Metabolomic analysis reveals linkage between chemical composition and sensory quality of different floral honey samples.

Honey has a distinct flavor characterized by various volatiles and non-volatiles from diverse origins. In this study, metabolomics combined with sensory analysis was performed to identify relationships between chemical profile and sensory quality of honey. Targeted metabolomic analysis was conducted to determine volatile and non-volatile profiles of seven different honey. Volatile profile was analyzed using headspace solid-phase microextraction (HS-SPME) coupled to GC - MS. LC - MS/MS, HPLC - UV, and HPLC-RI were employed to analyze flavonoids, organic acids, and sugars, respectively. Authentic standards were utilized for confirmation of metabolites. Sensory evaluation included quantitative descriptive analysis and consumer acceptance test. The results showed that sucrose (sweetness) was responsible for a positive hedonic perception, while organic acids and flavonoids (sourness, astringency, bitterness) negatively affected consumer acceptance. Volatiles with floral notes (e.g. decyl formate) were preferred, but others with off-flavors (e.g. 2-methylbenzofuran) were not preferred by consumers. Flavor familiarity was strongly correlated with the consumer acceptance of honey, indicating that the balance between volatiles and non-volatiles is significant for honey flavor quality. This work demonstrates the role of key flavor compounds in honey quality, and may be applicable to the quality control of honey.

Efficacy of scrambler therapy in patients with painful diabetic peripheral neuropathy: A single-arm, prospective, pilot study.

BACKGROUND: A variety of medications are available to manage painful diabetic peripheral neuropathy (DPN), but the proper treatment remains challenging. Accordingly, various neuromodulation modalities have been used. However, no prospective clinical trials have evaluated the use of scrambler therapy (ST) in painful DPN. This study aimed to explore the long-term effects of ST in managing painful DPN. METHODS: The patients received 10 consecutive STs of 45 minutes every 1 to 2 days. The primary outcome was pain score. We measured the visual analog scale (VAS) pain scores at baseline, during ST, immediately after ST, and at 1, 2, 3, and 6 months after ST. The secondary outcomes were Michigan Neuropathy Screening Instrument (MNSI), Semmes-Weinstein monofilament test, and Leeds Assessment of Neuropathic Symptoms and Signs pain scores, which were measured at baseline, immediately after ST, and at 1, 2, 3, and 6 months after ST. RESULTS: VAS scores showed significant improvement at the 8th, 9th, and 10th sessions during ST and 1 month after ST. The MNSI self-report component score was decreased 1 month after the ST. However, all other outcomes did not show significant differences compared to the baseline. CONCLUSION: ST may have short-term effects and limited long-term effects on painful DPN.

Chromosome-level genome assembly of the Asian aspen Populus davidiana Dode.

The genome of Populus davidiana, a keystone aspen species, has been sequenced to improve our understanding of the evolutionary and functional genomics of the Populus genus. The Hi-C scaffolding genome assembly resulted in a 408.1 Mb genome with 19 pseudochromosomes. The BUSCO assessment revealed that 98.3% of the genome matched the embryophytes dataset. A total of 31,862 protein-coding sequences were predicted, of which 31,619 were functionally annotated. The assembled genome was composed of 44.9% transposable elements. These findings provide new knowledge about the characteristics of the P. davidiana genome and will facilitate comparative genomics and evolutionary research on the genus Populus.

Inhibition of CXXC5 function rescues Alzheimer's disease phenotypes by restoring Wnt/ß-catenin signaling pathway.

Alzheimer's disease (AD) is the most prevalent type of dementia and is characterized by cognitive deficits and accumulation of pathological plaques. Owing to the complexity of AD development, paradigms for AD research and drug discovery have shifted to target factors that mediate multiple pathogenesis in AD. Increasing evidence suggests that the suppression of the Wnt/ß-catenin signaling pathway plays substantial roles in AD progression. However, the underlying mechanism for the suppression of Wnt/ß-catenin pathway associated with AD pathogenesis remains unexplored. In this study, we identified that CXXC5, a negative feedback regulator of the Wnt/ß-catenin pathway, was overexpressed in the tissues of AD patients and 5xFAD transgenic mice paired with the suppression of Wnt/ß-catenin pathway and its target genes related to AD. The level of CXXC5 was upregulated, upon aging of 5xFAD mice. AD characteristics including cognitive deficits, amyloid-ß (Aß) plaques, neuronal inflammation, and age-dependent increment of AD-related markers were rescued in Cxxc5-/-/5xFAD mice. 5-methoxyindirubin-3'-oxime (KY19334), a small molecule that restores the suppressed Wnt/ß-catenin pathway via interference of the CXXC5-Dvl interaction, significantly improved the overall pathogenic phenotypes of 5xFAD mice. Collectively, our findings revealed that CXXC5 plays a key role in AD pathogenesis and suggest inhibition of CXXC5-Dvl interaction as a new therapeutic approach for AD.

Vascular Endothelial Growth Factor Receptor 1 Targeting Fusion Polypeptides with Stimuli-Responsiveness for Anti-angiogenesis.

Genetically engineered fusion polypeptides have been investigated to introduce unique bio-functionality and improve some therapeutic activity for anti-angiogenesis. We report herein that stimuli-responsive, vascular endothelial growth factor receptor 1 (VEGFR1) targeting fusion polypeptides composed of a VEGFR1 (fms-like tyrosine kinase-1 (Flt1)) antagonist, an anti-Flt1 peptide, and a thermally responsive elastin-based polypeptide (EBP) were rationally designed at the genetic level, biosynthesized, and purified by inverse transition cycling to develop potential anti-angiogenic fusion polypeptides to treat neovascular diseases. A series of hydrophilic EBPs with different block lengths were fused with an anti-Flt1 peptide, forming anti-Flt1-EBPs, and the effect of EBP block length on their physicochemical properties was examined. While the anti-Flt1 peptide decreased phase-transition temperatures of anti-Flt1-EBPs, compared with EBP blocks, anti-Flt1-EBPs were soluble under physiological conditions. The anti-Flt1-EBPs dose dependently inhibited the binding of VEGFR1 against vascular endothelial growth factor (VEGF) as well as tube-like network formation of human umbilical vein endothelial cells under VEGF-triggered angiogenesis in vitro because of the specific binding between anti-Flt1-EBPs and VEGFR1. Furthermore, the anti-Flt1-EBPs suppressed laser-induced choroidal neovascularization in a wet age-related macular degeneration mouse model in vivo. Our results indicate that anti-Flt1-EBPs as VEGFR1-targeting fusion polypeptides have great potential for efficacious anti-angiogenesis to treat retinal-, corneal-, and choroidal neovascularization.

Draft Genome Sequence for the Symbiotic Pine Mushroom Tricholoma matsutake.

We report the high-quality genome sequence of Tricholoma matsutake strain 2001, which was isolated from a mushroom fruiting body in South Korea. The genome has 80 contigs, a size of 162.6 Mb, and an N50 value of 5,103,859 bp and will provide insight into the symbiotic association between T. matsutake and Pinus densiflora.

A retrospective study on the clinical characteristics and prognosis of alopecia totalis and universalis: An update on prognosis.

Alopecia totalis (AT) and alopecia universalis (AU) is known to have a poor prognosis with high relapse rate, and treatment failure is observed in most patients, regardless of the type of therapy. Although treatment and the prognosis of AT and AU have improved in recent years, old data are routinely cited in recent review papers without questioning them. The authors aimed to study the clinical characteristics and prognosis of AT and AU to update and compare the results with those of previously reported studies. The authors retrospectively reviewed patients diagnosed with AT and AU from 2006 to 2017 in a single institution. Of the 419 patients, the mean age at first episode was 22.9 years, and 24.6% had early onset (≤13 years). During follow-up, 53.9% had more than 50% hair growth, and 19.6% of patients showed >90% hair growth. Among patients who showed >50% improvement, 36.7% had no recurrence. In early studies conducted in the 1950s and 1960s, the chance of full hair regrowth was reported to be <10%. In our study, patients with >90% improvement in AT and AU accounted for 19.6% of patients. The authors provide an update on data regarding the prognoses of AT and AU.

Long-acting recombinant human follicle-stimulating hormone (SAFA-FSH) enhances spermatogenesis.

Introduction: Administration of follicle-stimulating hormone (FSH) has been recommended to stimulate spermatogenesis in infertile men with hypogonadotropic hypogonadism, whose sperm counts do not respond to human chorionic gonadotropin alone. However, FSH has a short serum half-life requiring frequent administration to maintain its therapeutic efficacy. To improve its pharmacokinetic properties, we developed a unique albumin-binder technology, termed "anti-serum albumin Fab-associated" (SAFA) technology. We tested the feasibility of applying SAFA technology to create long-acting FSH as a therapeutic candidate for patients with hypogonadotropic hypogonadism. Methods: SAFA-FSH was produced using a Chinese hamster ovary expression system. To confirm the biological function, the production of cyclic AMP and phosphorylation of ERK and CREB were measured in TM4-FSHR cells. The effect of gonadotropin-releasing hormone agonists on spermatogenesis in a hypogonadal rat model was investigated. Results: In in vitro experiments, SAFA-FSH treatment increased the production of cyclic AMP and increased the phosphorylation of ERK and CREB in a dose-dependent manner. In animal experiments, sperm production was not restored by human chorionic gonadotropin treatment alone, but was restored after additional recombinant FSH treatment thrice per week or once every 5 days. Sperm production was restored even after additional SAFA-FSH treatment at intervals of once every 5 or 10 days. Discussion: Long-acting FSH with bioactivity was successfully created using SAFA technology. These data support further development of SAFA-FSH in a clinical setting, potentially representing an important advancement in the treatment of patients with hypogonadotropic hypogonadism.

Stimuli-responsive plasmonic core-satellite hybrid nanostructures with tunable nanogaps.

Incorporating stimuli-responsive block copolymers to hierarchical metallic nanoparticles (MNPs) is of particular interest due to their tunable plasmonic properties responding to environmental stimuli. We herein report thermo-responsive plasmonic core-satellite hybrid nanostructures with tunable nanogaps as surface-enhanced Raman scattering (SERS) nanotags. Two different diblock copolymers with opposite charges, poly(acrylic acid-b-N-isopropylacrylamide) (p(AAc-b-NIPAM)) and poly(N,N-dimethylaminoethyl methacrylate-b-N-isopropylacrylamide) (p(DMAEMA-b-NIPAM)), were synthesized. The negatively charged p(AAc-b-NIPAM)s were bound to gold nanospheres (GNSs), while the positively charged p(DMAEMA-b-NIPAM)s were conjugated to gold nanorods (GNRs) via gold-sulfur bonds. When p(AAc-b-NIPAM)-GNSs and p(DMAEMA-b-NIPAM)-GNRs were electrostatically complexed, plasmonic hybrid nanostructures consisting of both GNS satellites and a GNR core were formed. Dynamic tuning of electromagnetic coupling of their nanogaps was achieved via a temperature-triggered conformational change of p(NIPAM) blocks. Furthermore, a sandwich-type immunoassay for the detection of immunoglobulin G was performed to demonstrate these core-satellites as potential SERS nanotags. Our results showed that these plasmonic core-satellites with stimuli-responsiveness are promising for SERS-based biosensing applications.

High-echoic line tracing of transthoracic echocardiography accurately assesses right ventricular enlargement in adult patients with atrial septal defect.

Accurate measurement of right ventricular (RV) size using transthoracic echocardiography (TTE) is important for evaluating the severity of congenital heart diseases. The RV end-diastolic area index (RVEDAi) determined using TTE is used to assess RV dilatation; however, the tracing line of the RVEDAi has not been clearly defined by the guidelines. This study aimed to determine the exact tracing method for RVEDAi using TTE. We retrospectively studied 107 patients with atrial septal defects who underwent cardiac magnetic resonance imaging (CMR) and TTE. We measured the RVEDAi according to isoechoic and high-echoic lines, and compared it with the RVEDAi measured using CMR. The isoechoic line was defined as the isoechoic endocardial border of the RV free wall, whereas the high-echoic line was defined as the high-echoic endocardial border of the RV free wall more outside than the isoechoic line. RVEDAi measured using high-echoic line (high-RVEDAi) was more accurately related to RVEDAi measured using CMR than that measured using isoechoic line (iso-RVEDAi). The difference in the high-RVEDAi was 0.3 cm2/m2, and the limit of agreement (LOA) was - 3.7 to 4.3 cm2/m2. With regard to inter-observer variability, high-RVEDAi was superior to iso-RVEDAi. High-RVEDAi had greater agreement with CMR-RVEDAi than with iso-RVEDAi. High-RVEDAi can become the standard measurement of RV size using two-dimensional TTE.

Phospholipase D1 promotes astrocytic differentiation through the FAK/AURKA/STAT3 signaling pathway in hippocampal neural stem/progenitor cells.

Phospholipase D1 (PLD1) plays a crucial role in cell differentiation of different cell types. However, the involvement of PLD1 in astrocytic differentiation remains uncertain. In the present study, we investigate the possible role of PLD1 and its product phosphatidic acid (PA) in astrocytic differentiation of hippocampal neural stem/progenitor cells (NSPCs) from hippocampi of embryonic day 16.5 rat embryos. We showed that overexpression of PLD1 increased the expression level of glial fibrillary acidic protein (GFAP), an astrocyte marker, and the number of GFAP-positive cells. Knockdown of PLD1 by transfection with Pld1 shRNA inhibited astrocytic differentiation. Moreover, PLD1 deletion (Pld1-/-) suppressed the level of GFAP in the mouse hippocampus. These results indicate that PLD1 plays a crucial role in regulating astrocytic differentiation in hippocampal NSPCs. Interestingly, PA itself was sufficient to promote astrocytic differentiation. PA-induced GFAP expression was decreased by inhibition of signal transducer and activation of transcription 3 (STAT3) using siRNA. Furthermore, PA-induced STAT3 activation and astrocytic differentiation were regulated by the focal adhesion kinase (FAK)/aurora kinase A (AURKA) pathway. Taken together, our findings suggest that PLD1 is an important modulator of astrocytic differentiation in hippocampal NSPCs via the FAK/AURKA/STAT3 signaling pathway.

House dust mite-induced Akt-ERK1/2-C/EBP beta pathway triggers CCL20-mediated inflammation and epithelial-mesenchymal transition for airway remodeling.

House dust mite (HDM) allergens cause inflammatory responses and chronic allergic diseases such as bronchial asthma and atopic dermatitis. Here, we investigate the mechanism by which HDM induces C-C chemokine ligand 20 (CCL20) expression to promote chronic inflammation and airway remodeling in an HDM-induced bronchial asthma mouse model. We showed that HDM increased CCL20 levels via the Akt-ERK1/2-C/EBPß pathway. To investigate the role of CCL20 in chronic airway inflammation and remodeling, we made a mouse model of CCL20-induced bronchial asthma. Treatment of anti-CCL20Ab in this mouse model showed the reduced airway hyper-responsiveness and inflammatory cell infiltration into peribronchial region by neutralizing CCL20. In addition, CCL20 induced the Nod-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome activation through NLRP3 deubiquitination and transcriptional upregulation in BEAS-2B cells. As expected, anti-CCL20Ab markedly suppressed NLRP3 activation induced by CCL20. Moreover, HDM-induced CCL20 leads to epithelial-mesenchymal transition in the lung epithelium which appears to be an important regulator of airway remodeling in allergic asthma. We also found that anti-CCL20Ab attenuates airway inflammation and remodeling in an HDM-induced mouse model of bronchial asthma. Taken together, our results suggest that HDM-induced CCL20 is required for chronic inflammation that contributes airway remodeling in a mouse model of asthma.

Injectable Hydrogels of Stimuli-Responsive Elastin and Calmodulin-Based Triblock Copolypeptides for Controlled Drug Release.

A variety of block copolypeptides with stimuli responsiveness have been of growing interest for dynamic self-assembly. Here, multistimuli-responsive triblock copolypeptides composed of thermosensitive elastin-based polypeptides (EBP) and ligand-responsive calmodulin (CalM) were genetically engineered, over-expressed, and nonchromatographically purified by inverse transition cycling. Diluted EBP-CalM-EBP (ECE) triblock copolypeptides under physiological conditions self-assembled into vesicles at the nanoscale by temperature-triggered aggregation of the EBP block with lower critical solution temperature behaviors. Furthermore, concentrated ECE triblock copolypeptides under identical conditions exhibited thermally induced gelation, resulting in physically crosslinked hydrogels. They showed controlled rheological and mechanical properties depending on the conformational change of the CalM middle block induced by binding either Ca2+ or Ca2+ and trifluoperazines (TFPs) as ligands. In addition, both Ca2+-free and Ca2+-bound ECE triblock copolypeptide hydrogels exhibited biocompatibility, while those bound to both Ca2+ and TFPs showed severe cytotoxicity because of controlled TFP release of the CalM blocks. The ECE triblock hydrogels with stimuli responsiveness would be useful as injectable drug delivery depots for biomedical applications.

Indirubin-3'-alkoxime derivatives for upregulation of Wnt signaling through dual inhibition of GSK-3ß and the CXXC5-Dvl interaction.

Glycogen synthase kinase-3ß (GSK-3ß) appears to be ordinarily expressed, and functionally redundant in Wnt/ß-catenin signaling. The Wnt proteins induce transduction of a cytoplasmic protein, Dishevelled (Dvl) which negatively modulates GSK-3ß activity. CXXC5 is a negative modulator of the Wnt/ß-catenin signaling through the interaction with Dvl in the cytosol. This indicates that Wnt/ß-catenin signaling could be efficiently modulated by controlling GSK-3ß and the CXXC5-Dvl interaction. In this study, we designed a series of indirubin-3'-oxime and indirubin-3'-alkoxime derivatives containing various functional groups at the 5- or 6-position (R1) alongside alkyl or benzylic moieties at the 3'-oxime position (R2). These activate Wnt signaling through inhibitions of both GSK-3ß and the CXXC5-Dvl protein-protein interaction, in addition, the improvement of pharmacological properties. The potent activity profiles of the synthesized compounds suggested that dual inhibition of GSK-3ß and the CXXC5-Dvl interaction could be an appropriate approach towards safely and efficientlyactivating Wntsignaling. Thus, dual-targeting inhibitors are potentially better candidates for efficient activation ofWntsignaling compared to GSK-3ß inhibitors.

Chromosome-level genome assembly of the fully mycoheterotrophic orchid Gastrodia elata.

Gastrodia elata, an obligate mycoheterotrophic orchid, requires complete carbon and mineral nutrient supplementation from mycorrhizal fungi during its entire life cycle. Although full mycoheterotrophy occurs most often in the Orchidaceae family, no chromosome-level reference genome from this group has been assembled to date. Here, we report a high-quality chromosome-level genome assembly of G. elata, using Illumina and PacBio sequencing methods with Hi-C technique. The assembled genome size was found to be 1045 Mb, with an N50 of 50.6 Mb and 488 scaffolds. A total of 935 complete (64.9%) matches to the 1440 embryophyte Benchmarking Universal Single-Copy Orthologs were identified in this genome assembly. Hi-C scaffolding of the assembled genome resulted in 18 pseudochromosomes, 1008 Mb in size and containing 96.5% of the scaffolds. A total of 18,844 protein-coding sequences (CDSs) were predicted in the G. elata genome, of which 15,619 CDSs (82.89%) were functionally annotated. In addition, 74.92% of the assembled genome was found to be composed of transposable elements. Phylogenetic analysis indicated a significant contraction of genes involved in various biosynthetic processes and cellular components and an expansion of genes for novel metabolic processes and mycorrhizal association. This result suggests an evolutionary adaptation of G. elata to a mycoheterotrophic lifestyle. In summary, the genomic resources generated in this study will provide a valuable reference genome for investigating the molecular mechanisms of G. elata biological functions. Furthermore, the complete G. elata genome will greatly improve our understanding of the genetics of Orchidaceae and its mycoheterotrophic evolution.

The Effects of Transglutaminase and Refrigerated Storage on the Physicochemical Properties of Whole Wheat Dough and Noodles.

This study investigated the effects of transglutaminase (TG) concentrations (0, 0.1% and 1%) on the physicochemical properties of whole wheat dough (WWD) and noodles (WWN) during refrigerated storage (0, 1, 2, and 3 days). The yield, ferulic acid (FA) content, molecular weight (Mw), and apparent viscosity (AV) of water extractable arabinoxylan (WEAX) from refrigerated WWDs were analysed. The WEAX yield and FA tended to increase with refrigerated storage, while the Mw decreased. WEAX FA of from WWD with TG tended to be smaller than the control during refrigeration. The AV for all WEAXs gradually decreased during refrigeration. The TG concentration effects on WWD resistance to extension and extensibility and the WWN cooking properties and texture profile analysis (TPA) were studied. The water absorption and swelling index tended to decrease in WWNs with TG depending on refrigeration time compared to the control samples. The TPA results showed that WWNs with TG were significantly harder than the control after two days of refrigeration. This study demonstrated that TG affected not only WWD composition but also WWN physical properties during refrigerated storage.

The complete chloroplast genome of Korean Gastrodia elata Blume.

The completed chloroplast genome of Gastrodia elata Blume (G. elata) from Korea was determined in this study. The cpDNA is 35,230 bp in length and lacked the large and small single copy (LSC and SSC) regions, due to the lost inverted repeat (IR). The overall AT content is 73.30%, and the cpDNA contains 20 protein-coding genes, 5 tRNA genes, and 3 rRNA genes. Remarkably, the Korean G. elata cp genome was 74 bp smaller than that of the Chinese G. elata. It revealed substantial sequence variants 495 SNPs and 75 InDels between the two G. elata genomes.

Elaborate evaluation of serial changes in electrocardiograms of atrial septal defects after transcatheter closure for a better understanding of the recovery process.

Serial changes of electrocardiograms (ECG) could be used to assess their clinical features in atrial septal defects (ASD) after transcatheter closure together with other clinical parameters. We retrospectively studied 100 ASD patients who underwent transcatheter closure. Complications of persistent atrial fibrillation occurred in five ASD patients, and they were excluded. We divided the other 95 patients according to PQ intervals before closure (normal: < 200 ms, n = 51; prolonged: ≥ 200 ms, n = 44) to evaluate their clinical characteristics and parameters such as echocardiography, chest X-rays, and brain natriuretic protein (BNP) levels. Individuals in the prolonged PQ group were significantly older, had higher incidences of paroxysmal atrial fibrillation (PAF) and heart failure (HF) treated with more ß-blockers and diuretics, and with a higher tendency of NYHA functional classification and BNP levels than the normal PQ group. The prolonged PQ group also had a significantly higher incidence of complete right bundle branch block, wider QRS intervals, and larger cardiothoracic ratios in chest X-rays accompanied by larger right atrial-areas and larger left atrial dimensions in echocardiograms. Furthermore, the prolonged PQ intervals with less PQ interval shortening after transcatheter closure revealed that the patients were the oldest at the time of closures and showed less structural normalization of the right heart and left atrium after ASD closure. PAF and HF also occurred more frequently in this subgroup. These results suggested that the ASD patients with prolonged PQ intervals with less PQ shortening were accompanied by more advanced clinical conditions. Together with other clinical parameters, detailed analyses of ECG and their changes after closure could elucidate the clinical characteristics and status of ASD patients with transcatheter closure and were useful for predicting structural normalization after transcatheter closure.

Sulforaphene Suppresses Adipocyte Differentiation via Induction of Post-Translational Degradation of CCAAT/Enhancer Binding Protein Beta (C/EBPß).

Adipocyte differentiation (adipogenesis) is a crucial process that determines the total number and size of mature adipocytes that will develop. In this study, the anti-adipogenic effect of sulforaphene (SFEN), a dietary isothiocyanate (ITC) derived from radish, is investigated both in 3T3-L1 pre-adipocytes and in human adipose tissue-derived stem cells. The results revealed that SFEN significantly inhibit adipogenic cocktail-induced adipocyte differentiation and lipid accumulation at the early stage of adipogenesis. Additionally, the effects are more potent compared to those of other ITCs derived from various cruciferous vegetables. As a related molecular mechanism of action, SFEN promotes the post-translational degradation of CCAAT/enhancer-binding protein (C/EBP) ß by decreasing the stability of C/EBPß, which is responsible for decreasing the expression of master regulatory proteins such as peroxisome proliferator-activated receptor γ and C/EBPα. Collectively, these results suggest that the intake of SFEN-enriched natural materials could be helpful as a strategy for preventing obesity.