Drug Treatment Attenuates Retinal Ganglion Cell Death by Inhibiting Collapsin Response Mediator Protein 2 Phosphorylation in Mouse Models of Normal Tension Glaucoma.

Normal tension glaucoma (NTG) is a progressive neurodegenerative disease in glaucoma families. Typical glaucoma develops because of increased intraocular pressure (IOP), whereas NTG develops despite normal IOP. As a subtype of open-angle glaucoma, NTG is characterized by retinal ganglion cell (RGC) degeneration, gradual loss of axons, and injury to the optic nerve. The relationship between glutamate excitotoxicity and oxidative stress has elicited great interest in NTG studies. We recently reported that suppressing collapsin response mediator protein 2 (CRMP2) phosphorylation in S522A CRMP2 mutant (CRMP2 KIKI) mice inhibited RGC death in NTG mouse models. This study evaluated the impact of the natural compounds huperzine A (HupA) and naringenin (NAR), which have therapeutic effects against glutamate excitotoxicity and oxidative stress, on inhibiting CMRP2 phosphorylation in mice intravitreally injected with N-methyl-D-aspartate (NMDA) and GLAST mutant mice. Results of the study demonstrated that HupA and NAR significantly reduced RGC degeneration and thinning of the inner retinal layer, and inhibited the elevated CRMP2 phosphorylation. These treatments protected against glutamate excitotoxicity and suppressed oxidative stress, which could provide insight into developing new effective therapeutic strategies for NTG.

Childhood maltreatment and engaging in NSSI for automatic-negative reinforcement: The mediating role of alexithymia and moderating role of help-seeking attitudes.

BACKGROUND: There is evidence indicating that childhood maltreatment is linked to the occurrence of non-suicidal self-injury (NSSI). Nevertheless, the association between childhood maltreatment and the automatic-negative reinforcement aspect of NSSI remains understudied. Chapman's (2006) experiential avoidance model posits that the main factor in sustaining NSSI is negative reinforcement, specifically through the avoidance or escape from distressful emotional experiences. The current study examines a conceptual framework based on this theory and the available literature that explores the potential mediation role of alexithymia in the relation between childhood maltreatment and the automatic-negative reinforcement of NSSI. Additionally, this study investigates how this process may be influenced by individuals' attitudes toward seeking professional help. METHODS: 3657 adolescents (1616 females) completed questionnaires regarding childhood maltreatment, alexithymia, help-seeking attitudes, the NSSI, and its functions. RESULTS: The findings of the study exposed a positive link between childhood maltreatment and the automatic-negative reinforcement of NSSI, with the mediating role of alexithymia. Interestingly, it was unexpected to discover that individuals with high help-seeking attitudes experienced an intensification of the relationship between childhood maltreatment and both alexithymia and the automatic-negative reinforcement of NSSI. LIMITATION: The study's cross-sectional design hindered the inference of causality. CONCLUSION: The present study demonstrated that it is crucial to consider the impact of both alexithymia and help-seeking attitudes in adolescents who have experienced maltreatment. These findings hold implications for preventive interventions that target the reduction of NSSI behaviors driven by automatic-negative reinforcement.

IL-27p28 specifically regulates MHC II expression in macrophages through CIITA.

Antigen-presenting cells (APCs) constantly express major histocompatibility complex II (MHC II), including macrophages and dendritic cells (DCs) which deliver antigens to CD4+ T cells and play an important role in adaptive immunity. The expression of MHC II is controlled by the transcriptional coactivator CIITA. Interleukin-27 (IL-27), a newly discovered IL-12 family cytokine, is composed of p28 and EBI3 subunits. In this study, we used IL-27p28 conditional knock-out mice to investigate the regulatory effects of IL-27p28 on macrophage polarization and the expression of MHC II in macrophages. We found that MHC II expression was upregulated in the bone marrow-derived and peritoneal exudate macrophages (BMDMs; PEMs) from IL-27p28-deficient mice, with their inflammation regulating function unaffected. We also demonstrated that in the APCs, IL-27p28 selectively regulated MHC II expression in macrophages but not in dendritic cells. During Pseudomonas aeruginosa (P. aeruginosa) reinfection, higher survival rate, bacterial clearance, and ratio of CD4+/CD8+ T cells in the spleen during the specific immune phase were observed in IL-27p28 defect mice, as well as an increased MHC II expression in alveolar macrophages (AMs). But these did not occur in the first infection. For the first time we discovered that IL-27p28 specifically regulates the expression of MHC II in macrophages by regulating CIITA, while its absence enhances antigen presentation and adaptive immunity against P. aeruginosa.

A novel fault classification feature extraction method for rolling bearing based on multi-sensor fusion technology and EB-1D-TP encoding algorithm.

To improve the accuracy of bearing fault diagnosis in a multisensor monitoring environment, it is necessary to obtain more accurate and effective fault classification features for bearings. Accordingly, a bearing fault classification feature extraction method based on multisensor fusion technology and an enhanced binary one-dimensional ternary pattern (EB-1D-TP) algorithm were proposed in this study. First, an optimal equalization weighting algorithm was established to realize high-precision fusion of bearing signals by introducing an optimal equalization factor and determining the theoretical optimal equalization factor value. Second, an enhanced binary encoding method similar to balanced ternary encoding was developed, which increases the difference between the different fault features of the bearing. Finally, the new sequence obtained after encoding was used as the input to a support vector machine to classify and diagnose the faults of the rolling bearing. The experimental results show that the algorithm can significantly improve the accuracy and speed of rolling-bearing fault classification. Combining fusion-encoding features with other intelligent classification methods, the classification results were improved.

Cytotoxicity of 4 Wild Mushrooms in a Case of Yunnan Sudden Unexplained Death.

OBJECTIVES: To explore the cytotoxicity of four wild mushrooms involved in a case of Yunnan sudden unexplained death (YNSUD), to provide the experimental basis for prevention and treatment of YNSUD. METHODS: Four kinds of wild mushrooms that were eaten by family members in this YNSUD incident were collected and identified by expert identification and gene sequencing. Raw extracts from four wild mushrooms were extracted by ultrasonic extraction to intervene HEK293 cells, and the mushrooms with obvious cytotoxicity were screened by Cell Counting Kit-8 (CCK-8). The selected wild mushrooms were prepared into three kinds of extracts, which were raw, boiled, and boiled followed by enzymolysis. HEK293 cells were intervened with these three extracts at different concentrations. The cytotoxicity was detected by CCK-8 combined with lactate dehydrogenase (LDH) Assay Kit, and the morphological changes of HEK293 cells were observed under an inverted phase contrast microscope. RESULTS: Species identification indicated that the four wild mushrooms were Butyriboletus roseoflavus, Boletus edulis, Russula virescens and Amanita manginiana. Cytotoxicity was found only in Amanita manginiana. The raw extracts showed cytotoxicity at the mass concentration of 0.1 mg/mL, while the boiled extracts and the boiled followed by enzymolysis extracts showed obvious cytotoxicity at the mass concentration of 0.4 mg/mL and 0.7 mg/mL, respectively. In addition to the obvious decrease in the number of HEK293 cells, the number of synapses increased and the refraction of HEK293 cells was poor after the intervention of Amanita manginiana extracts. CONCLUSIONS: The extracts of Amanita manginiana involved in this YNSUD case has obvious cytotoxicity, and some of its toxicity can be reduced by boiled and enzymolysis, but cannot be completely detoxicated. Therefore, the consumption of Amanita manginiana is potentially dangerous, and it may be one of the causes of the YNSUD.

Engineered Cytokine-Primed Extracellular Vesicles with High PD-L1 Expression Ameliorate Type 1 Diabetes.

Type 1 diabetes (T1D), which is a chronic autoimmune disease, results from the destruction of insulin-producing ß cells targeted by autoreactive T cells. The recent discovery that mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) function as therapeutic tools for autoimmune conditions has attracted substantial attention. However, the in vivo distribution and therapeutic effects of MSC-EVs potentiated by pro-inflammatory cytokines in the context of T1D have yet to be established. Here, it is reported that hexyl 5-aminolevulinate hydrochloride (HAL)-loaded engineered cytokine-primed MSC-EVs (H@TI-EVs) with high expression of immune checkpoint molecule programmed death-legend 1 (PD-L1) exert excellent inflammatory targeting and immunosuppressive effects for T1D imaging and therapy. The accumulated H@TI-EVs in injured pancreas not only enabled the fluorescence imaging and tracking of TI-EVs through the intermediate product protoporphyrin (PpIX) generated by HAL, but also promoted the proliferative and anti-apoptotic effects of islet ß cells. Further analysis revealed that H@TI-EVs exhibited an impressive ability to reduce CD4+ T cell density and activation through the PD-L1/PD-1 axis, and induced M1-to-M2 macrophage transition to reshape the immune microenvironment, exhibiting high therapeutic efficiency in mice with T1D. This work identifies a novel strategy for the imaging and treatment of T1D with great potential for clinical application.

Whole exome sequencing with a focus on cardiac disease-associated genes in families of sudden unexplained deaths in Yunnan, southwest of China.

OBJECTIVES: To explore the causes of sudden unexpected death (SUD) and to search for high-risk people, whole exome sequencing (WES) was performed in families with SUDs.  METHODS: Whole exome sequencing of 25 people from 14 SUD families were screened based on cardiac disease-associated gene variants, and their echocardiograms and electrocardiograms (ECG) were also examined. The protein function of mutated genes was predicted by SIFT, PolyPhen2 and Mutation Assessor. RESULTS: In the group of 25 people from 14 SUD families, 49 single nucleotide variants (SNVs) of cardiac disease-associated genes were found and verified by Sanger sequencing. 29 SNVs of 14 cardiac disorder-related genes were predicted as pathogens by software. Among them, 7 SNVs carried by two or more members were found in 5 families, including SCN5A (c.3577C > T), IRX4 (c.230A > G), LDB3 (c.2104 T > G), MYH6 (c.3G > A), MYH6 (c.3928 T > C), TTN (c.80987C > T) and TTN (c.8069C > T). 25 ECGs were collected. In summary, 4 people had J-point elevation, 2 people had long QT syndrome (LQTS), 4 people had prolonged QT interval, 3 people had T-wave changes, 3 people had sinus tachycardia, 4 people had sinus bradycardia, 4 people had left side of QRS electrical axis, and 3 people had P wave broadening. Echocardiographic results showed that 1 person had atrial septal defect, 1 person had tricuspid regurgitation, and 2 people had left ventricular diastolic dysfunction. CONCLUSIONS: Of the 14 heart disease-associated genes in 14 SUDs families, there are 7 possible pathological SNVS may be associated with SUDs. Our results indicate that people with ECG abnormalities, such as prolonged QT interval, ST segment changes, T-wave change and carrying the above 7 SNVs, should be the focus of prevention of sudden death.

Mesenchymal stem cell-derived extracellular vesicles attenuate tPA-induced blood-brain barrier disruption in murine ischemic stroke models.

Intracerebral hemorrhage following blood-brain barrier (BBB) disruption resulting from thrombolysis of ischemic stroke with tissue plasminogen activator (tPA) remains a critical clinical problem. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) are promising nanotherapeutic agents that have the potential to repair the BBB after ischemic stroke; however, whether they can attenuate BBB disruption and hemorrhagic transformation after tPA thrombolysis is largely unknown. Here, we observed that MSC-EVs efficiently passed through the BBB and selectively accumulated in injured brain regions in ischemic stroke model mice in real time using aggregation-induced emission luminogens (AIEgens), which exhibit better tracking ability than the commercially available tracer DiR. Moreover, tPA administration promoted the homing of MSC-EVs to the ischemic brain and increased the uptake of MSC-EVs by astrocytes. Furthermore, the accumulated MSC-EVs attenuated the tPA-induced disruption of BBB integrity and alleviated hemorrhage by inhibiting astrocyte activation and inflammation. Mechanistically, miR-125b-5p delivered by MSC-EVs played an indispensable role in maintaining BBB integrity by targeting Toll-like receptor 4 (TLR4) and inhibiting nuclear transcription factor-kappaB (NF-κB) signaling in astrocytes. This study provides a noninvasive method for real-time tracking of MSC-EVs in the ischemic brain after tPA treatment and highlights the potential of MSC-EVs as thrombolytic adjuvants for ischemic stroke. STATEMENT OF SIGNIFICANCE: Although tPA thrombolysis is the most effective pharmaceutical strategy for acute ischemic stroke, its clinical application and therapeutic efficacy are challenged by tPA-induced BBB disruption and hemorrhagic transformation. Our study demonstrated that MSC-EVs can act as an attractive thrombolytic adjuvant to repair the BBB and improve thrombolysis in a mouse ischemic stroke model. Notably, by labeling MSC-EVs with AIEgens, we achieved accurate real-time imaging of MSC-EVs in the ischemic brain and therapeutic visualization. MSC-EVs inhibit astrocyte activation and associated inflammation through miR-125b-5p/TLR4/NF-κB pathway. Consequently, we revealed that MSC-EVs combined with tPA thrombolysis may be a promising approach for the treatment of ischemic stroke in clinical setting.

Functional analysis of HADH c.99C>G shows that the variant causes the proliferation of pancreatic islets and leu-sensitive hyperinsulinaemia.

A novel missense variant (NM_005327.7: c.99C>G, p.Ile33Met) was discovered in 3-hydroxyacyl-CoA dehydrogenase (HADH), which is involved in congenital hyperinsulinism (CHI). This variant may be damaging or deleterious, as assessed using protein prediction software. This study aimed at the impact of this variant on islets and if it caused the leu-sensitive insulin secretion. The adenoassociated virus containing the HADH missense variant (p.Ile33Met), wild-type (WT) HADH or empty vector (EV) was constructed, and the rats were infected with it. Three weeks after the transfection, 15 rats were dissected to observe the effect of the variant on the islet tissue. Then we treated the remaining rats with leucine or sodium carboxymethyl cellulose (CMC-Na) by gavage and drew blood from the rat tail vein to detect the variations in blood glucose, serum insulin and serum glucagon. Further, we dissected the rats to observe the fluctuation of insulin and glucagon contents in pancreatic islets under the combined action of leucine and p.Ile33Met. Insulin and glucagon were observed in the islet tissue under an inverted fluorescence microscope, serum insulin and glucagon were detected by ELISA, and the blood glucose value was determined using a Roche glucometer. The positive area and average gray value of islet fluorescence pictures were analysed using the software Image J (USA). Rats expressing p.Ile33Met showed significantly higher insulin and glucagon content, as well as the islet area, compared to WT and EV rats. Moreover, after intragastric administration of leucine, the serum insulin content of the variant rats increased but the blood sugar level decreased significantly. Meanwhile, there was an appreciable decrease in the insulin content in rat pancreatic islet tissues. Our results suggest that the variant NM_005327.7: c.99C>G promotes the proliferation of pancreatic islets, enhances the secretion of insulin, and induces leu-sensitive hyperinsulinaemia.

Macrophage-Membrane-Camouflaged Nonviral Gene Vectors for the Treatment of Multidrug-Resistant Bacterial Sepsis.

Sepsis is a life-threatening disease caused by systemic bacterial infections, with high morbidity and mortality worldwide. As the standard treatment for sepsis, antibiotic therapy faces the challenge of impaired macrophages and drug-resistant bacteria. In this study, we developed a membrane-camouflaged metal-organic framework (MOF) system for plasmid DNA (pDNA) delivery to combat sepsis. The antimicrobial gene LL37 was efficiently encapsulated in the pH-sensitive MOF, and the nanoparticles were decorated with macrophage membranes in a compatible manner. Macrophage membrane coating allows targeted delivery of LL37 to macrophages and creates macrophage factories for the continuous generation of antimicrobial peptides. Compared to naked nanoparticles, primary bone marrow mesenchymal macrophage membrane-modified nanoparticles greatly improved the survival rate of immunodeficient septic mice through the synergistic effect of efficient gene therapy and inflammatory cytokine sequestration. This study demonstrates an effective membrane biomimetic strategy for efficiently delivering pDNA, offering an excellent option for overcoming sepsis.

Biosynthetic Dendritic Cell-Exocytosed Aggregation-Induced Emission Nanoparticles for Synergistic Photodynamic Immunotherapy.

Dendritic cell (DC)-derived small extracellular vesicles (DEVs) are recognized as a highly promising alternative to DC vaccines; however, the clinical testing of DEV-based immunotherapy has shown limited therapeutic efficacy. Herein, we develop a straightforward strategy in which DCs serve as a cell reactor to exocytose high-efficient DEV-mimicking aggregation-induced emission (AIE) nanoparticles (DEV-AIE NPs) at a scaled-up yield for synergistic photodynamic immunotherapy. Exocytosed DEV-AIE NPs inherit not only the immune-modulation proteins from parental DCs, enabling T cell activation, but also the loaded AIE-photosensitizer MBPN-TCyP, inducing superior immunogenic cell death (ICD) by selectively accumulating in the mitochondria of tumor cells. Eventually, DEV-AIE synergistic photodynamic immunotherapy elicits dramatic immune responses and efficient eradication of primary tumors, distant tumors, and tumor metastases. In addition, cancer stem cells (CSCs) in 4T1 and CT26 solid tumors were significantly inhibited by the immune functional DEV-AIE NPs. Our work presents a facile method for the cellular generation of EV-biomimetic NPs and demonstrates that the integration of DEVs and AIE photosensitizers is a powerful direction for the production of clinical anticancer nanovaccines.

The efficacy of low-power cumulative high-intensity focused ultrasound treatment for recurrent desmoid tumor.

BACKGROUND: Desmoid tumors are rare neoplasms that are locally invasive. However, optimal treatment strategies for recurrent desmoid tumors remain controversial. High-intensity focused ultrasound (HIFU) has been reported as a noninvasive modality for treating recurrent desmoid tumors. However, its efficacy against massive desmoid tumors or those with complex anatomies remains unclear. METHODS: We developed a new therapeutic strategy called low-power cumulative HIFU and applied it to treat recurrent desmoid tumors. RESULTS: We retrospectively collected data from 91 patients with recurrent desmoid tumors who underwent low-power cumulative HIFU treatment after surgical treatment failure. The mean ablation proportion of the HIFU treatment was 69.5%, and the objective response rate was 47.3%. The 5-year estimated progression-free survival rate for these patients was 69.3%. CONCLUSION: Low-power cumulative HIFU treatment could achieve significant efficacy and long-term control of recurrent desmoid tumors.

Construction of an Interfacial Photocatalytic Mode Based on Carbonized Mushrooms to Enhance Infrared Light-Assisted Photocatalytic Water Splitting Performance.

To find a more efficient way to generate photocatalytic hydrogen, we developed the interfacial photocatalytic mode, in which the photocatalytic reaction can be transferred to a high-energy interfacial area. The new interfacial mode in this work is assembled with the help of carbonized mushrooms, which is an ideal water transporter as well as an excellent photothermal converter. The higher temperature from efficient light-to-heat conversion performance and thermal localization promote the efficiency of hydrogen evolution, and some effects peculiar to the interfacial mode can make the departure of hydrogen from the active sites of the photocatalyst smoother. As a result, the active sites can be exposed in a timely manner to allow the progress of the next cycle of the photocatalytic reaction to be smoother. The efficiency of interfacial photocatalytic hydrogen production can reach >10 times that of the corresponding sample in the traditional bulk water mode. This work has allowed further exploration of the construction of the interfacial photocatalytic mode, provided a reliable experimental basis for the development of the interfacial mode, and illuminated a new path for the development of photocatalytic water splitting.

Coassembly of hypoxia-sensitive macrocyclic amphiphiles and extracellular vesicles for targeted kidney injury imaging and therapy.

BACKGROUND: Hypoxia is a major contributor to global kidney diseases. Targeting hypoxia is a promising therapeutic option against both acute kidney injury and chronic kidney disease; however, an effective strategy that can achieve simultaneous targeted kidney hypoxia imaging and therapy has yet to be established. Herein, we fabricated a unique nano-sized hypoxia-sensitive coassembly (Pc/C5A@EVs) via molecular recognition and self-assembly, which is composed of the macrocyclic amphiphile C5A, the commercial dye sulfonated aluminum phthalocyanine (Pc) and mesenchymal stem cell-excreted extracellular vesicles (MSC-EVs). RESULTS: In murine models of unilateral or bilateral ischemia/reperfusion injury, MSC-EVs protected the Pc/C5A complex from immune metabolism, prolonged the circulation time of the complex, and specifically led Pc/C5A to hypoxic kidneys via surface integrin receptor α4ß1 and αLß2, where Pc/C5A released the near-infrared fluorescence of Pc and achieved enhanced hypoxia-sensitive imaging. Meanwhile, the coassembly significantly recovered kidney function by attenuating cell apoptosis, inhibiting the progression of renal fibrosis and reducing tubulointerstitial inflammation. Mechanistically, the Pc/C5A coassembly induced M1-to-M2 macrophage transition by inhibiting the HIF-1α expression in hypoxic renal tubular epithelial cells (TECs) and downstream NF-κB signaling pathway to exert their regenerative effects. CONCLUSION: This synergetic nanoscale coassembly with great translational potential provides a novel strategy for precise kidney hypoxia diagnosis and efficient kidney injury treatment. Furthermore, our strategy of coassembling exogenous macrocyclic receptors with endogenous cell-derived membranous structures may offer a functional platform to address multiple clinical needs.

Mesoporous N-P Codoped Carbon Nanosheets as Superior Cathodic Catalysts of Neutral Metal-Air Batteries.

Development of high-efficiency oxygen reduction reaction (ORR) catalysts under neutral conditions has made little research progress. In this work, we synthesized a three-dimensional porous N/P codoped carbon nanosheet composites (CNP@PNS) by high-temperature thermal treatment of dicyandiamide, starch, and triphenylphosphine and subsequent porous structure-making treatment using the NaCl molten salt template. In the neutral solution, the electrocatalytic performance of the CNP@PNS-4 catalyst exhibits an onset potential of 0.98 V (vs reversible hydrogen electrode) and a half-wave potential of 0.91 V for ORR, which greatly surpasses commercial Pt/C (40%). Three kinds of neutral metal-air batteries (Zn-air, Al-air, and Fe-air) using the prepared samples as cathodic catalysts were constructed, corresponding to the maximum power density of 120.2, 78.3, and 18.9 mW·cm-2, respectively. Also, they reveal outstanding discharge stability under different current densities. The density functional theory calculation depicts the reduction of the free energy of the determining step and subsequent decline of the overpotential for ORR.

CoNi Nanoparticles Supported on N-Doped Bifunctional Hollow Carbon Composites as High-Performance ORR/OER Catalysts for Rechargeable Zn-Air Batteries.

Searching for high-quality air electrode catalysts is the long-term goal for the practical application of Zn-air batteries. Here, a series of coexistent composite materials (CoNi/NHCS-TUC-x) of cobalt-nickel supported on nitrogen-doped hollow spherical carbon and tubular carbon are obtained using a simple pyrolysis strategy. Co and Ni in the composites are mainly present in the form of alloy nanoparticles, M-Nx and M-Cx (M = Co or Ni) species, with high oxygen reduction reaction (ORR)/oxygen evolution reaction (OER) electroactivity. The materials containing different proportions of spherical carbon and tubular carbon obtained by simply adjusting the raw materials for generating tubular carbon exhibit interesting bifunctional performance: samples with an abundant tubular content have the highest ORR onset potential (0.91 V vs reversible hydrogen electrode), while those with a rich spherical content have the highest ORR current density (5.13 mA·cm-2). Furthermore, CoNi/NHCS-TUC-3 provides the lowest potential difference (ΔE = Ej=10 - E1/2) of 0.806 V. We then test the potential possibility of CoNi/NHCS-TUC-3 as an air electrode for primary and rechargeable Zn-air batteries. The primary battery delivers an open-circuit potential of 1.59 V, a peak power density of 361.8 mA·cm-2, and a specific capacity of 756.5 mA h·gZn-1. The rechargeable battery could be cycled stably for more than 55 h at 10 mA·cm-2. These characteristics make CoNi/NHCS-TUC-3 a superior electrocatalyst for both the ORR and OER, as well as a suitable bifunctional electrode applied to a rechargeable Zn-air battery.

Differential Responses of Transplanted Stem Cells to Diseased Environment Unveiled by a Molecular NIR-II Cell Tracker.

Stem cell therapy holds high promises in regenerative medicine. The major challenge of clinical translation is to precisely and quantitatively evaluate the in vivo cell distribution, migration, and engraftment, which cannot be easily achieved by current techniques. To address this issue, for the first time, we have developed a molecular cell tracker with a strong fluorescence signal in the second near-infrared (NIR-II) window (1,000-1,700 nm) for real-time monitoring of in vivo cell behaviors in both healthy and diseased animal models. The NIR-II tracker (CelTrac1000) has shown complete cell labeling with low cytotoxicity and profound long-term tracking ability for 30 days in high spatiotemporal resolution for semiquantification of the biodistribution of transplanted stem cells. Taking advantage of the unique merits of CelTrac1000, the responses of transplanted stem cells to different diseased environments have been discriminated and unveiled. Furthermore, we also demonstrate CelTrac1000 as a universal and effective technique for ultrafast real-time tracking of the cellular migration and distribution in a 100 µm single-cell cluster spatial resolution, along with the lung contraction and heart beating. As such, this NIR-II tracker will shift the optical cell tracking into a single-cell cluster and millisecond temporal resolution for better evaluating and understanding stem cell therapy, affording optimal doses and efficacy.

Smart Self-Assembly Amphiphilic Cyclopeptide-Dye for Near-Infrared Window-II Imaging.

Development of novel nanomaterials for disease theranostics represents an important direction in chemistry and precision medicine. Fluorescent molecular probes in the second near-infrared window (NIR-II, 1000-1700 nm) show high promise because of their exceptional high detection sensitivity, resolution, and deep imaging depth. Here, a sharp pH-sensitive self-assembling cyclopeptide-dye, SIMM1000, as a smart nanoprobe for NIR-II imaging of diseases in living animals, is reported. This small molecule assembled nanoprobe exhibits smart properties by responding to a sharp decrease of pH in the tumor microenvironment (pH 7.0 to 6.8), aggregating from small nanoprobe (80 nm at pH 7.0) into large nanoparticles (>500 nm at pH 6.8) with ≈20-30 times enhanced fluorescence compared with the non-self-assembled CH-4T. It yields micrometer-scale resolution in blood vessel imaging and high contrast and resolution in bone and tumor imaging in mice. Because of its self-aggregation in acidic tumor microenvironments in situ, SIMM1000 exhibits high tumor accumulation and extremely long tumor retention (>19 days), while being excretable from normal tissues and safe. This smart self-assembling small molecule strategy can shift the paradigm of designing new nanomaterials for molecular imaging and drug development.

The efficacy of a new high-intensity focused ultrasound therapy for metastatic pancreatic cancer.

PURPOSE: To compare the survival benefit, pain control and safety of low-power cumulative and traditional high-intensity focused ultrasound (HIFU) for metastatic pancreatic cancer. METHOD: We retrospectively analyzed 55 patients with metastatic pancreatic cancer who received HIFU treatment between January 2008 and April 2014 in our department. 23 patients received low-power cumulative HIFU treatment (L group), 32 received the traditional HIFU treatment (T group). Performance status, cancer-related pain and serum biochemistry results were assessed before and after treatment. All patients were followed up until death. The survival rate and adverse events of the two groups were compared. RESULTS: The baseline characteristics of the two groups were generally well balanced (p > 0.05). The average KPS score after treatment was significantly improved in both groups compared with the baseline score. 36 patients exhibited tumor-related pain at baseline. The pain response rate was significantly higher in the L group (92.3%) than in the T group (52.2%) (p = 0.025). The median overall survival (OS) for the L group was 7.0 months, which was significantly longer than that of the T group (p = 0.000). The 3-month and 6-month survival rates were higher in the L group. The adverse events in both groups included abdominal pain, elevated C-reactive protein (CRP) and elevated amylase. The incidence was lower in the L group than in the T group. CONCLUSION: Compared with traditional HIFU treatment, low-power cumulative HIFU treatment showed a significantly higher pain relief rate and survival benefit with a better safety profile in patients with metastatic pancreatic cancer.

Impacts of Local Effects and Surface Loads on the Common Mode Error Filtering in Continuous GPS Measurements in the Northwest of Yunnan Province, China.

While seasonal hydrological mass loading, derived from Gravity Recovery and Climate Experiment (GRACE) measurements, shows coherent spatial patterns and is an important source for the common mode error (CME) in continuous global positioning system (cGPS) measurements in Yunnan, it is a challenge to quantify local effects and detailed changes in daily GPS measurements by using GRACE data due to its low time and spatial resolutions. In this study, we computed and compared two groups of CMEs for nine cGPS sites in the northwest Yunnan province; rCMEs were computed with the residual cGPS time series having high inter-station correlations, while oCMEs were computed with all the GPS time series. The rCMEs-filtered time series had smaller variances and larger root mean square (RMS) reductions than those that were oCMEs-filtered, and when the stations local effects were not removed, spurious transient-like signals occurred. Compared with hydrological mass loading (HYDL), its combination with non-tidal atmosphere pressure and ocean mass reached a better agreement with the CME in the vertical component, with the Nash-Sutcliffe efficiency (NSE) increasing from 0.28 to 0.55 and the RMS reduction increasing from 15.19% to 33.4%, respectively. Our results suggest that it is necessary to evaluate the inter-station correlation and remove the possible noisy stations before conducting CME filtering, and that one should carefully choose surface loading models to correct the raw cGPS time series if CME filtering is not conducted.