photo-isomerizable double bonds can be converted into initiators for Cu-mediated controlled/living radical polymerization enabling the synthesis of star-shaped motor-polymer conjugates. This approach enables scalability, precise control over the molecular structure, block copolymer structures, and high-end group fidelity. Moreover, it is demonstrated that these materials can be crosslinked to form gels with quasi-ideal network topology, exhibiting light-triggered contraction. The influence of arm length and polymer structure is investigated, and the first molecular dynamics simulation framework to gain deeper insights into the contraction processes is developed. Leveraging this scalable methodology, the creation of bilayer soft robotic devices and cargo-lifting artificial muscles is showcased, highlighting the versatility and potential applications of this advanced polymer chemistry approach. It is anticipated that the integrated experimental and simulation framework will accelerate scalable approaches for active polymer materials based on molecular machines, opening up new horizons in materials science and bioscience.

A clinicopathologic feature-based nomogram for preoperative estimation of splenic hilar lymph node metastasis in advanced proximal gastric cancer without invasion of the greater curvature.

BACKGROUND: The indications for splenic hilar lymph node dissection in advanced proximal gastric cancer without invasion of the greater curvature are controversial. We aimed to develop a preoperative nomogram for individualized prediction of splenic hilar lymph node metastasis in non-greater curvature advanced proximal gastric cancer. METHODS: From January 2014 to December 2021, 558 patients with non-greater curvature advanced proximal gastric cancer who underwent D2 lymphadenectomy (including splenic hilar lymph node) were retrospectively analyzed and divided into a training cohort (n = 361) and validation cohort (n = 197), depending on the admission time. A preoperative predictive nomogram of splenic hilar lymph node metastasis was established based on independent predictors identified by multivariate analysis, and the performance and prognostic value were confirmed. RESULTS: In the training and validation cohorts, 48 (13.3%) and 24 patients (12.2%) had pathologically confirmed splenic hilar lymph node metastasis, respectively. Tumor located in the posterior wall, tumor size ≥5 cm, Borrmann type IV, and splenic hilar lymph node lymphadenectasis on computed tomography were preoperative factors independently associated with splenic hilar lymph node metastasis. The nomogram developed based on these four parameters had a high concordance index of 0.850 (95% confidence interval, 0.793-0.907) and 0.825 (95% confidence interval, 0.743-0.908) in the training and validation cohorts, respectively, with well-fitting calibration plots and better net benefits in the decision curve analysis. In addition, disease-free survival and overall survival were significantly shorter in the high-risk group, with hazard ratios of 3.660 (95% confidence interval, 2.228-6.011; log-rank P < .0001) and 3.769 (95% confidence interval, 2.279-6.231; log-rank P < .0001), respectively. CONCLUSION: The nomogram has good performance in predicting the risk of splenic hilar lymph node metastasis in non-greater curvature advanced proximal gastric cancer preoperatively, which can help surgeons make rational clinical decisions.

How does exotic Spartina alterniflora affect the contribution of iron-bound organic carbon to soil organic carbon in salt marshes?

Iron-bound organic carbon (OC-FeR) is important for the stability of soil organic carbon (SOC) in salt marshes, and the Spartina alterniflora invasion reshaped local salt marshes and changed the SOC pool. To evaluate the effects of S. alterniflora invasion on the contribution of OC-FeR to SOC, we determined the OC-FeR content and soil characteristics in the 0-50 cm soil profile along the vegetation sequence, including mudflats (MF), S. alterniflora marshes established in 2003 (SA03) and 1989 (SA89), the ecotone of S. alterniflora and Phragmites australis (SE), S. salsa marsh (SS), and P. australis marsh (PA). The SOC content was 6.55-17.5 mg g-1 in the S. alterniflora marshes. Reactive iron oxides (Fed, Feo, Fep) accumulated significantly in the S. alterniflora and P. australis salt marshes. PA and S. alterniflora marshes had higher DOC contents of 0.28-0.77 mg g-1. The OC-FeR content in the 0-50 cm soil profile in these ecosystems ranged from 0.3 to 3.29 mg g-1, with a contribution to the SOC content (fOC-FeR) of approximately 11 %, which was highest in SA03 (16.3 % ~ 18.8 %), followed by SA89, SE, and PA. In addition, the molar ratios of OC-FeR to Fed were <1, indicating that the iron oxides were associated with SOC through sorption more than coprecipitation. According to the structural equation model, SOC, DOC and iron oxides were the direct driving factors of OC-FeR formation, while the vegetation zone indirectly functioned by regulating organic C inputs, iron oxide formation, and pH. This study suggested that S. alterniflora invasion promotes iron-bound organic carbon accumulation by increasing organic C inputs and regulating iron oxide formation in salt marshes, but such promotion will degenerate with development duration.

Epigenetic age acceleration and risk of aortic valve stenosis: a bidirectional Mendelian randomization study.

BACKGROUND: Aortic valve stenosis (AVS) is the most prevalent cardiac valve lesion in developed countries, and pathogenesis is closely related to aging. DNA methylation-based epigenetic clock is now recognized as highly accurate predictor of the aging process and associated health outcomes. This study aimed to explore the causal relationship between epigenetic clock and AVS by conducting a bidirectional Mendelian randomization (MR) analysis. METHODS: Summary genome-wide association study statistics of epigenetic clocks (HannumAge, HorvathAge, PhenoAge, and GrimAge) and AVS were obtained and assessed for significant instrumental variables from Edinburgh DataShare (n = 34,710) and FinnGen biobank (cases = 9870 and controls = 402,311). The causal association between epigenetic clock and AVS was evaluated using inverse variance weighted (IVW), weighted median (WM), and MR-Egger methods. Multiple analyses (heterogeneity analysis, pleiotropy analysis, and sensitivity analysis) were performed for quality control assessment. RESULTS: The MR analysis showed that the epigenetic age acceleration of HorvathAge and PhenoAge was associated with an increased risk of AVS (HorvathAge: OR = 1.043, P = 0.016 by IVW, OR = 1.058, P = 0.018 by WM; PhenoAge: OR = 1.058, P = 0.005 by IVW, OR = 1.053, P = 0.039 by WM). Quality control assessment proved our findings were reliable and robust. However, there was a lack of evidence supporting a causal link from AVS to epigenetic aging. CONCLUSION: The present MR analysis unveiled a causal association between epigenetic clocks, especially HorvathAge and PhenoAge, with AVS. Further research is required to elucidate the underlying mechanisms and develop strategies for potential interventions.

Elevated uric acid/albumin ratio as a predictor of poor coronary collateral circulation development in patients with non-ST segment elevation myocardial infarction.

BACKGROUND: Uric acid/albumin ratio (UAR) is a novel composite biomarker with superior predictive value for cardiovascular disease. OBJECTIVE: To investigate the relationship between UAR and coronary collateral circulation (CCC) in patients with non-ST segment elevation myocardial infarction (NSTEMI). METHODS: A total of 205 NSTEMI patients who underwent coronary arteriography with at least one major coronary stenosis, 95% were included. Patients were divided into two groups according to CCC development: poorly-developed CCC group (Rentrop 0-1) and well-developed CCC (Rentrop 2-3). Univariate analysis and logistic regression analysis were utilized to investigate the factors influencing adverse CCC formation in NSTEMI patients. The receiver operating characteristic (ROC) curve was plotted to evaluate the predictive value of UAR, C-reactive protein (CRP), uric acid, and albumin for patients with poorly developed CCC, and the area under the curve (AUC) was compared. RESULTS: The UAR values of NSTEMI patients were significantly higher in the poorly developed CCC group than those in the well-developed CCC group (10.19 [8.80-11.74] vs. 7.79 [6.28-9.55], p < .001). In the multiple logistic regression tests, UAR (odds ratio [OR]: 1.365, 95% confidence interval [CI]: 1.195-1.560, p < .001), CRP (OR: 1.149, 95% CI: 1.072-1.231, p < .001), and diabetes (OR: 2.924, 95% CI: 1.444-5.920, p = .003) were independent predictors of poorly developed CCC. The ROC curve analysis showed that the optimal cut-off value of UAR was 8.78 in predicting poorly developed CCC with a sensitivity of 76.8% and specificity of 62.4%, with the AUC of 0.737 (95% Cl: 0.668-0.805, p < .001). CONCLUSION: Elevated UAR may be an independent and effective biomarker for predicting poorly-developed CCC development in NSTEMI patients.

The short- and long-term outcomes of laparoscopic D2 lymphadenectomy plus complete mesogastrium excision for lymph node-negative gastric cancer.

BACKGROUND: Patients with T1-3N0M0 gastric cancer (GC) who undergo radical gastrectomy maintain a high recurrence rate. The free cancer cells in the mesogastric adipose connective tissue (Metastasis V) maybe the reason for recurrence in these individuals. We aimed to evaluate whether D2 lymphadenectomy plus complete mesogastrium excision (D2 + CME) was superior to D2 lymphadenectomy with regard to safety and oncological efficacy for T1-3N0M0 GC. METHODS: Patients with T1-3N0M0 GC who underwent radical resection from January 2014 to July 2018 were retrospectively analyzed; there were 323 patients, of whom 185 were in the D2 + CME group and 138 in the D2 group. The primary endpoint was 5-year disease-free survival (DFS). Secondary endpoints include the 5-year overall survival (OS), recurrence pattern, morbidity, mortality, and surgical outcomes. RESULTS: D2 + CME was associated with less intraoperative bleeding loss, a greater number of lymph nodes harvested, and less time to first postoperative flatus, but the postoperative morbidity was similar. The 5-year DFS was 95.6% (95% CI 92.7-98.5%) and 90.4% (95% CI 85.5-95.3%) in the D2 + CME group and the D2 group, respectively, with a hazard ratio (HR) of 0.455 (95% CI 0.188-1.097; p = 0.071). In terms of recurrence patterns, local recurrence was more prone to occur in the D2 group (p = 0.031). Subgroup analysis indicated that for patients with T1b-3N0M0 GC, the 5-year DFS in the D2 + CME group was considerably greater than that in the D2 group (95.3% [95% CI 91.6-99.0%] vs. 87.6% [95% CI 80.7-94.5%], HR 0.369, 95% CI 0.138-0.983; log-rank p = 0.043). CONCLUSION: Laparoscopic D2 + CME for T1-3N0M0 GC is safe and feasible. Furthermore, it not only reduces the local recurrence rate but also improves the 5-year DFS in cases of T1b-3N0M0 GC.

Transporter mining and metabolic engineering of Escherichia coli for high-level D-allulose production from D-fructose by thermo-swing fermentation.

D-Allulose is an ultra-low-calorie sweetener with broad market prospects in the fields of food, beverage, health care, and medicine. The fermentative synthesis of D-allulose is still under development and considered as an ideal route to replace enzymatic approaches for large-scale production of D-allulose in the future. Generally, D-allulose is synthesized from D-fructose through Izumoring epimerization. This biological reaction is reversible, and a high temperature is beneficial to the conversion of D-fructose. Mild cell growth conditions seriously limit the efficiency of producing D-allulose through fermentation. FryABC permease was identified to be responsible for the transport of D-allulose in Escherichia coli by comparative transcriptomic analysis. A cell factory was then developed by expression of ptsG-F, dpe, and deletion of fryA, fruA, manXYZ, mak, and galE. The results show that the newly engineered E. coli was able to produce 32.33 ± 1.33 g L-1 of D-allulose through a unique thermo-swing fermentation process, with a yield of 0.94 ± 0.01 g g-1 on D-fructose.

Hierarchical Mechanical Transduction of Precision-Engineered DNA Hydrogels with Sacrificial Bonds.

Engineering the response to external signals in mechanically switchable hydrogels is important to promote smart materials applications. However, comparably little attention has focused on embedded precision mechanisms for autonomous nonlinear response in mechanical profiles in hydrogels, and we lack understanding of how the behavior from the molecular scale transduces to the macroscale. Here, we design a nonlinear stress-strain response into hydrogels by engineering sacrificial DNA hairpin loops into model network hydrogels formed from star-shaped building blocks. We characterize the force-extension response of single DNA hairpins and are able to describe how the specific topology influences the nonlinear mechanical behavior at different length scales. For this purpose, we utilize force spectroscopy as well as microscopic and macroscopic deformation tests. This study contributes to a better understanding of designing nonlinear strain-adaptive features into hydrogel materials.

Transmission of sub-terahertz signals over a fiber-FSO-5†G NR hybrid system with an aggregate net bit rate of 227.912 Gb/s.

Transmission of sub-terahertz (sub-THz) signals over a fiber-free-space optical (FSO)-fifth-generation (5 G) new radio (NR) hybrid system is successfully realized. It is a promising system that utilizes multiple media of optical fiber, optical wireless, and 5 G NR wireless to achieve a 227.912-Gb/s record-high aggregate net bit rate. The system concurrently transmits a 59.813-Gb/s net bit rate in the 150-GHz sub-THz frequency, 74.766-Gb/s in the 250-GHz sub-THz frequency, and 93.333-Gb/s in the 325-GHz sub-THz frequency through the fiber-FSO-wireless convergence, including 25-km single-mode fiber, 100-m FSO, and 30-m/25-m/20-m sub-THz-wave transmissions. This system achieves sufficiently low bit error rates (< hard-decision forward error correction (FEC) threshold of 3.8 × 10-3 at 16 and 20 Gbaud symbol rates; < soft-decision FEC threshold of 2 × 10-2 at 28 Gbaud symbol rate) and clear and distinct constellation diagrams, meeting the demands of 5 G NR communications in the sub-THz band. The development of fiber-FSO-5 G NR hybrid system represents a substantial development in the field of advanced communications. It has the ability to enhance the way we communicate in the future.

Automated diagnosis of pancreatic mucinous and serous cystic neoplasms with modality-fusion deep neural network using multi-modality MRIs.

Background: Pancreatic cystic neoplasms are increasingly diagnosed with the development of medical imaging technology and people's self-care awareness. However, two of their sub-types, serous cystic neoplasms (SCN) and mucinous cystic neoplasms (MCN), are often misclassified from each other. Because SCN is primarily benign and MCN has a high rate of malignant transformation. Distinguishing SCN and MCN is challenging and essential. Purpose: MRIs have many different modalities, complete with SCN and MCN diagnosis information. With the help of an artificial intelligence-based algorithm, we aimed to propose a multi-modal hybrid deep learning network that can efficiently diagnose SCN and MCN using multi-modality MRIs. Methods: A cross-modal feature fusion structure was innovatively designed, combining features of seven modalities to realize the classification of SCN and MCN. 69 Patients with multi-modalities of MRIs were included, and experiments showed performances of every modality. Results: The proposed method with the optimized settings outperformed all other techniques and human radiologists with high accuracy of 75.07% and an AUC of 82.77%. Besides, the proposed disentanglement method outperformed other fusion methods, and delayed contrast-enhanced T1-weighted MRIs proved most valuable in diagnosing SCN and MCN. Conclusions: Through the use of a contemporary artificial intelligence algorithm, physicians can attain high performance in the complex challenge of diagnosing SCN and MCN, surpassing human radiologists to a significant degree.

A continuous age-specific standardized mortality ratio for estimating the unascertained rates in the early epidemic of COVID-19 in different regions.

The difference in age structure and aging population level was an important factor that caused the difference in COVID-19's case fatality rate (CFR) in various regions. To eliminate the age effect on estimating the CFR of COVID-19, our study applied nonlinear logistic model and maximum likelihood method to fit the age-fatality curves of COVID-19 in different countries and regions. We further computed the standardized mortality ratio from the age-fatality curves of COVID-19 in the above regions and found that the risk of COVID-19 death in Wuhan was of a moderate level, while the non-Hubei region was even lower, compared with other regions. Regarding the disparity of CFRs among different regions in the country, we believed that there might be an unascertained phenomenon in high-endemic regions. Based on age-fatality rate curves, we estimated unascertained rates in cities with severe epidemics such as Wuhan and New York, and it was found that the total unascertained rates in Wuhan and New York were 81.6% and 81.2%, respectively. Meanwhile, we also found that the unascertained rates varied greatly with age.

A portable microfluidic device integrated with electrochemical sensing platform for detection of multiple binders in ancient wall paintings.

The aging of the proteinaceous binders will cause the cultural relics to suffer from diseases such as flaking, cracks, and even peeling. Identifying the type of binders in a timely manner is conducive to restore diseased cultural relics. High-throughput and portable detection system are of great significance for researching cultural relic materials on the archaeological site. Therefore, in this work, a portable electrochemical microfluidic device for the simultaneous detection of casein, ovalbumin, and peach gum binders was developed. The proposed electrochemical immunosensor technology integrated with microfluidic device achieve the goals of miniaturization, portability and reagent-saving. For casein, ovalbumin and peach gum, excellent performance was obtained in terms of their limits of detection (LOD) at 0.237, 0.507, and 0.403 ng mL-1 (S/N = 3), respectively. In addition, the microfluidic sensing platform exhibited acceptable anti-interference ability, stability, and storage capacity. In order to evaluate the practical application value, the proposed microfluidic sensing device was applied for detecting eight archaeological samples from different historic sites. This work demonstrates great potential for high-throughput, portable detection of cultural relic proteinaceous binder materials.

Targeting ASIC1a Promotes Neural Progenitor Cell Migration and Neurogenesis in Ischemic Stroke.

Cell replacement therapy using neural progenitor cells (NPCs) has been shown to be an effective treatment for ischemic stroke. However, the therapeutic effect is unsatisfactory due to the imbalanced homeostasis of the local microenvironment after ischemia. Microenvironmental acidosis is a common imbalanced homeostasis in the penumbra and could activate acid-sensing ion channels 1a (ASIC1a), a subunit of proton-gated cation channels following ischemic stroke. However, the role of ASIC1a in NPCs post-ischemia remains elusive. Here, our results indicated that ASIC1a was expressed in NPCs with channel functionality, which could be activated by extracellular acidification. Further evidence revealed that ASIC1a activation inhibited NPC migration and neurogenesis through RhoA signaling-mediated reorganization of filopodia formation, which could be primarily reversed by pharmacological or genetic disruption of ASIC1a. In vivo data showed that the knockout of the ASIC1a gene facilitated NPC migration and neurogenesis in the penumbra to improve behavioral recovery after stroke. Subsequently, ASIC1a gain of function partially abrogated this effect. Moreover, the administration of ASIC1a antagonists (amiloride or Psalmotoxin 1) promoted functional recovery by enhancing NPC migration and neurogenesis. Together, these results demonstrate targeting ASIC1a is a novel strategy potentiating NPC migration toward penumbra to repair lesions following ischemic stroke and even for other neurological diseases with the presence of niche acidosis.

Hybrid framework for single-pointer meter identification.

Automated identification of single-pointer meter identification in substations is widely used in the construction of digital substations and it must accurately identify the value of the pointer meter. Current single-pointer meter identification methods are not universally applicable and can only identify one type of meter. In this study, we present a hybrid framework for single-pointer meter identification. First, the input image of the single-pointer meter is modeled to gain a priori knowledge, including the template image, dial position information, the pointer template image, and scale value positions. Based on a convolutional neural network to generate the input image and the template image feature points, image alignment is then applied through a feature point match to mitigate slight changes in the camera angle. Next, a pixel loss-free method of arbitrary point image rotation correction is presented for rotation template matching. Finally, by rotating the input gray mask image of the dial and matching it to the pointer template to get the optimal rotation angle, the meter value is calculated. The experimental findings demonstrate the method's effectiveness in identifying nine different types of single-pointer meters in substations with various ambient illuminations. This study provides a feasible reference for substations to identify the value of different types of single-pointer meters.

A prediction nomogram for postoperative gastroparesis syndrome in right colon cancer: a retrospective study.

PURPOSE: To investigate the high-risk factors for postoperative gastroparesis syndrome (PGS) in right colon cancer and to build a prediction nomogram for personalized prediction of PGS. METHODS: Our study retrospectively analyzed 361 patients with right colon cancer who underwent right hemicolectomy at The First Hospital of Putian City in Fujian Province, China and who were hospitalized between January 2012 and July 2022. Multivariate logistic regression was used to determine the independent risk factors for PGS and to establish a nomogram model. Furthermore, discrimination, calibration, and clinical benefits were used to evaluate the model. RESULTS: The multivariate logistic regression revealed that dissection of the subpyloric lymph nodes (No. 206 lymph node) (OR 5.242, P = 0.005), preoperative fasting blood glucose level (OR 3.708, P = 0.024), preoperative albumin level (OR 3.503, P = 0.020), and total operative time (OR 4.648, P = 0.014) were independent risk factors for PGS. Based on the above four factors, the area under the ROC curve (AUC) and C-index of the nomogram were 0.831. The prediction nomogram's calibration curve was closer to the ideal diagonal, and the Hosmer‒Lemeshow test indicated that the nomogram fit well (P = 0.399). Moreover, the decision curve analysis revealed that the model can present better clinical benefits when the threshold probability was between 1 and 28%, and the internal validation verified the dependability of the model (C-index = 0.948). CONCLUSIONS: A risk prediction nomogram based on perioperative factors provided the physician with a simple, visual, and efficient tool for the prediction and management of PGS in right colon cancer.

Dapagliflozin alleviates myocardial ischemia/reperfusion injury by reducing ferroptosis via MAPK signaling inhibition.

Reperfusion is essential for ischemic myocardium but paradoxically leads to myocardial damage that worsens cardiac functions. Ferroptosis often occurs in cardiomyocytes during ischemia/reperfusion (I/R). The SGLT2 inhibitor dapagliflozin (DAPA) exerts cardioprotective effects independent of hypoglycemia. Here, we investigated the effect and potential mechanism of DAPA against myocardial ischemia/reperfusion injury (MIRI)-related ferroptosis using the MIRI rat model and hypoxia/reoxygenation (H/R)-induced H9C2 cardiomyocytes. Our results show that DAPA significantly ameliorated myocardial injury, reperfusion arrhythmia, and cardiac function, as evidenced by alleviated ST-segment elevation, ameliorated cardiac injury biomarkers including cTnT and BNP and pathological features, prevented H/R-triggered cell viability loss in vitro. In vitro and in vivo experiments showed that DAPA inhibited ferroptosis by upregulating the SLC7A11/GPX4 axis and FTH and inhibiting ACSL4. DAPA notably mitigated oxidative stress, lipid peroxidation, ferrous iron overload, and reduced ferroptosis. Subsequently, network pharmacology and bioinformatics analysis suggested that the MAPK signaling pathway was a potential target of DAPA and a common mechanism of MIRI and ferroptosis. DAPA treatment significantly reduced MAPK phosphorylation in vitro and in vivo, suggesting that DAPA might protect against MIRI by reducing ferroptosis through the MAPK signaling pathway.

An Elastic Cross-Linked Binder for Silicon Anodes in Lithium-Ion Batteries with a High Mass Loading.

Due to the urgent demand for lithium-ion batteries (LIBs) with a high energy density, silicon (Si) possessing an ultrahigh capacity has aroused wide attention. However, its practical application is seriously hindered by enormous volume changes of the Si anode during cycling. Developing novel binders suitable for the Si anode has proven to be an effective strategy to improve its electrochemical performance. Herein, we constructed a three-dimensional network binder, in which the polyacrylic acid (PAA) long chains are cross-linked with one kind of amino acid, lysine (Lys). The abundant polar groups in PAA/Lys enable it to tightly adhere to the Si particles via hydrogen bonds, and the cross-linked structure prevents irreversible slipping of the PAA chains upon volume variation of the particles. The Si used was obtained from a sustainable route by recycling photovoltaic waste silicon. With high elasticity and strong adhesion, the PAA/Lys binder can effectively keep the structural integrity of the Si electrode and improve its electrochemical performance. The Si electrode using the PAA/Lys binder exhibits a good cycling stability (1008 mAh g-1 at 2 A g-1 after 250 cycles). Even with a high mass loading of 3.03 mg cm-2, the Si anode can remain stable for 100 cycles at a high fixed areal capacity of 3.03 mAh cm-2. This work gives a practical method to make stable Si electrodes using sustainable Si source and environmentally friendly amino acid-based binders.

Knockout of transient receptor potential ankyrin 1 (TRPA1) modulates the glial phenotype and alleviates perihematomal neuroinflammation after intracerebral hemorrhage in mice via MAPK/NF-κB signaling.

The objective is to explore the role of astrocytic transient receptor potential ankyrin 1 (TRPA1) in glial phenotype transformation in neuroinflammation after intracerebral hemorrhage (ICH). Wild-type astrocytes and TRPA1-/- astrocytes were subjected to 6-h hemin treatment, and the calcium ions and transcriptome sequencing were assessed. A mouse autologous blood injection ICH model was established to evaluate the proliferation and phenotypes of astrocytes and microglia around the hematoma. The neuroinflammation and behavioral performance of wild-type ICH mice and TRPA1-/- ICH mice were assessed. Knockout of astrocytic TRPA1 decreased calcium ions of astrocytes after hemin treatment in-vitro, and microglial and astrocytes around the hematoma proliferated after the ICH model. Furthermore, RNA-sequencing (RNA-seq), immunofluorescence, and Western blotting results showed that the activated astrocytes transformed into the A2 phenotype in TRPA1-/- ICH mice. The 'ameboid' microglia were observed around the hematoma in TRPA1-/- ICH mice. The proliferation of A2 astrocytes and 'ameboid' microglia ameliorated the neuroinflammation after ICH. The inflammatory response was reduced by inhibiting the mitogen-activated protein kinase/nuclear factor kappa-B signaling pathway, and neurologic deficits were improved in TRPA1-/- ICH mice compared with wild-type ICH mice. This research suggests that astrocytic TRPA1 is a new therapeutic target to rescue neuroinflammation by modulating the glial phenotype after ICH.

Pyrrolidine Dithiocarbamate Enhances the Cytotoxic Effect of Arsenic Trioxide on Acute Promyelocytic Leukemia Cells.

BACKGROUND: More than 95% patients with acute promyelocytic leukemia (APL) carry the PML-RARα fusion oncoprotein. Arsenic trioxide (ATO) is an efficacious therapeutic agent for APL, and the mechanism involves the binding with PML and degradation of PML-RARα protein. Pyrrolidine dithiocarbamate (PDTC) demonstrates the function of facilitating the cytotoxic effect of ATO. PURPOSE: To investigate whether PDTC is potential to enhance the cytotoxic effect of ATO to APL cells by acting on PML-RARα oncoproteins. METHODS: Inhibitory effects of drugs on cell viability were examined by CCK-8 test, and apoptosis was evaluated by flow cytometry. Western blotting and immunofluorescence assays were used to explore the mechanism. RESULTS: PDTC improved the effect of ATO on inhibiting proliferation of NB4 cells in vitro. Further, PDTC-ATO promoted apoptosis and cell cycle arrest in NB4 cells. The expression of caspase- 3 and Bcl-2 was reduced in PDTC-ATO-treated NB4 cells, while cleaved caspase-3 and Bax was up-regulated. Furthermore, less PML-RARα expression were found in PDTC-ATO-treated NB4 cells than that in NB4 cells treated with ATO singly. Laser confocal microscopy showed that protein colocalization of PML and RARα was disrupted more significantly by PDTC-ATO treatment than that with ATO monotherapy. CONCLUSION: In conclusion, PDTC enhanced the cytotoxic effect of ATO on APL, and the mechanism was, at least in part, related to the promotion of ATO-induced degradation of PML-RARα fusion protein via forming a complex PDTC-ATO.

Cyclophilin D-induced mitochondrial impairment confers axonal injury after intracerebral hemorrhage in mice.

The mitochondrial permeability transition pore is a nonspecific transmembrane channel. Inhibition of mitochondrial permeability transition pore opening has been shown to alleviate mitochondrial swelling, calcium overload, and axonal degeneration. Cyclophilin D is an important component of the mitochondrial permeability transition pore. Whether cyclophilin D participates in mitochondrial impairment and axonal injury after intracerebral hemorrhage is not clear. In this study, we established mouse models of intracerebral hemorrhage in vivo by injection of autologous blood and oxyhemoglobin into the striatum in Thy1-YFP mice, in which pyramidal neurons and axons express yellow fluorescent protein. We also simulated intracerebral hemorrhage in vitro in PC12 cells using oxyhemoglobin. We found that axonal degeneration in the early stage of intracerebral hemorrhage depended on mitochondrial swelling induced by cyclophilin D activation and mitochondrial permeability transition pore opening. We further investigated the mechanism underlying the role of cyclophilin D in mouse models and PC12 cell models of intracerebral hemorrhage. We found that both cyclosporin A inhibition and short hairpin RNA interference of cyclophilin D reduced mitochondrial permeability transition pore opening and mitochondrial injury. In addition, inhibition of cyclophilin D and mitochondrial permeability transition pore opening protected corticospinal tract integrity and alleviated motor dysfunction caused by intracerebral hemorrhage. Our findings suggest that cyclophilin D is used as a key mediator of axonal degeneration after intracerebral hemorrhage; inhibition of cyclophilin D expression can protect mitochondrial structure and function and further alleviate corticospinal tract injury and motor dysfunction after intracerebral hemorrhage. Our findings provide a therapeutic target for preventing axonal degeneration of white matter injury and subsequent functional impairment in central nervous diseases.