An immunophenotype-coupled transcriptomic atlas of human hematopoietic progenitors.

Analysis of the human hematopoietic progenitor compartment is being transformed by single-cell multimodal approaches. Cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) enables coupled surface protein and transcriptome profiling, thereby revealing genomic programs underlying progenitor states. To perform CITE-seq systematically on primary human bone marrow cells, we used titrations with 266 CITE-seq antibodies (antibody-derived tags) and machine learning to optimize a panel of 132 antibodies. Multimodal analysis resolved >80 stem, progenitor, immune, stromal and transitional cells defined by distinctive surface markers and transcriptomes. This dataset enables flow cytometry solutions for in silico-predicted cell states and identifies dozens of cell surface markers consistently detected across donors spanning race and sex. Finally, aligning annotations from this atlas, we nominate normal marrow equivalents for acute myeloid leukemia stem cell populations that differ in clinical response. This atlas serves as an advanced digital resource for hematopoietic progenitor analyses in human health and disease.

Upstream stimulating factor 2 aggravates neuropathic pain induced in spinal nerve ligation-induced mice via regulating SNHG5/miR-181b-5p.

BACKGROUND: Upstream stimulating factor 2 (USF2) belongs to basic-Helix-Loop-Helix-Leucine Zipper transcription factor family, regulating expression of genes involved in immune response or energy metabolism network. Role of USF2 in neuropathic pain was evaluated. METHODS: Mice were intraspinally injected with adenovirus for knockdown of USF2 (Ad-shUSF2), and then subjected to spinal nerve ligation (SNL) to induce neuropathic pain. Distribution and expression of USF2 was detected by western blot and immunofluorescence. Mechanical and thermal pain sensitivity were examined by paw withdrawal thresholds (PWT) and paw withdrawal latency (PWL). Chromatin immunoprecipitation (ChIP) and luciferase activity assays were performed to detect binding ability between USF2 and SNHG5. RESULTS: The expression of USF2 was elevated and colocalized with astrocytes and microglia in L5 dorsal root ganglion (DRG) of SNL-induced mice. Injection of Ad-shUSF2 attenuated SNL-induced decrease of PWT and PWL in mice. Knockdown of USF2 increased level of IL-10, but decreased TNF-α, IL-1ß, and IL-6 in SNL-induced mice. Silence of USF2 enhanced protein expression of CD206, while reduced expression of CD16 and CD32 in SNL-induced mice. USF2 bind to promoter of SNHG5, and weakened SNL-induced up-regulation of SNHG5. SNHG5 bind to miR-181b-5p, and miR-181b-5p to interact with CXCL5. CONCLUSION: Silence of USF2 ameliorated neuropathic pain, suppressed activation of M1 microglia and inhibited inflammation in SNL-induced mice through regulation of SNHG5/miR-181b-5p/CXCL5 axis. Therefore, USF2/SNHG5/miR-181b-5p/CXCL5 might be a promising target for neuropathic pain. However, the effect of USF2/SNHG5/miR-181b-5p/CXCL5 on neuropathic pain should also be investigated in further research.

SiC@NiO Core-Shell Nanowire Networks-Based Optoelectronic Synapses for Neuromorphic Computing and Visual Systems at High Temperature.

1D nanowire networks, sharing similarities of structure, information transfer, and computation with biological neural networks, have emerged as a promising platform for neuromorphic systems. Based on brain-like structures of 1D nanowire networks, neuromorphic synaptic devices can overcome the von Neumann bottleneck, achieving intelligent high-efficient sensing and computing function with high information processing rates and low power consumption. Here, high-temperature neuromorphic synaptic devices based on SiC@NiO core-shell nanowire networks optoelectronic memristors (NNOMs) are developed. Experimental results demonstrate that NNOMs attain synaptic short/long-term plasticity and modulation plasticity under both electrical and optical stimulation, and exhibit advanced functions such as short/long-term memory and "learning-forgetting-relearning" under optical stimulation at both room temperature and 200 °C. Based on the advanced functions under light stimulus, the constructed 5 × 3 optoelectronic synaptic array devices exhibit a stable visual memory function up to 200 °C, which can be utilized to develop artificial visual systems. Additionally, when exposed to multiple electronic or optical stimuli, the NNOMs effectively replicate the principles of Pavlovian classical conditioning, achieving visual heterologous synaptic functionality and refining neural networks. Overall, with abundant synaptic characteristics and high-temperature thermal stability, these neuromorphic synaptic devices offer a promising route for advancing neuromorphic computing and visual systems.

TRIM33 drives prostate tumor growth by stabilizing androgen receptor from Skp2-mediated degradation.

Androgen receptor (AR) is a master transcription factor that drives prostate cancer (PCa) development and progression. Alterations in the expression or activity of AR coregulators significantly impact the outcome of the disease. Using a proteomics approach, we identified the tripartite motif-containing 33 (TRIM33) as a novel transcriptional coactivator of AR. We demonstrate that TRIM33 facilitates AR chromatin binding to directly regulate a transcription program that promotes PCa progression. TRIM33 further stabilizes AR by protecting it from Skp2-mediated ubiquitination and proteasomal degradation. We also show that TRIM33 is essential for PCa tumor growth by avoiding cell-cycle arrest and apoptosis, and TRIM33 knockdown sensitizes PCa cells to AR antagonists. In clinical analyses, we find TRIM33 upregulated in multiple PCa patient cohorts. Finally, we uncover an AR-TRIM33-coactivated gene signature highly expressed in PCa tumors and predict disease recurrence. Overall, our results reveal that TRIM33 is an oncogenic AR coactivator in PCa and a potential therapeutic target for PCa treatment.

Circ ubiquitin-like-containing plant homeodomain and RING finger domains protein 1 increases the stability of G9a and ubiquitin-like-containing plant homeodomain and RING finger domains protein 1 messenger RNA through recruiting eukaryotic translation initiation factor 4A3, transcriptionally inhibiting PDZ and homeobox protein domain protein 1, and promotes the metastasis of hepatocellular carcinoma.

BACKGROUND AND AIM: Circular ubiquitin-like, containing PHD and ring finger domains 1 (circUHRF1) is aberrantly upregulated in human hepatocellular carcinoma (HCC) tissues. However, the underlying molecular mechanisms remain obscure. The present study aimed at elucidating the interactive function of circUHRF1-G9a-ubiquitin-like, containing PHD and ring finger domains 1 (UHRF1) mRNA-eukaryotic translation initiation factor 4A3 (EIF4A3)-PDZ and LIM domain 1 (PDLIM1) network in HCC. METHODS: Expression of circUHRF1, mRNAs of G9a, UHRF1, PDLIM1, epithelial-mesenchymal transition (EMT)-related proteins, and Hippo-Yap pathway components was determined by quantitative polymerase chain reaction (Q-PCR), immunofluorescence, or Western blot analysis. Tumorigenic and metastatic capacities of HCC cells were examined by cellular assays including Cell Counting Kit-8, colony formation, wound healing, and transwell assays. Molecular interactions between EIF4A3 and UHRF1 mRNA were detected by RNA pull-down experiment. Complex formation between UHRF1 and PDLIM1 promoter was detected by chromatin immunoprecipitation assay. Co-immunoprecipitation was performed to examine the binding between UHRF1 and G9a. RESULTS: Circular ubiquitin-like, containing PHD and ring finger domains 1, G9a, and UHRF1 were upregulated, while PDLIM1 was downregulated in HCC tissue samples and cell lines. Cellular silencing of circUHRF1 repressed HCC proliferation, invasion, migration, and EMT. G9a formed a complex with UHRF1 and inhibited PDLIM1 transcription. CONCLUSION: Eukaryotic translation initiation factor 4A3 regulated circUHRF1 expression by binding to UHRF1 mRNA promoter. circUHRF1 increased the stability of G9a and UHRF1 mRNAs through recruiting EIF4A3. Overexpression of circUHRF1 aggravated HCC progression through Hippo-Yap pathway and PDLIM1 inhibition. By elucidating the molecular function of circUHRF1-G9a-UHRF1 mRNA-EIF4A3-PDLIM1 network, our data shed light on the HCC pathogenesis and suggest a novel therapeutic strategy for future HCC treatment.

Circ_0001982 aggravates breast cancer development through the circ_0001982-miR-144-3p-GSE1 axis.

This study was designed to explore the role of circ_0001982 in breast cancer (BC) development. Quantitative real-time polymerase chain reaction and western blot analysis assays were used to determine circ_0001982, miR-144-3p, and gse1 coiled-coil protein (GSE1) expression. Functional assays were performed to evaluate cell proliferation, apoptosis, migration, and invasion. The glycolysis was analyzed with commercial kits. Dual-luciferase reporter assay and RNA immunoprecipitation assays were conducted to analyze the relationships among circ_0001982, miR-144-3p, and GSE1. A murine xenograft model assay was performed to determine circ_0001982-induced effects on BC cell tumor properties in vivo. Circ_0001982 expression was upregulated, but miR-144-3p was reduced in BC tissues and cells in comparison with normal breast tissues and normal human mammary epithelial cells. Circ_0001982 knockdown or miR-144-3p overexpression inhibited BC cell proliferation, glycolysis, migration and invasion, and promoted apoptosis. Circ_0001982 sponged miR-144-3p and negatively regulated miR-144-3p expression in BC cells. In addition, GSE1 was identified as a target mRNA of miR-144-3p. Ectopic GSE1 expression relieved circ_0001982 depletion-induced effects on BC cell tumor properties. Furthermore, circ_0001982 absence suppressed BC cell tumor properties in vivo. Circ_0001982 contributed to the BC cell tumor properties by regulating the miR-144-3p-GSE1 axis.

The trends of pediatric duodenal ulcer and predictors of recurrence.

BACKGROUND: Duodenal ulcer (DU) causes various symptoms in children. The prevalence of Helicobacter pylori (Hp)-associated DU has been reducing in some regions, yet the updated trend in Taiwan is unknown. Risk factors of DU recurrence have not been comprehensively investigated in children. METHODS: This retrospective study included children diagnosed with DU to evaluate the demographics, symptoms, diagnostics, treatment, and outcomes. Specific populations (infant, surgery required) were sorted for subgroup analysis. Predictors of DU recurrence was analyzed in patients who received endoscopic follow-ups. RESULTS: A total of 488 children were included. Most patients were male (72.5%), school-aged (11.3 ± 4.8 years old), and with varied underlying diseases in one-fifth. The annual incidences were around 3-5%, with a declining trend of case numbers and the Hp-positive proportion. Hp infection, concurrent gastric ulcer, perforation, and mortality were noted in 32.7%, 16%, 1.6%, and 1% of patients. Patients with or without Hp infection showed different clinical features but similar outcomes. The characteristics of subpopulations were depicted respectively. Male sex, lower Hb level, and perforation were independent risk factors associated with recurrence. CONCLUSIONS: Hp-positive DU seems to wane. Patients with male sex, lower Hb level, or perforation at diagnosis carried a higher risk of recurrence, which may warrant active surveillance and endoscopic follow-up.

Ni-anchored g-C3N4for improved hydrogen evolution in photocatalysis.

In this study, we present a facile wet chemical method for synthesizing Ni-modified polymeric carbon nitride (g-C3N4) nanosheets. X-ray absorption fine structure spectroscopy reveals the formation of a unique Ni-N structure, resulting from Ni atoms anchoring in cavities of g-C3N4. The Ni anchoring on the surface N sites modifies the electronic structure of g-C3N4, demonstrating remarkable effectiveness even at low anchoring amounts. The as-prepared Ni/g-C3N4catalysts show robust performance for photocatalytic hydrogen evolution under visible light irradiation, attributed to the unique Ni-N interactions. Specifically, the photocatalytic H2production rate of the Ni/CN-45 catalyst reached 8482.14µmol·g-1·h-1with an apparent quantum efficiency of 0.75% under light irradiation at 427 nm. This rate surpasses most of the previously reported g-C3N4based photocatalysts and is nearly 8 times higher than that of the pure g-C3N4catalyst (1116.07µmol·g-1·h-1).

Blockage of ATPase-mediated energy supply inducing metabolic disturbances in algal cells under silver nanoparticles stress.

Adenosine triphosphate (ATP) generation of aquatic organisms is often subject to nanoparticles (NPs) stress, involving extensive reprogramming of gene expression and changes in enzyme activity accompanied by metabolic disturbances. However, little is known about the mechanism of energy supply by ATP to regulate the metabolism of aquatic organisms under NPs stress. Here, we selected extensively existing silver nanoparticles (AgNPs) to investigate their implications on ATP generation and relevant metabolic pathways in alga (Chlorella vulgaris). Results showed that ATP content significantly decreased by 94.2% of the control (without AgNPs) in the algal cells at 0.20 mg/L AgNPs, which was mainly attributed to the reduction of chloroplast ATPase activity (81.4%) and the downregulation of ATPase-coding genes atpB and atpH (74.5%-82.8%) in chloroplast. Molecular dynamics simulations demonstrated that AgNPs competed with the binding sites of substrates adenosine diphosphate and inorganic phosphate by forming a stable complex with ATPase subunit beta, potentially resulting in the reduced binding efficiency of substrates. Furthermore, metabolomics analysis proved that the ATP content positively correlated with the content of most differential metabolites such as D-talose, myo-inositol, and L-allothreonine. AgNPs remarkably inhibited ATP-involving metabolic pathways, including inositol phosphate metabolism, phosphatidylinositol signaling system, glycerophospholipid metabolism, aminoacyl-tRNA biosynthesis, and glutathione metabolism. These results could provide a deep understanding of energy supply in regulating metabolic disturbances under NPs stress.

Case-Control Study of Clostridium innocuum Infection, Taiwan.

Vancomycin-resistant Clostridium innocuum was recently identified as an etiologic agent for antibiotic-associated diarrhea in humans. We conducted a case-control study involving 152 C. innocuum-infected patients during 2014-2019 in Taiwan, using 304 cases of Clostridioides difficile infection (CDI) matched by diagnosis year, age (+2 years), and sex as controls. The baseline characteristics were similar between the 2 groups. C. innocuum-infected patients experienced more extraintestinal clostridial infection and gastrointestinal tract-related complications than did patients with CDI. The 30-day mortality rate among C. innocuum-infected patients was 14.5%, and the overall rate was 23.0%. Chronic kidney disease, solid tumor, intensive care unit admission, and shock status were 4 independent risk factors for death. C. innocuum identified from clinical specimens should be recognized as a pathogen requiring treatment, and because of its intrinsic vancomycin resistance, precise identification is necessary to guide appropriate and timely antimicrobial therapy.

Transcaval transcatheter aortic valve implantation in bicuspid aortic valve: A step-by-step procedural guidance.

We report the case of a 78-year-old female with Sapien 3 transcatheter heart valve implantation in the transcaval approach. In this setting, we describe the step-by-step management and technique of the transcaval transcatheter aortic valve implantation.

Rotation characteristics and neo-commissural alignment of transcatheter heart valve in type-0 bicuspid aortic valve.

AIMS: This study sought to characterize the rotation of the transcatheter heart valve (THV) and evaluate the neo-commissures overlap with coronary arteries in type-0 bicuspid aortic valve (BAV). METHODS AND RESULTS: This was a single-center, 10-patient, retrospective observational cohort. Pre-TAVI computed tomography and procedural fluoroscopy were analyzed. Coplanar fluoroscopic views were coregistered to pre-TAVI computed tomography to characterize THV rotation and determine coronary overlap. The incidence of severe coronary artery overlap with one coronary artery was 90%. According to our prediction line, type-0 BAV has predicted a higher incidence of overlap with one coronary artery, but lower incidence with both coronary arteries compared to the tricuspid aortic valve (TAV). The rotational angles in two different phases were 3.8 ± 3.2° versus 11.8 ± 8.0° (p = .01) in patients with mixed cusp fusion. Commissural angles in final and initial deployment were 9.6 ± 6.6 versus 18.1 ± 11.0° (p = .021). Applying hypothetic "commissure-middle view" in 0°, ±5°, and ±10°, the incidence of overlap with one coronary artery are 20%, 40%, and 90% separately. CONCLUSIONS: The THV rotation existed and was activated in the last 1/3 deploying phase. With the observed tendency of "automatic commissural alignment," applying the "commissure-middle" view in type-0 BAV may optimize valve alignment and avoid coronary artery overlap.

Primary endoscopic variceal ligation reduced acute variceal bleeding events but not long-term mortality in pediatric-onset portal hypertension.

BACKGROUND/PURPOSE: Esophageal variceal bleeding (EVB) is a medical emergency in patients with portal hypertension (PHT). However, studies on the long-term outcomes of prophylactic endoscopic variceal ligation (EVL) in pediatric-onset PHT are lacking. METHODS: Between 1999 and 2020, patients who received EVL in the Electronic Report System of the Pediatric Endoscopy Unit were included in this retrospective study. EVL was classified as primary prophylaxis when it was performed for esophageal varices (EVs) without previous bleeding. If it was implemented in acute EVB, the subsequent EVL was classified as secondary prophylaxis. RESULTS: Fifty-eight patients aged 10 months to 33 years with 31 males were included. Thirty-eight patients were classified as primary prophylaxis group, and twenty, secondary prophylaxis group. The primary prophylaxis group experienced fewer 5-year EVB events than the secondary prophylaxis group (cumulative risk: 14.4% versus 32.4%). Still, it didn't significantly affect overall survival and biliary atresia transplant-free survival. Long-term mortality was significantly associated with higher serum direct bilirubin levels (≥0.55 mg/dL) and lower albumin levels (≤2.54 mg/dL) at the first EVL. Aspartate aminotransferase-to-platelet ratio index (APRI) with a cut-off value of 1.24 helped to predict EV presence at the initial esophagogastroduodenoscopy (EGD) (AUROC = 0.762, sensitivity 75.0%, and specificity 66.7%). CONCLUSION: Primary prophylactic EVL, despite reducing acute EVB, may not change overall survival and biliary atresia transplant-free survival. APRI > 1.24 may predict EV presence at the first EGD and help to schedule a surveillance EGD. Higher direct bilirubin and lower albumin levels at the first EVL may relate to long-term mortality.

Infectious recombinant Senecavirus A expressing novel reporter proteins.

Senecavirus A (SVA) is an emerging picornavirus that has been associated with vesicular disease and neonatal mortality in swine. The construction of SVA virus carrying foreign reporter gene provides a powerful tool in virus research. However, it is often fraught with rescuing a recombinant picornavirus harboring a foreign gene or maintaining the stability of foreign gene in the virus genome. Here, we successfully generated recombinant SVA GD05/2017 viruses (V-GD05-clone) expressing the green fluorescent protein (iLOV), red fluorescent protein (RFP), or NanoLuc luciferase (Nluc). These recombinant viruses have comparable growth kinetics to the parental virus. Genetic stability analysis indicated that V-GD05-iLOV was highly stable in retaining iLOV gene for more than 10 passages, while V-GD05-RFP and V-GD05-Nluc lost the foreign genes in five passages. In addition, high-intensity fluorescent signals were found in the V-GD05-RFP- and V-GD05-iLOV-infected cells by fluorescence observation and flow cytometry analysis, and the luciferase activity assay could quantitatively monitor the replication of V-GD05-Nluc. In order to identify the porcine cell receptor for SVA, anthrax toxin receptor 1 (ANTXR1) was knocked out or overexpressed in the ST-R cells. The ANTXR1 knock-out cells lost the ability for SVA infection, while overexpression of ANTXR1 significantly increased the cell permissivity. These results confirmed that ANTXR1 was the receptor for SVA to invade porcine cells as reported in the human cells. Overall, this study suggests that these SVA reporter viruses will be useful tools in elucidating virus pathogenesis and developing control measures. KEY POINTS: • We successfully generated SVA viruses expressing the iLOV, RFP, or Nluc. • The iLOV was genetically stable in the V-GD05-iLOV genome over ten passages. • ANTXR1 was the receptor for SVA to invade porcine cells.

A scoping review of clinical reasoning research with Asian healthcare professionals.

Clinical reasoning is the thought process that guides practice. Although a plethora of clinical reasoning studies in healthcare professionals exists, the majority appear to originate from Western cultures. A scoping review was undertaken to examine clinical reasoning related research across Asian cultures. PubMed, SciVerse Scopus, Web of Science and Airiti Library databases were searched. Inclusion criteria included full-text articles published in Asian countries (2007 to 2019). Search terms included clinical reasoning, thinking process, differential diagnosis, decision making, problem-based learning, critical thinking, healthcare profession, institution, medical students and nursing students. After applying exclusion criteria, n = 240 were included in the review. The number of publications increased in 2012 (from 5%, n = 13 in 2011 to 9%, n = 22) with a steady increase onwards to 12% (n = 29) in 2016. South Korea published the most articles (19%, n = 46) followed by Iran (17%, n = 41). Nurse Education Today published 11% of the articles (n = 26), followed by BMC Medical Education (5%, n = 13). Nursing and Medical students account for the largest population groups studied. Analysis of the articles resulted in seven themes: Evaluation of existing courses (30%, n = 73) being the most frequently identified theme. Only seven comparative articles showed cultural implications, but none provided direct evidence of the impact of culture on clinical reasoning. We illuminate the potential necessity of further research in clinical reasoning, specifically with a focus on how clinical reasoning is affected by national culture. A better understanding of current clinical reasoning research in Asian cultures may assist curricula developers in establishing a culturally appropriate learning environment.

A Dilemma in the Extremely Low-Placed Venus A-Valve in a Cardiogenic Shock Patient.

Transcatheter aortic valve replacement (TAVR) is regarded as an alternative to balloon aortic valvuloplasty in patients with severe aortic valve stenosis in cardiogenic shock. A low implantation of transcatheter heart valve (THV) can result in "supraskirt" paravalvular aortic regurgitation (PAR) and prosthesis-patient mismatch (P-PM), causing a dilemma in such a setting. A 64-year-old man presented to our emergency department with severe aortic stenosis and acute heart failure causing cardiogenic shock. An urgent transfemoral TAVR was performed under general anesthesia in a hybrid room. Predilatation was performed with a 22-mm compliant balloon, and a 26-mm Venus A-Valve (Venus MedTech, Hangzhou, China) was deployed. After valve implantation, the hemodynamic conditions of the patient rapidly deteriorated; therefore, cardiopulmonary resuscitation and extracorporeal circulation support were initiated. Aortography and transthoracic echocardiography (TEE) illustrated an extremely low implantation of THV, with moderate to severe supraskirt PAR and moderate P-PM. After evaluation of the hemodynamic tolerability of PAR, a median sternotomy was done, and surgery was performed. The patient died due to severe sepsis and hyperkalemia 14 days after the procedure. The management of urgent TAVR in cardiogenic shock should be revised and reexamined. A widespread and practical percutaneous technique to manage implant failure of THV is required to avoid surgical bailout.

Long Noncoding RNA SNHG5 Knockdown Alleviates Neuropathic Pain by Targeting the miR-154-5p/CXCL13 Axis.

Neuropathic pain is an unneglectable pain condition with limited treatment options owing to its enigmatic underlying mechanisms. Long noncoding RNA small nucleolar RNA host gene 5 (SNHG5) is involved in the progression of a spectrum of human cancers. However, its role in neuropathic pain remains undiscovered. In the present study, we established a mouse spinal nerve ligation (SNL) model, and a significant upregulation of SNHG5 was observed. Then we knocked down SNHG5 level in mouse L5 dorsal root ganglion (DRG) by delivering specific short hairpin RNA against SNHG5 with adenovirus vehicle. Mouse paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) in response to mechanical stimuli was increased after SNHG5 knockdown, accompanied with decreased protein levels of glial fibrillary acidic protein (GFAP) and ionized calcium binding adapter molecule 1 (IBA-1). Besides, SNHG5 directly modulated the expression of miR-154-5p, which was downregulated in SNL mice. MiR-154-5p inhibition abolished the effect of SNHG5 knockdown on mouse behavioral tests and GFAP and IBA-1 levels. In addition, we validated that C-X-C motif chemokine 13 (CXCL13) was a novel downstream target of miR-154-5p, and CXCL13 level was positively related to that of SNHG5 in SNL mice. In conclusion, our study demonstrated that SNHG5 knockdown alleviated neuropathic pain and inhibited the activation of astrocytes and microglia by targeting the miR-154-5p/CXCL13 axis, which might be a novel therapeutic target for neuropathic treatment clinically.

Azetidine-based selective glycine transporter-1 (GlyT1) inhibitors with memory enhancing properties.

A strategy to conformationally restrain a series of GlyT1 inhibitors identified potent analogs that exhibited slowly interconverting rotational isomers. Further studies to address this concern led to a series of azetidine-based inhibitors. Compound 26 was able to elevate CSF glycine levels in vivo and demonstrated potency comparable to Bitopertin in an in vivo rat receptor occupancy study. Compound 26 was subsequently shown to enhance memory in a Novel Object Recognition (NOR) behavioral study after a single dose of 0.03 mg/kg, and in a contextual fear conditioning (cFC) study after four QD doses of 0.01-0.03 mg/kg.

Comparison of Chemotherapeutic Activities of Rhodamine-Based GUMBOS and NanoGUMBOS.

Rhodamine derivatives have been widely investigated for their mitochondrial targeting and chemotherapeutic properties that result from their lipophilic cationic structures. In previous research, we have found that conversion of Rhodamine 6G into nanoGUMBOS, i.e., nanomaterials derived from a group of uniform materials based on organic salts (GUMBOS), led to selective chemotherapeutic toxicity for cancer cells over normal cells. Herein, we investigate the chemotherapeutic activity of GUMBOS derived from four different rhodamine derivatives, two bearing an ester group, i.e., Rhodamine 123 (R123) and SNAFR-5, and two bearing a carboxylic acid group, i.e., rhodamine 110 (R110) and rhodamine B (RB). In this study, we evaluate (1) relative hydrophobicity via octanol-water partition coefficients, (2) cytotoxicity, and (3) cellular uptake in order to evaluate possible structure-activity relationships between these different compounds. Intriguingly, we found that while GUMBOS derived from R123 and SNAFR-5 formed nanoGUMBOS in aqueous medium, no distinct nanoparticles are observed for RB and R110 GUMBOS. Further investigation revealed that the relatively high water solubility of R110 and RB GUMBOS hinders nanoparticle formation. Subsequently, while R123 and SNAFR-5 displayed selective chemotherapeutic toxicity similar to that of previously investigated R6G nanoGUMBOS, the R110 and RB GUMBOS were lacking in this property. Additionally, the chemotherapeutic toxicities of R123 and SNAFR-5 nanoGUMBOS were also significantly greater than R110 and RB GUMBOS. Observed results were consistent with decreased cellular uptake of R110 and RB as compared to R123 and SNAFR-5 compounds. Moreover, these results are also consistent with previous observations that suggest that nanoparticle formation is critical to the observed selective chemotherapeutic properties as well as the chemotherapeutic efficacy of rhodamine nanoGUMBOS.

VEGF attenuates lung injury by inducing homing of CD133+ progenitors via VEGFR1.

Although vascular endothelial growth factor (VEGF) promotes vascular permeability and results in edema, studies have suggested it may protect the lung from inflammatory injury via poorly understood mechanisms. Using a mouse model of extracorporeal circulation (ECC), we found that levels of intravenous VEGF increased in lung tissue and inhibited inflammation, thereby attenuating lung injury. These effects could be obtained by intravenous injection or inhalation of VEGF, and they were abolished by treatment with anti-VEGF antibody. Detailed analyses using immunofluorescence and flow cytometry showed that VEGF increased the homing of CD133+ VEGFR1+ progenitors to lung tissue, and this homing could be mimicked in a dose-dependent manner by treatment with VEGF receptor 1 (VEGFR1) agonist and blocked by treatment with anti-VEGFR1 antibody. Interestingly, we found that exposing pulmonary monocytes in vitro to VEGF did not inhibit ECC-induced inflammation. Our results suggest that VEGF enters lung tissues from the circulation and that it attenuates lung injury not by directly inhibiting release of pro-inflammatory factors but by binding to VEGFR1 to recruit CD133+ progenitors. These progenitors then inhibit local inflammation.