Heterojunction polarization enhancement and shielding for AlGaN-based solar-blind ultraviolet avalanche detectors.

AlGaN-based solar-blind ultraviolet avalanche detectors have huge potentials in the fields of corona discharge monitoring, biological imaging, etc. Here, we study the impact of the heterojunction polarization-related effects on the AlGaN-based solar-blind ultraviolet avalanche detectors. Our work confirms that the polarization heterojunction is beneficial to reducing avalanche bias and lifting avalanche gain by improving the electric field in the depletion region, while the polarization-induced fixed charges will lead to a redistribution of the electrons, in turn shielding the charges and weakening the electric field enhancement effect. This shielding effect will need external bias to eliminate, and that is why the polarization heterojunction cannot work at relatively low bias but has an enhancement effect at high bias. Controlling the doping level between the hetero-interface can affect the shielding effect. An unintentionally doped polarization heterojunction can effectively reduce the shielding effect, thus reducing the avalanche bias. The conclusions also hold true for the negative polarization regime. We believe our findings can provide some useful insights for the design of the AlGaN-based solar-blind ultraviolet detectors.

FYB1-targeted modulation of CAPG promotes AML progression.

Acute myeloid leukemia (AML) is a rare and heterogeneous disease. Over the past few decades, patient prognosis has improved with continuous improvements in treatment, but outcomes for some patients with primary drug resistance or relapse after treatment remain poor. Additional therapies to improve outcomes for these patients are urgently needed. FYB1 expression differs substantially between AML tissues and normal tissues. High FYB1 expression is correlated with poorer overall survival (OS), indicating that FYB1 may regulate AML progression. Therefore, understanding the effect of FYB1 on AML could improve the success rate of therapeutic approaches and prognosis for patients with AML. In this study, through analysis of large databases and both in vivo and in vitro experiments, we assessed the expression and role of FYB1 in AML and the relationship of FYB with patient prognosis. Downstream targets of the FYB1 gene were analyzed by RNA-seq. Database mining and in vitro experiments were used to further clarify the effect of the downstream target gelsolin-like actin-capping protein (CAPG) on AML cells and its relationship with patient prognosis. FYB1 expression was significantly higher in AML tissue and corresponded with a poor prognosis. FYB1 knockdown inhibited AML cell proliferation, promoted cell apoptosis, reduced cell adhesion capability and significantly reduced the tumor formation rate in mice. In addition, FYB1 knockdown induced a notable decrease in CAPG expression. The suppression of CAPG significantly inhibited cell proliferation and increased cell apoptosis. The conclusions of this study underscore the pivotal role of the FYB1/CAPG axis in promoting AML. We propose that the FYB1/CAPG axis could serve as a new thread in the development of therapeutic strategies for AML.

Multicomponent reactions to access S-aryl dithiocarbamates via an electron donor-acceptor complex under open-to-air conditions.

A simple and efficient transition-metal/photocatalyst-free visible-light-driven one-pot three-component reaction between thianthrenium salts, carbon disulfide and amines under an air atmosphere for the preparation of biologically relevant S-aryl dithiocarbamates is developed. This methodology is robust and scalable, and exhibits a broad substrate scope and excellent functional group tolerance. Of note, a wide range of primary aliphatic amines bearing different groups are suitable for this strategy. The synthetic utility was further demonstrated by a two-step one-pot multi-component reaction and photo-flow decagram-scale synthesis. Preliminary mechanistic studies suggest that the association of the dithiocarbamate anion with thianthrenium salts formed an electron donor-acceptor complex, which upon excitation with visible light produced an aryl radical via single-electron transfer.

Potent, Gut-Restricted Inhibitors of Divalent Metal Transporter 1: Preclinical Efficacy against Iron Overload and Safety Evaluation.

Divalent metal transporter 1 (DMT1) cotransports ferrous iron and protons and is the primary mechanism for uptake of nonheme iron by enterocytes. Inhibitors are potentially useful as therapeutic agents to treat iron overload disorders such as hereditary hemochromatosis or ß-thalassemia intermedia, provided that inhibition can be restricted to the duodenum. We used a calcein quench assay to identify human DMT1 inhibitors. Dimeric compounds were made to generate more potent compounds with low systemic exposure. Direct block of DMT1 was confirmed by voltage clamp measurements. The lead compound, XEN602, strongly inhibits dietary nonheme iron uptake in both rats and pigs yet has negligible systemic exposure. Efficacy is maintained for >2 weeks in a rat subchronic dosing assay. Doses that lowered iron content in the spleen and liver by >50% had no effect on the tissue content of other divalent cations except for cobalt. XEN602 represents a powerful pharmacological tool for understanding the physiologic function of DMT1 in the gut. SIGNIFICANCE STATEMENT: This report introduces methodology to develop potent, gut-restricted inhibitors of divalent metal transporter 1 (DMT1) and identifies XEN602 as a suitable compound for in vivo studies. We also report novel animal models to quantify the inhibition of dietary uptake of iron in both rodents and pigs. This research shows that inhibition of DMT1 is a promising means to treat iron overload disorders.

Role of the cAMP-PKA-NF-κB pathway in Mucin1 over-expression in A549 cells during Respiratory syncytial virus infection.

Respiratory syncytial virus (RSV) is the most common pathogen associated with acute lower respiratory tract infections in infants and young children worldwide. RSV commonly presents as bronchiolitis in young children; however, it can sometimes progress to pneumonia, respiratory failure, apnoea and even death. Although mucin1 (MUC1), a type of transmembrane glycoprotein present on airway epithelial surfaces, plays a crucial anti-inflammatory role in airway infections; however, its roles in RSV-associated acute lower respiratory tract infections have rarely been explored. In this study, we first revealed very high MUC1 protein levels in the exacerbation phase in sputum samples from children with RSV bronchiolitis. Because MUC1 is the downstream target of tumour necrosis factor-alpha (TNF-α) in RSV-infected A549 cells, we observed the inhibition of NF-κB activity, main downstream signalling of TNF-α and remarkably reduced levels of MUC1 in RSV-infected and TNF-α treated A549 cells. Furthermore, the cyclic adenosine monophosphate (cAMP) analogue (dbcAMP) downregulated the protein levels of p-IκBα and MUC1 in TNF-α-treated A549 cells. By contrast, a protein kinase A inhibitor (KT5720) up-regulated the levels of those proteins. dbcAMP and KT5720 had the same effects on MUC1 protein levels in RSV-infected A549 cells. In conclusion, we found that the cAMP-PKA-NF-κB pathway may play a role in the regulation of MUC-1 over-expression during RSV infection.

Mycobacterium abscessus pulmonary disease presenting with spontaneous pneumomediastinum and subcutaneous emphysema in childhood acute lymphoblastic leukemia: a case report and literature review.

INTRODUCTION: Mycobacterium abscessus is a rapidly growing mycobacterium commonly identified in adults with underlying pulmonary diseases but is rarely observed in children. A better understanding of this pathogen in children is essential. CASE PRESENTATION: We report the case of a 49-month-old female child without previous underlying pulmonary diseases but with acute lymphoblastic leukemia (ALL). The patient was complicated with pneumonia during chemotherapy, which was primarily characterized by spontaneous pneumomediastinum and subcutaneous emphysema on chest computed tomography (CT). M. abscessus sequences were detected by metagenomic next-generation sequencing in bronchoalveolar lavage fluid. With mechanical ventilation, closed thoracic drainage, and anti-infective therapy for 6 months, the patient's infection was controlled. The patient completed 2.5 years of treatment for ALL, and the drugs were discontinued. The patient currently remains in complete hematologic remission. DISCUSSION: We reviewed the literature on 33 children with M. abscessus pulmonary disease. These children mostly had underlying immunodeficiency. Chest CT most often showed nodular shadows, consolidation, and bronchiectasis. Spontaneous pneumomediastinum and subcutaneous emphysema were not reported as major manifestations. CONCLUSION: Spontaneous pneumomediastinum and subcutaneous emphysema were our patient's main characteristics on chest CT, and this study enriches the knowledge regarding possible imaging changes in M. abscessus pulmonary disease in children. This case report reflects good clinical experience in maintaining the balance between chemotherapy and anti-infective therapy in childhood ALL.

Efficacy and safety of direct-acting antiviral therapies and baseline predictors for treatment outcomes in hepatitis C patients: A multicenter, real-world study in Guangdong, China.

The data on direct-acting antivirals (DAAs) in chronic hepatitis C (CHC) patients in southern China with multiple genotypes circulating are limited. This study aims to evaluate the efficacy and safety of DAA regimens among CHC patients in Guangdong, China. A total of 220 patients receiving a variety of DAA were enrolled. The primary outcome was sustained virologic response (SVR) at 12 weeks. Resistance associated substitutions (RASs) were evaluated by deep sequencing. The overall SVR rate was 96.4%, and was 97.7% for genotype 1, 100% for genotype 2, 91.9% for genotype 3, 95.7% for genotype 6, and 100% for untyped. The overall incidence of adverse events (AEs) was 8.2% (18/220) and all the AEs were mild. Nonstructural proteins 5A RAS, 30K/31M, and Y93H were most prevalent at baseline and the end of treatment in non-SVR patients, respectively. Logistics regression showed that elevated alanine aminotransferase (ALT) and aspartate aminotransferase (AST) at baseline were specifically associated with non-SVR in patients with genotype 3 and 6 infections (p = 0.029 and p = 0.017) but not genotype 1 infection (p = 0.746 and p = 0.971), and baseline AST was the best predictor for SVR in genotypes 3 and 6 patients (area under curve = 0.890). Our studies demonstrated all DAA regimens achieved ideal SVR and were well tolerated. NS5A RAS were prevalent in non-SVR patients. Elevated ALT and AST as baseline predictors for non-SVR in genotypes 3 and 6 infections warrant further research in a larger cohort.

The URL1-ROC5-TPL2 transcriptional repressor complex represses the ACL1 gene to modulate leaf rolling in rice.

Moderate leaf rolling is beneficial for leaf erectness and compact plant architecture. However, our understanding regarding the molecular mechanisms of leaf rolling is still limited. Here, we characterized a semi-dominant rice (Oryza sativa L.) mutant upward rolled leaf 1 (Url1) showing adaxially rolled leaves due to a decrease in the number and size of bulliform cells. Map-based cloning revealed that URL1 encodes the homeodomain-leucine zipper (HD-Zip) IV family member RICE OUTERMOST CELL-SPECIFIC 8 (ROC8). A single-base substitution in one of the two conserved complementary motifs unique to the 3'-untranslated region of this family enhanced URL1 mRNA stability and abundance in the Url1 mutant. URL1 (UPWARD ROLLED LEAF1) contains an ethylene-responsive element binding factor-associated amphiphilic repression motif and functions as a transcriptional repressor via interaction with the TOPLESS co-repressor OsTPL2. Rather than homodimerizing, URL1 heterodimerizes with another HD-ZIP IV member ROC5. URL1 could bind directly to the promoter and suppress the expression of abaxially curled leaf 1 (ACL1), a positive regulator of bulliform cell development. Knockout of OsTPL2 or ROC5 or overexpression of ACL1 in the Url1 mutant partially suppressed the leaf-rolling phenotype. Our results reveal a regulatory network whereby a transcriptional repression complex composed of URL1, ROC5, and the transcriptional corepressor TPL2 suppresses the expression of the ACL1 gene, thus modulating bulliform cell development and leaf rolling in rice.

Association between detectable SARS-COV-2 RNA in anal swabs and disease severity in patients with coronavirus disease 2019.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA was found in the intestines and feces, but its clinical significance is not completely clear. We aim to characterize the longitudinal test results of SARS-CoV-2 RNA in anal swabs and to explore the association with disease severity. METHODS: We included laboratory-confirmed coronavirus disease 2019 (COVID-19) patients, who were hospitalized in Guangzhou Eighth People's Hospital and excluded those who had not received anal swabs for SARS-COV-2 RNA testing. Epidemiological, clinical, and laboratory data were obtained. Throat swabs and anal swabs were collected periodically for SARS-COV-2 RNA detection. RESULTS: Two hundred and seventeen eligible patients (median aged 50 years, 50.2% were females) were analyzed. 21.2% (46/217) of the patients were detected with SARS-CoV-2 RNA in anal swabs. The duration of viral RNA was longer, but the viral load was lower in anal swabs than throat swabs in the early stage of the disease. During a median follow-up of 20 days, 30 (13.8%) patients were admitted to the intensive care unit (ICU) for high-flow nasal cannula or higher-level oxygen support measures to correct hypoxemia. Detectable viral RNA in anal swabs (adjusted hazard ratio [aHR], 2.50; 95% confidence interval [CI], 1.20-5.24), increased C-reactive protein (aHR, 3.14; 95% CI, 1.35-7.32) and lymphocytopenia (aHR, 3.12; 95% CI, 1.46-6.67) were independently associated with ICU admission. The cumulative incidence of ICU admission was higher among patients with detectable viral RNA in anal swabs (26.3% vs 10.7%, P = .006). CONCLUSION: Detectable SARS-CoV-2 RNA in the digestive tract was a potential warning indicator of severe disease.

Identification of aryl sulfonamides as novel and potent inhibitors of NaV1.5.

We describe the synthesis and biological evaluation of a series of novel aryl sulfonamides that exhibit potent inhibition of NaV1.5. Unlike local anesthetics that are currently used for treatment of Long QT Syndrome 3 (LQT-3), the most potent compound (-)-6 in this series shows high selectivity over hERG and other cardiac ion channels and has a low brain to plasma ratio to minimize CNS side effects. Compound (-)-6 is also effective inshortening prolonged action potential durations (APDs) in a pharmacological model of LQT-3 syndrome in pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). Unlike most aryl sulfonamide NaV inhibitors that bind to the channel voltage sensors, these NaV1.5 inhibitors bind to the local anesthetic binding site in the central pore of the channel.

Two novel mutations in TCIRG1 induced infantile malignant osteopetrosis: a case report.

BACKGROUND: Infantile malignant osteopetrosis (IMO) is a rare autosomal recessive disease characterized by a higher bone density in bone marrow caused by the dysfunction of bone resorption. Clinically, IMO can be diagnosed with medical examination, bone mineral density test and whole genome sequencing. CASE PRESENTATION: We present the case of a 4-month-old male infant with abnormal skull development, hypocalcemia and premature closure of the cranial sutures. Due to the hyper bone density showed by his radiographic examination, which are characteristic patterns of IMO, we speculated that he might be an IMO patient. In order to confirm this diagnosis, a high-precision whole exome sequencing of the infant and his parents was performed. The analysis of high-precision whole exome sequencing results lead to the identification of two novel heterozygous mutations c.504-1G > C (a splicing site mutation) and c.1371delC (p.G458Afs*70, a frameshift mutation) in gene TCIRG1 derived from his parents. Therefore, we propose that there is a close association between these two mutations and the onset of IMO. CONCLUSIONS: To date, these two novel mutations in gene TCIRG1 have not been reported in the reference gene database of Chinese population. These variants have likewise not been reported outside of China in the Genome Aggregation Database (gnomAD). Our case suggests that the use of whole exome sequencing to detect these two mutations will improve the identification and early diagnosis of IMO, and more specifically, the identification of homozygous individuals with TCIRG1 gene mutation. We propose that these mutations in gene TCIRG1 could be a novel therapeutic target for the IMO in the future.

Characteristics of Blood Transfusion During Induction Remission in Children With Acute Lymphoblastic Leukemia: A Single-Center Retrospective Investigation.

OBJECTIVE: To investigate the allogeneic blood transfusion (ABT) characteristics of children with acute lymphoblastic leukemia (ALL) in different risk stratification during vincristine, daunorubicin, L-asparaginase and prednisone (VDLP) induction remission. SUBJECTS AND METHODS: By referring to electronic medical records, the demographic characteristics, diagnosis, test, and treatment information including ABT were collected. According to the risk stratification of the CCCG-ALL-2015 protocol, ABTs between groups were compared, and the differences were statistically analyzed. RESULTS: One hundred sixty-three newly treated children with ALL were enrolled in this study, who received 643.5 U of red blood cells and 377.6 U of platelets (PLTs) during the VDLP. The amount of ABT in the intermediate-risk (IR) group (n=102) was significantly higher than that in the low-risk group (n=61), which were reflected in the red blood cells in the first half of VDLP (P=0.033) and the PLTs in the second half of VDLP (P<0.001). Meanwhile, the PLT counts in the IR group were significantly lower in the same period. The time node was bounded by the minimal residual disease test on the 19th day. CONCLUSIONS: Children in the IR group or with unsatisfactory induction may need more ABTs during the VDLP, and the relatively low PLT counts seem to contribute to this. The results of this study can provide a basis for patient blood management, as well as a reference for studying the long-term effects of ABT on children with ALL.

HpoR, a novel c-di-GMP effective transcription factor, links the second messenger's regulatory function to the mycobacterial antioxidant defense.

Cyclic di-GMP (c-di-GMP) is a global signaling molecule that widely modulates diverse cellular processes. However, whether or not the c-di-GMP signal participates in regulation of bacterial antioxidant defense is unclear, and the involved regulators remain to be explored. In this study, we characterized HpoR as a novel c-di-GMP effective transcription factor and found a link between the c-di-GMP signal and the antioxidant regulation in Mycobacterium smegmatis. H2O2 stress induces c-di-GMP accumulation in M. smegmatis. High level of c-di-GMP triggers expression of a redox gene cluster, designated as hpoR operon, which is required for the mycobacterial H2O2 resistance. HpoR acts as an inhibitor of the hpoR operon and recognizes a 12-bp motif sequence within the upstream regulatory region of the operon. c-di-GMP specifically binds with HpoR at a ratio of 1:1. Low concentrations of c-di-GMP stimulate the DNA-binding activity of HpoR, whereas high concentrations of the signal molecule inhibit the activity. Strikingly, high level of c-di-GMP de-represses the intracellular association of HpoR with the regulatory region of the hpoR operon in M. smegmatis and enhances the mycobacterial H2O2 resistance. Therefore, we report a novel c-di-GMP effective regulator in mycobacteria, which extends the second messenger's function to bacterial antioxidant defense.

Cyclic di-GMP integrates functionally divergent transcription factors into a regulation pathway for antioxidant defense.

Cyclic diguanylate monophosphate (c-di-GMP) is a global signaling molecule that modulates diverse cellular processes through its downstream receptors. However, no study has fully clarified the mechanisms by which c-di-GMP organizes functionally divergent regulators to drive the gene expression for coping with environmental stress. Here, we reported that c-di-GMP can integrate two functionally opposite receptor transcription factors, namely, LtmA and HpoR, into a pathway to regulate the antioxidant processes in Mycobacterium smegmatis. In contrast to HpoR, LtmA is an activator that positively regulates the expression of redox gene clusters and the mycobacterial H2O2 resistance. LtmA can physically interact with HpoR. A high level of c-di-GMP stimulates the positive regulation of LtmA and boosts the physical interaction between the two regulators, further enhancing the DNA-binding ability of LtmA and reducing the inhibitory activity of HpoR. Therefore, upon exposure to oxidative stress, c-di-GMP can orchestrate functionally divergent transcription factors to trigger antioxidant defense in mycobacteria. This finding presents a noteworthy example of how a bacterium remodels its transcriptional network via c-di-GMP in response to environmental stress.

Three-dimensional manipulation of single cells using surface acoustic waves.

The ability of surface acoustic waves to trap and manipulate micrometer-scale particles and biological cells has led to many applications involving "acoustic tweezers" in biology, chemistry, engineering, and medicine. Here, we present 3D acoustic tweezers, which use surface acoustic waves to create 3D trapping nodes for the capture and manipulation of microparticles and cells along three mutually orthogonal axes. In this method, we use standing-wave phase shifts to move particles or cells in-plane, whereas the amplitude of acoustic vibrations is used to control particle motion along an orthogonal plane. We demonstrate, through controlled experiments guided by simulations, how acoustic vibrations result in micromanipulations in a microfluidic chamber by invoking physical principles that underlie the formation and regulation of complex, volumetric trapping nodes of particles and biological cells. We further show how 3D acoustic tweezers can be used to pick up, translate, and print single cells and cell assemblies to create 2D and 3D structures in a precise, noninvasive, label-free, and contact-free manner.

A Novel Human Pegivirus, HPgV-2 (HHpgV-1), Is Tightly Associated With Hepatitis C Virus (HCV) Infection and HCV/Human Immunodeficiency Virus Type 1 Coinfection.

Background: Human pegivirus type 2 (HPgV-2) is a novel blood-borne human pegivirus that mainly infects hepatitis C virus (HCV)-infected subjects. We have investigated the prevalence of HPgV-2 in China, its association with HCV and human immunodeficiency virus type 1 (HIV-1), and the impact on HCV viral load and liver damage. Methods: A cross-sectional study was conducted with both blood donors and HCV- and HIV-1-infected patients in Guangzhou, China. All subjects were screened for anti-HPgV-2 and HPgV-2 RNA. Demographic and clinical information were obtained from electronic medical records. Results: We tested 8198 serum or plasma samples. Only 0.15% (6/4017) of healthy blood donors were positive for anti-HPgV-2 and negative for HPgV-2 RNA. No HPgV-2 viremia was detected in hepatitis B virus- or HIV-1-monoinfected individuals. The relatively high frequency of HPgV-2 infection was observed in 1.23% (30/2440) and 0.29% (7/2440) of HCV-infected persons by serological assay and reverse-transcription polymerase chain reaction, respectively. Furthermore, anti-HPgV-2 and HPgV-2 RNA were detected in 8.91% (18/202) and 3.47% (7/202), respectively, of HCV/HIV-1-coinfected subjects. HPgV-2 persistent infection was documented in about 30% of anti-HPgV-2-positive individuals. In addition, HPgV-2 infection may not affect HCV-related liver injury and HCV viral load. Conclusions: Our results indicate the rarity of HPgV-2 infection in the general population and tight association with HCV, in particular with HCV/HIV-1 coinfection. HPgV-2 appears not to worsen HCV-related liver damage. Our study provides new findings about the association of HPgV-2 and HCV/HIV-1 and the impact of HPgV-2 infection on HCV replication and pathogenesis.

A novel predictor of severe dengue: The aspartate aminotransferase/platelet count ratio index (APRI).

To evaluate risk factors for the development of dengue into severe dengue in Guangdong. A retrospective analysis of clinical data from 212 dengue patients between June and October 2014. A total of 174 (82.1%) patients in our study had classic dengue, of which 38 (17.9%) had severe diseases. The frequencies of jaundice, pleural effusion, ascites, and vaginal bleeding were significantly different between the two groups (P < 0.05). The routine laboratory test results for alanine aminotransferase, aspertate aminotransferase, albumin, leukocyte count, platelet count, activated partial prothrombin time, prothrombin time, and aspartate aminotransferase/platelet count ratio index showed a significant association with severe dengue (P < 0.01). The areas under the receiver operating characteristic curves (AUC) were 0.727 (95% CI 0.662-0.78), 0.699 (95%CI 0.632-0.760), 0.634 (95%CI 0.565-0.698), 0.757 (95%CI 0.694-0.813), 0.775 (95%CI 0.713-0.829), 0.713 (95%CI 0.647-0.773), 0.719 (95%CI 0.730-0.843), and 0.785 (95%CI 0.724-0.893), respectively. The logistic regression analysis identified three factors, including high WBC (OR 1.52), prolonged PT (OR 1.745). and high APRI (OR 1.05) may be associated with the discrimination criteria to identify patients with and without severe diseases. The combination of the three factors (WBC, PT, and APRI) showed better AUC (0.877) and OR (1.52) scores. Our study indicates that laboratory tests such as WBC, PT, and APRI, helped identify patients at risk of developing severe dengue. The APRI was identified as a valuable predictor of patients with severe dengue. Combining the WBC, PT, and APRI scores allowed a better prediction of severe dengue.

Cyclic stretch induces VEGFA alternative splicing via Serine/Arginine-Rich Splicing Factor 1.

Abnormal proliferation of vascular smooth muscle cells (VSMCs) induced by high cyclic stretch is crucial in the vascular remodeling during hypertension. Vascular endothelial growth factor A (VEGFA) alternative splicing plays important roles in the pathological process of vascular diseases and remodeling. However, the roles of VEGFA isoforms in modulating VSMC functions in response to cyclic stretch remain unclear. We hypothesize that high cyclic stretch may induce VEGFA alternative splicing via Serine/arginine-rich splicing factor 1 (SRSF1) which subsequently induce VSMC proliferation. In the present research, hypertensive rat model was established using the abdominal aortic constriction method. In comparison with sham-operated group, immunohistology staining showed translocation of SRSF1 into nuclei in hypertensive rat thoracic aorta, and RT-PCR detected a shift of VEGFA expression pattern, including the increased expression of VEGFA120 and VEGFA164, but not VEGFA188.Then VSMCs were subjected to cyclic stretch in vitro using a Flexercell strain unit. VEGFA ELISA assay showed 15% cyclic stretch increased the secretion of VEGFA which significantly increased proliferation of VSMCs. Western blot and immunofluorescence detected accumulation of SRSF1 in nuclei after 15% cyclic stretch application. Furthermore, SRSF1-specific siRNA transfection reversed the VEGFA secretion induced by pathological high cyclic stretch. Our present results suggested that pathologically high cyclic stretch induces the shuttling of SRSF1 which results in the secretive pattern splicing of VEGFA and finally contributes to the proliferation of VSMCs.

Immune Cell-Mediated Biodegradable Theranostic Nanoparticles for Melanoma Targeting and Drug Delivery.

Although tremendous efforts have been made on targeted drug delivery systems, current therapy outcomes still suffer from low circulating time and limited targeting efficiency. The integration of cell-mediated drug delivery and theranostic nanomedicine can potentially improve cancer management in both therapeutic and diagnostic applications. By taking advantage of innate immune cell's ability to target tumor cells, the authors develop a novel drug delivery system by using macrophages as both nanoparticle (NP) carriers and navigators to achieve cancer-specific drug delivery. Theranostic NPs are fabricated from a unique polymer, biodegradable photoluminescent poly (lactic acid) (BPLP-PLA), which possesses strong fluorescence, biodegradability, and cytocompatibility. In order to minimize the toxicity of cancer drugs to immune cells and other healthy cells, an anti-BRAF V600E mutant melanoma specific drug (PLX4032) is loaded into BPLP-PLA nanoparticles. Muramyl tripeptide is also conjugated onto the nanoparticles to improve the nanoparticle loading efficiency. The resulting nanoparticles are internalized within macrophages, which are tracked via the intrinsic fluorescence of BPLP-PLA. Macrophages carrying nanoparticles deliver drugs to melanoma cells via cell-cell binding. Pharmacological studies also indicate that the PLX4032 loaded nanoparticles effectively kill melanoma cells. The "self-powered" immune cell-mediated drug delivery system demonstrates a potentially significant advancement in targeted theranostic cancer nanotechnologies.

Development of Ultrasound-switchable Fluorescence Imaging Contrast Agents based on Thermosensitive Polymers and Nanoparticles.

In this work we first introduced a recently developed high-resolution, deep-tissue imaging technique, ultrasound-switchable fluorescence (USF). The imaging principles based on two types of USF contrast agents were reviewed. To improve USF imaging techniques further, excellent USF contrast agents were developed based on high-performance thermoresponsive polymers and environment-sensitive fluorophores. Herein, such contrast agents were synthesized and characterized with five key parameters: (1) peak excitation and emission wavelengths (λex and λem), (2) the fluorescence intensity ratio between on and off states (IOn/IOff), (3) the fluorescence lifetime ratio between on and off states (τOn/τOff), (4) the temperature threshold to switch on fluorophores (Tth), and (5) the temperature transition bandwidth (TBW). We mainly investigated fluorescence intensity and lifetime changes of four environment-sensitive dyes [7-(2-Aminoethylamino)-N,N-dimethyl-4-benzofurazansulfonamide (DBD-ED), St633, Sq660, and St700] as a function of temperature, while the dye was attached to poly(N-isopropylacrylamide) linear polymers or encapsulated in nanoparticles. Six fluorescence resonance energy transfer systems were invented in which both the donor (DBD-ED or ST425) and the acceptor (Sq660) were adopted. Our results indicate that three Förster resonance energy transfer systems, where both IOn/IOff and τOn/τOff are larger than 2.5, are promising for application in future surface tissue bioimaging by USF technique.