Synthesis and characterization of a macromolecular magnetic resonance imaging and delivery system with hyaluronic acid as a carrier.

Using hyaluronic acid (HA) as macromolecular drug carriers, a glutathione-responsive imaging drug delivery system HA-SS-a-Gd-DOTA was formed by conjugating gadolinium chelates and cytarabine. This system exhibited T1-reflexivity (21.9 mmol-1 L s-1, 0.5 T) that was higher than that of gadoterate meglumine. In an acidic environment, in vitro drug release reached 63.4% in 24 h. Low cytotoxicity indicated that this system has good biocompatibility. In vivo mouse imaging studies showed that tumor signaling was significantly enhanced. About 58% of the signal enhancement was obtained 50 min after injection of the drug. The degradation of the hyaluronic acid macromolecular chains in vivo makes it an ideal tumor imaging diagnostic agent because it did not cause damage to important organs of the mice.

Totally tubeless single access tract mini-percutaneous nephrolithotripsy in treatment of large burden > 2-cm and/or complex renal stones: a case series of 62 patients.

BACKGROUND: Limited literature has focused on the use of totally tubeless mini-percutaneous nephrolithotomy (PCNL) for the treatment of large renal stones. We present our findings of treating patients with large and/or complex renal stones using single renal access totally tubeless mini-PCNL. METHODS: From March 2018 to May 2021, 62 consecutive cases in which single tract totally tubeless mini-PCNL was used to treat complex renal stones were enrolled, all with calculi > 2 cm. All procedure of puncture and dilation were guided by fluoroscope. The complexity of stones was assessed according to the Guy's Scoring System (GSS). The surgical duration, length of hospital stay, analgesia requirement, stone-free rate, and perioperative morbidity were assessed. RESULTS: The mean preoperative stone burden was 36.69 ± 19.76 mm (above 2 cm in all cases), mean surgical duration was 61.93 ± 40.84 min (range 15-180 min), and mean hematocrit reduction was 4.67 ± 2.83%. Postoperative Nalbuphine was used in 6 patients. The mean length of stay was 2.46 ± 1.19 days (range 2-8 days), and the postoperative stone-free rate was 83.9% (52/62), and 87.1% (54/62) after auxiliary ESWL. The overall complication rate was 14.5%, the majority of complications being postoperative transient fever. CONCLUSION: For the treatment of large bursen > 2 cm and/or complex renal stones, totally tubeless single tract mini-PCNL ensures a feasible SFR, low morbidity and short hospital stay. According to the low complication rate in our study, the totally tubeless manner was not associated with an increased risk of postoperative morbidity, and patients benefited from decreased postoperative analgesics use.

[A new isoflavone from Dalbergia odorifera and inhibitory activity of its tyrosinase].

Twelve flavonoids were isolated and purified from the ethyl acetate fraction of 95% ethanol extract of Dalbergia odorifera by heat reflux extraction, solvent extraction, recrystallization, normal phase silica gel, Sephadex LH-20, MCI gel and HPLC methods. The structures were identified with multiple spectroscopic methods, including 1 D-NMR, 2 D-NMR and MS. The compounds were identified as 6,7,8-trimethoxy-5,4'-dihydroxy isoflavone(1), medicarpin(2), 7,2'-dihydroxy-4'-methoxy-isoflavanol(3), biochanin A(4), prunetin(5), genistein(6), pratensein(7), 3-(4-hydroxyphenyl)-6-isopentenyl-7-methoxy-4H-chromen-4-one(8), tectorigenin(9), irisolidone(10), vestitol(11), and formononetin(12). Compound 1 was a new isoflavone, and compound 8 was isolated from D. odorifera for the first time. The results showed that compounds 1-3 had inhibitory effects on tyrosinase, with inhibition rates of 35.58%, 38.63% and 51.34% at the concentration of 1.0 mmol·L~(-1), respectively.

Dual-Phase Emission AIEgen with ICT Properties for VOC Chromic Sensing.

In a film-based fluorescence sensor, luminogens are of vital importance since they play the role of probes or indicators. Traditional organic luminogens like pyrene show high luminescence quantum yields in dilute solutions, but their applications are usually limited by the aggregation-caused quenching (ACQ) effect and bad photochemical stability. Thus, this paper reports a novel aggregation-induced emission luminogen (AIEgen) containing both pyrene and o-carborane (CB-PY), which possesses unique dual-phase emission both in solution and solid state and intramolecular charge transfer (ICT) properties, fulfilling the gap between ACQ and AIE compounds. Importantly, the fluorophore presents extraordinary stability that there was almost no attenuation in the emission intensity of CB-PY in the solid state after 4 months of exposure at ambient conditions. It is these merits that make CB-PY exhibit outstanding sensing performances for volatile organic compounds (VOCs), where the fluorescence test strip shows fast, reversible, and visual discrimination of four organic solvents with varied polarities. Moreover, 92#, 95#, and 98# gasolines could be discriminated with CB-PY, showing different colors under UV illumination.

A genome-wide association study reveals a substantial genetic basis underlying the Ebbinghaus illusion.

The Ebbinghaus illusion (EI) is an optical illusion of relative size perception that reflects the contextual integration ability in the visual modality. The current study investigated the genetic basis of two subtypes of EI, EI overestimation, and EI underestimation in humans, using quantitative genomic analyses. A total of 2825 Chinese adults were tested on their magnitudes of EI overestimation and underestimation using the method of adjustment, a standard psychophysical protocol. Heritability estimation based on common single nucleotide polymorphisms (SNPs) revealed a moderate heritability (34.3%) of EI overestimation but a nonsignificant heritability of EI underestimation. A meta-analysis of two phases (phase 1: n = 1986, phase 2: n = 839) of genome-wide association study (GWAS) discovered 1969 and 58 SNPs reaching genome-wide significance for EI overestimation and EI underestimation, respectively. Among these SNPs, 55 linkage-disequilibrium-independent SNPs were associated with EI overestimation in phase 1 with genome-wide significance and their associations could be confirmed in phase 2 cohort. Gene-based analyses found seven genes to be associated with EI overestimation at the genome-wide level, two from meta-analysis, and five from classical two-stage analysis. Overall, this study provided consistent evidence for a substantial genetic basis of the Ebbinghaus illusion.

Alpha-fetoprotein/endoplasmic reticulum stress signaling mitigates injury in hepatoma cells.

Alpha-fetoprotein (AFP) and endoplasmic reticulum (ER) stress play multiple roles in hepatocellular carcinoma. Here, we analyzed the crosstalk between AFP and ER stress in human hepatoma cells. We induced ER stress in human hepatoma cell lines (HepG2 and SK-Hep1 cells) with thapsigargin (TG, an ER stress inducer), and mitigated ER stress with 4-phenylbutyrate acid (4-PBA, an ER stress inhibitor). AFP expression was knocked down by AFP short hairpin RNA and rescued by the pCI-AFP vector. AFP expression and ER stress were examined, and their roles in apoptosis, necroptosis, and proliferation were analyzed. TG significantly induced ER stress, apoptosis, necroptosis, and intracellular AFP protein levels, and reduced proliferation and AFP mRNA expression as well as supernatant AFP protein levels in HepG2 and SK-Hep1 cells. 4-PBA pretreatment partially reversed those changes in HepG2 cells. By contrast to AFP overexpression, knockdown of AFP significantly exacerbated TG-induced ER stress, apoptosis, and necroptosis, and decreased proliferation and the expression of activating transcription factor 6 alpha. In conclusion, ER stress causes the accumulation of AFP protein, which may be related to the reduction of AFP secretion. Accumulated AFP mitigates apoptosis and necroptosis and restores the proliferation of hepatoma cells by reducing ER stress.

Clinical Experience of Steroid Switch from Prednisone to Dexamethasone in Patients with Metastatic Castration-Resistant Prostate Cancer Treated with Abiraterone Acetate.

OBJECTIVE: To evaluate the therapeutic efficacy of a steroid switch from prednisone to dexamethasone in Asians with metastatic castration-resistant prostate cancer (mCRPC) that progressed after docetaxel chemotherapy. METHODS: This study included postdocetaxel patients with mCRPC treated with abiraterone acetate combined with prednisone (AA + P) who had experienced prostate-specific antigen (PSA) progression. All patients underwent a steroid switch from prednisone (10 mg/day) to dexamethasone (1 mg/day). The PSA level and clinical symptoms were recorded. Moreover, follow-up was conducted until patients were either lost to follow-up or death. RESULTS: This study included 11 patients from a single center in Taiwan. The median follow-up time starting from AA + P treatment was 19.47 months. Seven patients (63.64%) had >30% PSA decline, and 6 patients (54.55%) had >50% PSA decline. The median percentage of PSA decline was 83.6%. The median time until PSA progression after the steroid switch was 11.38 months. No adverse events greater than grade 3 were noted. CONCLUSIONS: Steroid switching is a feasible and effective therapy in docetaxel-treated Asian patients with mCRPC.

Protocol for Stereoselective Construction of Highly Functionalized Dienyl Sulfonyl Fluoride Warheads.

A pyrrolidine-mediated Knoevenagel-type reaction for highly stereoselective construction of novel α-halo-1,3-dienylsulfonyl fluorides was achieved in up to 100% Z-selectivity and high yields at room temperature from condensation of the readily available aldehydes and halomethanesulfonyl fluorides. This protocol provided a class of unique α-halo-1,3-dienylsulfonyl fluorides with wide scope and excellent functional group compatibility. The α-halo-1,3-dienylsulfonyl fluorides were used as versatile building blocks in sulfur fluoride exchange click chemistry, Suzuki reaction, and Sonogashira reaction for the assembly of highly functionalized dienyl sulfonyl fluoride derivatives to be applied as covalent warheads for the discovery of new drugs.

Phosphorylation of eIF2α mitigates endoplasmic reticulum stress and hepatocyte necroptosis in acute liver injury.

INTRODUCTION AND OBJECTIVES: Necroptosis and endoplasmic reticulum (ER) stress has been implicated in acute and chronic liver injury. Activated eukaryotic initiation factor 2 alpha (eIF2α) attenuates protein synthesis and relieves the load of protein folding in the ER. In this study, we aimed to analyze the impact of eIF2α phosphorylation on hepatocyte necroptosis in acute liver injury. MATERIALS AND METHODS: Male BALB/c mice were injected with tunicamycin or d-galactosamine, and LO2 cells were incubated with tunicamycin to induce acute liver injury. 4-Phenylbutyric acid (PBA) and salubrinal were used to inhibit ER stress and eIF2α dephosphorylation, respectively. We analyzed the eIF2α phosphorylation, ER stress, and hepatocyte necroptosis in mice and cells model. RESULTS: Tunicamycin or d-galactosamine significantly induced ER stress and necroptosis, as well as eIF2α phosphorylation, in mice and LO2 cells (p<0.05). ER stress aggravated tunicamycin-induced hepatocyte necroptosis in mice and LO2 cells (p<0.05). Elevated eIF2α phosphorylation significantly mitigated hepatocyte ER stress (p<0.05) and hepatocyte necroptosis in mice (34.37±3.39% vs 22.53±2.18%; p<0.05) and LO2 cells (1±0.11 vs 0.33±0.05; p<0.05). Interestingly, tumor necrosis factor receptor (TNFR) 1 protein levels were not completely synchronized with necroptosis. TNFR1 expression was reduced in d-galactosamine-treated mice (p<0.05) and cells incubated with tunicamycin for 12 and 24h (p<0.05). ER stress partially restored TNFR1 expression and increased necroptosis in tunicamycin-incubated cells (p<0.05). CONCLUSIONS: These results imply that ER stress can mediate hepatocyte necroptosis independent of TNFR1 signaling and elevated eIF2α phosphorylation can mitigate ER stress during acute liver injury.

Genomic Analyses of Visual Cognition: Perceptual Rivalry and Top-Down Control.

Visual cognition in humans has traditionally been studied with cognitive behavioral methods and brain imaging, but much less with genetic methods. Perceptual rivalry, an important phenomenon in visual cognition, is the spontaneous perceptual alternation that occurs between two distinct interpretations of a physically constant visual stimulus (e.g., binocular rivalry stimuli) or a perceptually ambiguous stimulus (e.g., the Necker cube). The switching rate varies dramatically across individuals and can be voluntarily modulated by observers. Here, we adopted a genomic approach to systematically investigate the genetics underlying binocular rivalry, Necker cube rivalry and voluntary modulation of Necker cube rivalry in young Chinese adults (Homo sapiens, 81% female, 20 ± 1 years old) at multiple levels, including common single nucleotide polymorphism (SNP)-based heritability estimation, SNP-based genome-wide association study (GWAS), gene-based analysis, and pathway analysis. We performed a pilot GWAS in 2441 individuals and replicated it in an independent cohort of 943 individuals. Common SNP-based heritability was estimated to be 25% for spontaneous perceptual rivalry. SNPs rs184765639 and rs75595941 were associated with voluntary modulation, and imaging data suggested genotypic difference of rs184765639 in the surface area of the left caudal-middle frontal cortex. Additionally, converging evidence from multilevel analyses associated genes such as PRMT1 with perceptual switching rate, and MIR1178 with voluntary modulation strength. In summary, this study discovered specific genetic contributions to perceptual rivalry and its voluntary modulation in human beings. These findings may promote our understanding of psychiatric disorders, as perceptual rivalry is a potential psychiatric biomarker.SIGNIFICANCE STATEMENT Perceptual rivalry is an important visual phenomenon in which our perception of a physically constant visual input spontaneously switches between two different states. There are individual variations in perceptual switching rate and voluntary modulation strength. Our genomic analyses reveal several loci associated with these two kinds of variation. Because perceptual rivalry is thought to be relevant to and potentially an endophenotype for psychiatric disorders, these results may help understand not only visual cognition, but also psychiatric disorders.

p53 induces miR-199a-3p to suppress mechanistic target of rapamycin activation in cisplatin-induced acute kidney injury.

How p53 participates in acute kidney injury (AKI) progress and what are the underlying mechanisms remain illusive. For this issue, it is important to probe into the role of p53 in cisplatin-induced AKI. We find that p53 was upregulated in cisplatin-induced AKI, yet, pifithrin-α inhibites the p53 expression to attenuated renal injury and cell apoptosis both in vivo cisplatin-induced AKI mice and in vitro HK-2 human renal tubular epithelial cells. To knock down p53 by siRNA significantly decreased the miRNA, miR-199a-3p, expression in HK-2 cells. Blockade of miR-199a-3p significantly reduced cisplatin-induced cell apoptosis and inhibited caspase-3 activity. Mechanistically, we identified that miR-199a-3p directly bound to mechanistic target of rapamycin (mTOR) 3'-untranslated region and overexpressed miR-199a-3p reduce the expression and phosphorylation of mTOR. Furthermore, we demonstrated that p53 inhibited mTOR activation through activating miR-199a-3p. In conclusion, our findings reveal that p53, upregulating the expression of miR-199a-3p affects the progress of cisplatin-induced AKI, which might provide a promising therapeutic target of AKI.

MTD: a mammalian transcriptomic database to explore gene expression and regulation.

A systematic transcriptome survey is essential for the characterization and comprehension of the molecular basis underlying phenotypic variations. Recently developed RNA-seq methodology has facilitated efficient data acquisition and information mining of transcriptomes in multiple tissues/cell lines. Current mammalian transcriptomic databases are either tissue-specific or species-specific, and they lack in-depth comparative features across tissues and species. Here, we present a mammalian transcriptomic database (MTD) that is focused on mammalian transcriptomes, and the current version contains data from humans, mice, rats and pigs. Regarding the core features, the MTD browses genes based on their neighboring genomic coordinates or joint KEGG pathway and provides expression information on exons, transcripts and genes by integrating them into a genome browser. We developed a novel nomenclature for each transcript that considers its genomic position and transcriptional features. The MTD allows a flexible search of genes or isoforms with user-defined transcriptional characteristics and provides both table-based descriptions and associated visualizations. To elucidate the dynamics of gene expression regulation, the MTD also enables comparative transcriptomic analysis in both intraspecies and interspecies manner. The MTD thus constitutes a valuable resource for transcriptomic and evolutionary studies. The MTD is freely accessible at http://mtd.cbi.ac.cn.

Cascade Process for Direct Transformation of Aldehydes (RCHO) to Nitriles (RCN) Using Inorganic Reagents NH2OH/Na2CO3/SO2F2 in DMSO.

A simple, mild, and practical process for direct conversion of aldehydes to nitriles was developed feathering a wide substrate scope and great functional group tolerability (52 examples, over 90% yield in most cases) using inorganic reagents (NH2OH/Na2CO3/SO2F2) in DMSO. This method allows for transformations of readily available, inexpensive, and abundant aldehydes to highly valuable nitriles in a pot, atom, and step-economical manner without transition metals. This protocol will serve as a robust tool for the installation of cyano-moieties to complicated molecules.

SO2F2-Mediated Oxidative Dehydrogenation and Dehydration of Alcohols to Alkynes.

Direct synthesis of alkynes from inexpensive, abundant alcohols was achieved in high yields (greater than 40 examples, up to 95% yield) through a SO2F2-promoted dehydration and dehydrogenation process. This straightforward transformation of sp3-sp3 (C-C) bonds to sp-sp (C≡C) bonds requires only inexpensive and readily available reagents (no transition metals) under mild conditions. The crude alkynes are sufficiently free of impurities to permit direct use in further transformations, as illustrated by regioselective Huisgen alkyne-azide cycloaddition reactions with PhN3 to give 1,4-substituted 1,2,3-traiazoles (16 examples, up to 92% yield) and Sonogashira couplings (10 examples, up to 77% yield).

Multi-regional sequencing reveals intratumor heterogeneity and positive selection of somatic mtDNA mutations in hepatocellular carcinoma and colorectal cancer.

Recent studies have revealed significant intratumor heterogeneity (ITH) of nuclear genome mutations and highlighted its function in tumor progression and treatment resistance. However, the ITH of somatic mitochondrial DNA (mtDNA) mutations detected in cancers remains unknown. In this study, we performed multiregional mtDNA sequencing of tumor and paratumor tissue samples from 12 hepatocellular carcinoma (HCC) and 13 colorectal cancer (CRC) patients. A substantial level of mtDNA mutations was found in paired non-HCC inflammatory tissues, suggesting that these tissues might not be mtDNA-genetically "normal." Moreover, our data indicated that the ITH of somatic mtDNA mutations was a common feature in HCC and CRC patients. In addition, we found that shared mutations which were observed in at least 2 samples in each patient exhibited a significantly higher heteroplasmic level than mutations that were private to a specific tumor region from both HCC (p = 0.039) and CRC patients (p = 0.001). The heteroplasmic level of shared mutations was positively correlated with intratumoral recurrence of mtDNA mutations. We also found that shared mutations in tumor tissues with a higher degree of pathogenicity risk exhibited a higher heteroplasmic level and intratumoral recurrence in both HCC and CRC patients. These findings suggest that some mtDNA mutations may undergo positive selection during the clonal expansion. Taken together, our analyses identified various levels of ITH of somatic mtDNA mutations in HCC and CRC patients and provided evidence supporting the positive selection working on some somatic mtDNA mutations in tumor tissues.

Nature vs. nurture in human sociality: multi-level genomic analyses of social conformity.

Social conformity is fundamental to human societies and has been studied for more than six decades, but our understanding of its mechanisms remains limited. Individual differences in conformity have been attributed to social and cultural environmental influences, but not to genes. Here we demonstrate a genetic contribution to conformity after analyzing 1,140 twins and single-nucleotide polymorphism (SNP)-based studies of 2,130 young adults. A two-step genome-wide association study (GWAS) revealed replicable associations in 9 genomic loci, and a meta-analysis of three GWAS with a sample size of ~2,600 further confirmed one locus, corresponding to the NAV3 (Neuron Navigator 3) gene which encodes a protein important for axon outgrowth and guidance. Further multi-level (haplotype, gene, pathway) GWAS strongly associated genes including NAV3, PTPRD (protein tyrosine phosphatase receptor type D), ARL10 (ADP ribosylation factor-like GTPase 10), and CTNND2 (catenin delta 2), with conformity. Magnetic resonance imaging of 64 subjects shows correlation of activation or structural features of brain regions with the SNPs of these genes, supporting their functional significance. Our results suggest potential moderate genetic influence on conformity, implicate several specific genetic elements in conformity and will facilitate further research on cellular and molecular mechanisms underlying human conformity.

Amino acids/peptides conjugated heterocycles: A tool for the recent development of novel therapeutic agents.

Amino acids/peptide conjugated heterocycles represent an important class of therapeutical agents. Biologically active heterocycles are conjugated with amino acids or peptides to increase the drug resistance. Furthermore, the amino acid/peptide based drugs have low toxicity, ample bioavailability and permeability, modest potency and good metabolic and pharmacokinetic properties. Synthetic amino acid/peptides based heterocyclic conjugates constitute a promising choice for the development of new, less toxic and safer conventional pharmaceutical drugs in the near future. In this review, we discuss and highlight the recent findings of the structural features that encourage biological applications of amino acid/peptides based conjugates.

Free Flap Transfer for Head and Neck Reconstruction Using Local Anesthesia in Elderly Patients.

BACKGROUND: The incidence of skin cancer appearing on the head and neck areas is higher in elderly patients. Although free flap reconstruction is the mainstay after tumor excision, it is challenging to complete in elderly patients, owing to the high risk of complications and/or mortality rates associated with the use of general anesthesia. In this study, we used only local anesthesia in free tissue reconstruction of the head and neck in five elderly patients. MATERIALS AND METHODS: From 2013 to 2016, 5 elderly patients with high risk of general anesthesia underwent reconstruction with either anterolateral thigh free flaps or groin free flap under local anesthesia, after wide excision of malignant tumors at head and neck. For each patient, the following information was collected: age, gender, body weight, anesthesia agents, intravenous fluid, blood loss, site of lesion, flap size, operation time, complications, and follow-up time. RESULTS: All flaps survived completely. The mean age of 5 patients (3 male patients and 2 female patients) was 84 years (range, 68-100 years), and mean flap size was 199.6 cm (range, 120-330 cm). The mean follow-up period was 26.6 months (range, 5-38 months). No complications were found. CONCLUSIONS: With proper local anesthesia, successful head and neck reconstruction with free flap was possible, and patient prognosis was positive. There are numerous advantages, including: (1) a safer and inexpensive operation; (2) no complications from general anesthesia; (3) the fact that free flap transfer can be performed in elderly patients, even if they cannot tolerate general anesthesia; and (4) allowance of the performance of free tissue transferring in countries without adequate medical resources.

Expeditious trifluoromethylthiolation and trifluoromethylselenolation of alkynyl(phenyl)iodoniums by [XCF3]- (X = S, Se) anions.

Trifluoromethylthiolation and trifluoromethylselenolation of alkynyl(phenyl)iodonium tosylates by [XCF3]- (X = S, Se) ions was accomplished in 5-10 minutes at room temperature under a N2 atmosphere and provided a variety of alkynyl trifluoromethyl sulfides and selenides in good yields. Compared to the known methods, this approach has several advantages such as short reaction times and metal- and additive-free conditions without needing excess [Me4N][XCF3] reagents. Moreover, the less efficient reactions of (phenylethynyl)benziodoxol(on)e with [Me4N][XCF3] under the standard conditions demonstrate that acyclic alkynyl(phenyl)iodoniums are more powerful alkynyl sources in the conversion. This protocol allows for a fast and convenient access to numerous alkynyl trifluoromethyl sulfides and selenides.

Natural Proline-Rich Cyclopolypeptides from Marine Organisms: Chemistry, Synthetic Methodologies and Biological Status.

Peptides have gained increased interest as therapeutics during recent years. More than 60 peptide drugs have reached the market for the benefit of patients and several hundreds of novel therapeutic peptides are in preclinical and clinical development. The key contributor to this success is the potent and specific, yet safe, mode of action of peptides. Among the wide range of biologically-active peptides, naturally-occurring marine-derived cyclopolypeptides exhibit a broad range of unusual and potent pharmacological activities. Because of their size and complexity, proline-rich cyclic peptides (PRCPs) occupy a crucial chemical space in drug discovery that may provide useful scaffolds for modulating more challenging biological targets, such as protein-protein interactions and allosteric binding sites. Diverse pharmacological activities of natural cyclic peptides from marine sponges, tunicates and cyanobacteria have encouraged efforts to develop cyclic peptides with well-known synthetic methods, including solid-phase and solution-phase techniques of peptide synthesis. The present review highlights the natural resources, unique structural features and the most relevant biological properties of proline-rich peptides of marine-origin, focusing on the potential therapeutic role that the PRCPs may play as a promising source of new peptide-based novel drugs.