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Blocking the association between the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein receptor-binding domain (RBD) and the human angiotensin-converting enzyme 2 (ACE2) is an attractive therapeutic approach to prevent the virus from entering human cells. While antibodies and other modalities have been developed to this end, d-amino acid peptides offer unique advantages, including serum stability, low immunogenicity, and low cost of production. Here, we designed potent novel D-peptide inhibitors that mimic the ACE2 α1-binding helix by searching a mirror-image version of the PDB. The two best designs bound the RBD with affinities of 29 and 31 nM and blocked the infection of Vero cells by SARS-CoV-2 with IC50 values of 5.76 and 6.56 μM, respectively. Notably, both D-peptides neutralized with a similar potency the infection of two variants of concern: B.1.1.7 and B.1.351 in vitro. These potent D-peptide inhibitors are promising lead candidates for developing SARS-CoV-2 prophylactic or therapeutic treatments.

Previously, our research group isolated Bifidobacterium breve IDCC4401 from infant feces as a potential probiotic. For this study, we evaluated the safety of B. breve IDCC4401 using genomic and phenotypic analyses. Whole genome sequencing was performed to identify genomic characteristics and investigate the potential presence of genes encoding virulence, antibiotic resistance, and mobile genetic elements. Phenotypic analyses including antibiotic susceptibility, enzyme activity, production of biogenic amines (BAs), and proportion of D-/L-lactate were evaluated using E-test, API ZYM test, high-performance liquid chromatography (HPLC), and D-/L-lactic acid assay respectively. The genome of B. breve IDCC4401 consists of 2,426,499 bp with a GC content of 58.70% and 2,016 coding regions. Confirmation of the genome as B. breve was provided by its 98.93% similarity with B. breve DSM20213. Furthermore, B. breve IDCC4401 genes encoding virulence and antibiotic resistance were not identified. Although B. breve IDCC4401 showed antibiotic resistance against vancomycin, we confirmed that this was an intrinsic feature since the antibiotic resistance gene was not present. B. breve IDCC4401 showed leucine arylamidase, cystine arylamidase, α-galactosidase, β-galactosidase, and α-glucosidase activities, whereas it did not show production of harmful enzymes such as β-glucosidase and β-glucuronidase. In addition, B. breve IDCC4401 did not produce any tyramine, histamine, putrescine, cadaverine, or 2-phenethylamine, which are frequently detected BAs during fermentation. B. breve IDCC4401 produced 95.08% of L-lactate and 4.92% of Dlactate. Therefore, our findings demonstrate the safety of B. breve IDCC 4401 as a potential probiotic for use in the food industry.

A new Ba2CuO4-y superconductor with critical temperature (Tc) exceeding 70 K was discovered. The X-ray absorption measurement gives evidence that this cuprate resembles La2CuO4 but is doped with a fairly large amount of holes, while in contrast to the so far known hole-doped high-Tc cuprates, the new cuprate possesses a much shorter local apical oxygen distance as well as much expanded in-plane Cu–O bond, leading to unprecedented compressed local octahedron. In compressed local octahedron, the Cu3d3z2–r2 orbital level will be lifted above the Cu3dx2-y2 orbital level with more three-dimensional features, implying that pairing symmetry may carry admixtures from more than one gap, suggesting that Ba2CuO4-y composed of alkaline earth copper oxides that are the essential elements to form cuprate superconductors may belong to a new branch of cuprate superconductors.

The genus Fragaria encompass fruits with diverse colors influenced by the distribution and accumulation of anthocyanin. Particularly, the fruit colors of strawberries with different ploidy levels are determined by expression and natural variations in the vital structural and regulatory genes involved in the anthocyanin pathway. Among the regulatory genes, MYB10 transcription factor is crucial for the expression of structural genes in the anthocyanin pathway. In the present study, we performed a genome wide investigation of MYB10 in the diploid and octoploid Fragaria species. Further, we identified seven quantitative trait loci (QTLs) associated with fruit color in octoploid strawberry. In addition, we predicted 20 candidate genes primarily influencing the fruit color based on the QTL results and transcriptome analysis of fruit skin and flesh tissues of light pink, red, and dark red strawberries. Moreover, the computational and transcriptome analysis of MYB10 in octoploid strawberry suggests that the difference in fruit colors could be predominantly influenced by the expression of MYB10 from the F. iinumae subgenome. The outcomes of the present endeavor will provide a platform for the understanding and tailoring of anthocyanin pathway in strawberry for the production of fruits with aesthetic colors.

Background Palmijihwanghwan (PJH) is a traditional medicine and eight constituents derived from PJH possess anti-inflammatory activities. However, the scientific evidence for its potential as a therapeutic agent for inflammatory lung disease has not yet been studied. In this study, we examined the protective effect of PJH in a mouse model of chronic obstructive pulmonary disease (COPD) induced by cigarette smoke (CS) with lipopolysaccharide (LPS). Methods Mice received CS exposure for 8 weeks and intranasal instillation of LPS on weeks 1, 3, 5 and 7. PJH (100 and 200 mg/kg) was administrated daily 1 h before CS treatment for the last 4 weeks. Results Compared with CS plus LPS-exposed mice, mice in the PJH-treated group showed significantly decreased inflammatory cells count and reduced inflammatory cytokines including interleukin-1 beta (IL-1β), IL-6 and tumor necrosis factor alpha (TNF-α) levels in broncho-alveolar lavage fluid (BALF) and lung tissue. PJH also suppressed the phosphorylation of nuclear factor kappa B (NF-κB) and extracellular signal-regulated kinase1/2 (ERK1/2) caused by CS plus LPS exposure. Furthermore, CS plus LPS induced increases in matrix metallopeptidase (MMP)-7, MMP-9, and transforming growth factor-β (TGF-β) expression and collagen deposition that were inhibited in PJH-treated mice. Conclusions This study demonstrates that PJH prevents respiratory inflammation and airway remodeling caused by CS with LPS exposure suggesting potential therapy for the treatment of COPD.

The nanoscale hierarchical design that draws inspiration from nature's biomaterials allows the enhancement of material performance and enables multifarious applications. Self-assembly of block copolymers represents one of these artificial techniques that provide an elegant bottom-up strategy for the synthesis of soft colloidal hierarchies. Fast-growing polymerization-induced self-assembly (PISA) renders a one-step process for the polymer synthesis and in situ self-assembly at high concentrations. Nevertheless, it is exceedingly challenging for the fabrication of hierarchical colloids via aqueous PISA, simply because most monomers produce kinetically trapped spheres except for a few PISA-suitable monomers. We demonstrate here a sequential one-pot synthesis of hierarchically self-assembled polymer colloids with diverse morphologies via aqueous PISA that overcomes the limitation. Complex formation of water-immiscible monomers with cyclodextrin via "host-guest" inclusion, followed by sequential aqueous polymerization, provides a linear triblock terpolymer that can in situ self-assemble into hierarchical nanostructures. To access polymer colloids with different morphologies, three types of linear triblock terpolymers were synthesized through this methodology, which allows the preparation of AXn-type colloidal molecules (CMs), core-shell-corona micelles, and raspberry-like nanoparticles. Furthermore, the phase separations between polymer blocks in nanostructures were revealed by transmission electron microscopy and atomic force microscopy-infrared spectroscopy. The proposed mechanism explained how the interfacial tensions and glass transition temperatures of the core-forming blocks affect the morphologies. Overall, this study provides a scalable method of the production of CMs and other hierarchical structures. It can be applied to different block copolymer formulations to enrich the complexity of morphology and enable diverse functions of nano-objects.

Background Lactobacillus rhamnosus GG (LGG) is the most widely used probiotic, but the mechanisms underlying its beneficial effects remain unresolved. Previous studies typically inoculated LGG in hosts with established gut microbiota, limiting the understanding of specific impacts of LGG on host due to numerous interactions among LGG, commensal microbes, and the host. There has been a scarcity of studies that used gnotobiotic animals to elucidate LGG-host interaction, in particular for gaining specific insights about how it modifies the metabolome. To evaluate whether LGG affects the metabolite output of pathobionts, we inoculated with LGG gnotobiotic mice containing Propionibacterium acnes, Turicibacter sanguinis, and Staphylococcus aureus (PTS). Results 16S rRNA sequencing of fecal samples by Ion Torrent and MinION platforms showed colonization of germ-free mice by PTS or by PTS plus LGG (LTS). Although the body weights and feeding rates of mice remained similar between PTS and LTS groups, co-associating LGG with PTS led to a pronounced reduction in abundance of P. acnes in the gut. Addition of LGG or its secretome inhibited P. acnes growth in culture. After optimizing procedures for fecal metabolite extraction and metabolomic liquid chromatography-mass spectrometry analysis, unsupervised and supervised multivariate analyses revealed a distinct separation among fecal metabolites of PTS, LTS, and germ-free groups. Variables-important-in-projection scores showed that LGG colonization robustly diminished guanine, ornitihine, and sorbitol while significantly elevating acetylated amino acids, ribitol, indolelactic acid, and histamine. In addition, carnitine, betaine, and glutamate increased while thymidine, quinic acid and biotin were reduced in both PTS and LTS groups. Furthermore, LGG association reduced intestinal mucosal expression levels of inflammatory cytokines, such as IL-1α, IL-1β and TNF-α. Conclusions LGG co-association had a negative impact on colonization of P. acnes, and markedly altered the metabolic output and inflammatory response elicited by pathobionts.

The mechanism of superconductivity in cuprates remains one of the big challenges of condensed matter physics.High Tc cuprates crystallize into layered perovskite structure featuring copper oxygen octahedral coordination. Due to the Jahn Teller effect in combination with the strong static Coulomb interaction, the octahedra in high Tc cuprates are elongated along the c axis, leading to a 3dx2-y2 orbital at the top of the band structure wherein the doped holes reside.This scenario gives rise to two dimensional characteristics in high Tc cuprates that favor d wave pairing symmetry. Here we report superconductivity in a cuprate Ba2CuO4-y wherein the local octahedron is in a very exceptional compressed version.The Ba2CuO4-y compound was synthesized at high pressure at high temperatures, and shows bulk superconductivity with critical temperature Tc above 70 K at ambient conditions. This superconducting transition temperature is more than 30 K higher than the Tc for the isostructural counterparts based on classical La2CuO4. X-ray absorption measurements indicate the heavily doped nature of the Ba2CuO4-y superconductor. In compressed octahedron the 3d3z2-r2 orbital will be lifted above the 3dx2-y2 orbital, leading to significant three dimensional nature in addition to the conventional 3dx2-y2 orbital. This work sheds important new light on advancing our comprehensive understanding of the superconducting mechanism of high Tc in cuprate materials., Comment: Total 28 pages incuding 9 Figures

Peroxisome proliferator-activated receptor (PPAR)-α/γ dual agonists have been developed to treat metabolic diseases; however, most of them exhibit side effects such as body weight gain and oedema. Therefore, we developed a novel PPARα/γ dual agonist that modulates glucose and lipid metabolism without adverse effects. We synthesised novel compounds composed of coumarine and chalcone, determined their crystal structures, and then examined their binding affinity toward PPARα/γ. We investigated the expression of PPARα and PPARγ target genes by chemicals in HepG2, differentiated 3T3-L1, and C2C12 cells. We examined the effect of chemicals on glucose and lipid metabolism in db/db mice. Only MD001 functions as a PPARα/γ dual agonist in vitro. MD001 increased the transcriptional activity of PPARα and PPARγ, resulting in enhanced expression of genes related to β-oxidation and fatty acid and glucose uptake. MD001 significantly improved blood metabolic parameters, including triglycerides, free fatty acids, and glucose, in db/db mice. In addition, MD001 ameliorated hepatic steatosis by stimulating β-oxidation in vitro and in vivo. Our results demonstrated the beneficial effects of the novel compound MD001 on glucose and lipid metabolism as a PPARα/γ dual agonist. Consequently, MD001 may show potential as a novel drug candidate for the treatment of metabolic disorders.

Background: Upregulation of the endocannabinoid enzyme fatty acid amide hydrolase (FAAH) has been linked to abnormal activity in frontoamygdalar circuits, a hallmark of posttraumatic stress disorder. We tested the hypothesis that FAAH levels in the amygdala were negatively correlated with functional connectivity between the amygdala and prefrontal cortex, subserving stress and affect control. Methods: Thirty-one healthy participants completed positron emission tomography (PET) imaging with the FAAH probe [C-11]CURB, and resting-state functional MRI scans. Participants were genotyped for the FAAH polymorphism rs324420, and trait neuroticism was assessed. We calculated amygdala functional connectivity using predetermined regions of interest (including the subgenual ventromedial prefrontal cortex [sgvmPFC] and the dorsal anterior cingulate cortex [dACC]) and a seed-to-voxel approach. We conducted correlation analyses on functional connectivity, with amygdala [C-11]CURB binding as a variable of interest. Results: The strength of amygdala functional connectivity with the sgvmPFC and dACC was negatively correlated with [C-11]CURB binding in the amygdala (sgvmPFC: r = −0.38, q = 0.04; dACC: r = –0.44; q = 0.03). Findings were partly replicated using the seed-to-voxel approach, which showed a cluster in the ventromedial prefrontal cortex, including voxels in the dACC but not the sgvmPFC (cluster-level, family-wise error rate corrected p < 0.05). Limitations: We did not replicate earlier findings of a relationship between an FAAH polymorphism (rs324420) and amygdala functional connectivity. Conclusion: Our data provide preliminary evidence that lower levels of FAAH in the amygdala relate to increased frontoamygdalar functional coupling. Our findings were consistent with the role of FAAH in regulating brain circuits that underlie fear and emotion processing in humans.

Recent technical developments brought negative side effects such as air pollution and large-scale fires, increasingly exposing people to diesel engine exhaust particles (DEP). Testing how DEP inhalation triggers pathophysiology in animal models could be useful in determining how it affects humans. To this end, the aim of this study was to investigate the effects of pulmonary exposure to DEP for seven consecutive days in experimental male C5BL6/N mice. Twenty-four C5BL6/N mice were treated with one of the three test materials: distilled water for control, a low DEP exposure (5 mg/kg), or a high DEP exposure (15 mg/kg). Exposure to DEP induced decreased body weight, however, it gradually increased pulmonary weight in a DEP-dose-dependent manner. DEP exposure significantly elevated soot accumulation in the lungs, with the alteration of pulmonary homeostasis. It also elevated infiltrated immune cells, thus significantly increasing inflammatory cytokine mRNA and protein production in the lungs and broncho-alveolar lavage fluid, respectively. Pulmonary DEP exposure also altered behavioral responses in the open field test (OFT). Low exposure elevated moving distance and speed, while significantly decreasing the number of trials to enter the central zone. Different concentrations of DEP resulted in different behavioral changes, however, while anxiety levels increased, their degree was independent of DEP concentrations. Results suggest that DEP exposure may possess pro-inflammatory responses in the lungs and trigger anxiety.

The COVID-19 pandemic has highlighted the need for diversity in the market and alternative materials for personal protective equipment (PPE). Paper has high coatability for tunable barrier performance, and an agile production process, making it a potential substitute for polyolefin-derived PPE materials. Bleached and newsprint papers were laminated with polyethylene (PE) coatings of different thicknesses, and characterised for their potential use as medical gowns for healthcare workers and COVID-19 patients. Thicker PE lamination improved coating homogeneity and water vapour resistance. 49 GSM bleached paper with 16 GSM PE coating showed high tensile and seam strength, and low water vapour transmission rate (WVTR). Phi-X174 bacteriophage testing revealed that paper laminated with 15 GSM coating hinders virus penetration. This research demonstrates that PE laminated paper is a promising material for low cost viral protective gowns., Graphical abstract Image 1

The epithelial cell adhesion molecule (EpCAM) is a tumor-associated antigen and a potential target for tumor vaccine. The EpCAM is a cell-surface glycoprotein highly expressed in colorectal carcinomas. The objective of the present study is to develop an edible vaccine system through Agrobacterium-mediated transformation in Chinese cabbage (Brassica rapa). For the transformation, two plant expression vectors containing genes encoding for the EpCAM recombinant protein along with the fragment crystallizable (Fc) region of immunoglobulin M (IgM) and Joining (J)-chain tagged with the KDEL endoplasmic reticulum retention motif (J-chain K) were constructed. The vectors were successfully transformed and expressed in the Chinese cabbage individually using Agrobacterium. The transgenic Chinese cabbages were screened using genomic polymerase chain reaction (PCR) in T0 transgenic plant lines generated from both transformants. Similarly, the immunoblot analysis revealed the expression of recombinant proteins in the transformants. Further, the T1 transgenic plants were generated by selfing the transgenic plants (T0) carrying EpCAM&ndash, IgM Fc and J-chain K proteins, respectively. Subsequently, the T1 plants generated from EpCAM&ndash, IgM Fc and J-chain K transformants were crossed to generate F1 plants carrying both transgenes. The presence of both transgenes was validated using PCR in the F1 plants. In addition, the expression of Chinese cabbage-derived EpCAM&ndash, IgM Fc &times, J-chain K was evaluated using immunoblot and ELISA analyses in the F1 plants. The outcomes of the present study can be utilized for the development of a potential anti-cancer vaccine candidate using Chinese cabbage.

Arylnaphthalene lignan lactones belong to a class of natural lignans, and more than 60 analogs have been isolated. Their pharmacological activities as well as unique structural features have attracted considerable attention from medicinal and synthetic chemists. Since the first synthesis in 1895, many synthetic methodologies with ionic or pericyclic reaction mechanisms have been reported. Transition metal catalysts sometimes provide exceptional synthetic versatility for the syntheses of natural compounds. Recently, transition metal-mediated methodologies were investigated for the construction of basic scaffolds of arylnaphthalene lignan lactones. Five kinds of transition metal catalysts containing gold, manganese, nickel, palladium, and silver have been explored. Most of the metal catalysts successfully created arylnaphthalene lactones by intermolecular or intramolecular annulative cyclization. In this review, all reports of transition metal-mediated annulative construction of arylnaphthalene lignan lactones were compiled, and synthetic approaches, mechanistic aspects, and successful applications were discussed.

Background The response of progenitor cells (PCs) to transient myocardial ischemia in patients with coronary artery disease remains unknown. We aimed to investigate the PC response to exercise‐induced myocardial ischemia (ExMI) and compare it to flow mismatch during pharmacological stress testing. Methods and Results A total of 356 patients with stable coronary artery disease underwent 99mTc‐sestamibi myocardial perfusion imaging during exercise (69%) or pharmacological stress (31%). CD 34 + and CD 34 + /chemokine (C‐X‐C motif) receptor 4 PC s were enumerated by flow cytometry. Change in PC count was compared between patients with and without myocardial ischemia using linear regression models. Vascular endothelial growth factor and stromal‐derived factor‐1α were quantified. Mean age was 63±9 years; 76% were men. The incidence of Ex MI was 31% and 41% during exercise and pharmacological stress testing, respectively. Patients with Ex MI had a significant decrease in CD 34 + /chemokine (C‐X‐C motif) receptor 4 (−18%, P =0.01) after stress that was inversely correlated with the magnitude of ischemia ( r =−0.19, P =0.003). In contrast, patients without Ex MI had an increase in CD 34 + /chemokine (C‐X‐C motif) receptor 4 (14.7%, P =0.02), and those undergoing pharmacological stress had no change. Plasma vascular endothelial growth factor levels increased (15%, P PC counts in those with Ex MI ( P =0.03), suggesting a greater decrease in PC s in those with a greater change in stromal‐derived factor‐1α level with exercise. Conclusions Ex MI is associated with a significant decrease in circulating levels of CD 34 + /chemokine (C‐X‐C motif) receptor 4 PC s, likely attributable, at least in part, to stromal‐derived factor‐1α–mediated homing of PC s to the ischemic myocardium. The physiologic consequences of this uptake of PC s and their therapeutic implications need further investigation.

The objective in routine analyses is generally to determine a small number of analytes. With samples containing ~103 or more components there will be insufficient peak capacity to resolve analytes from nonanalytes. This issue was addressed herein through a new type of separation mechanism in which small groups of targeted analytes are bound with high affinity to a soluble analyte-sequestering transport phase (ASTP) composed of a ~25 nm Stokes radius hydrophilic polymer core (HPC). When introduced into a 30 nm pore diameter size-exclusion chromatography (SEC) column, ASTP/analyte complexes elute within minutes, together, unretained, and relatively pure in the first chromatographic peak. Nonanalytes, in contrast, enter pore matrices of the packing material, are retarded in elution velocity, and are eluted later, separated from analytes. Fabrication of ASTPs was achieved by covalently coupling an antibody or some other affinity selector to a high molecular weight HPC. Beyond sequestering analytes, the function of ASTPs is to act as a molecular weight shifting agent, conveying an effective molecular weight to analytes that is much larger than that of nonanalytes and causing them to elute in the SEC void volume. This mode of separation is referred to as mobile affinity sorbent chromatography (MASC). Subsequent to their purification, ASTP/analyte complexes were detected by fluorescence spectrometry.

Pepper is an economically important horticultural plant that has been widely used for its pungency and spicy taste in worldwide cuisines. Therefore, the domestication of pepper has been carried out since antiquity. Owing to meet the growing demand for pepper with high quality, organoleptic property, nutraceutical contents, and disease tolerance, genomics assisted breeding techniques can be incorporated to develop novel pepper varieties with desired traits. The application of next-generation sequencing (NGS) approaches has reformed the plant breeding technology especially in the area of molecular marker assisted breeding. The availability of genomic information aids in the deeper understanding of several molecular mechanisms behind the vital physiological processes. In addition, the NGS methods facilitate the genome-wide discovery of DNA based markers linked to key genes involved in important biological phenomenon. Among the molecular markers, single nucleotide polymorphism (SNP) indulges various benefits in comparison with other existing DNA based markers. The present review concentrates on the impact of NGS approaches in the discovery of useful SNP markers associated with pungency and disease resistance in pepper. The information provided in the current endeavor can be utilized for the betterment of pepper breeding in future.

Watermelon (Citrullus lanatus (Thunb.) Matsum. & Nakai var. lanatus) is an economically important crop in South Korea. Although efforts have been made to develop disease-resistant cultivars, defense signal pathways in watermelon are still unknown. GNK2 domain containing proteins in plants are involved in oxidative stress and salt stress, and in defense signaling responses to pathogens and viruses. Arabidopsis thaliana plasmodesmata-located protein 5 (PDLP5) controls cell-to-cell communication and defense signaling. We identified five Arabidopsis PDLP5 (AtPDLP5) homologous in watermelon, using the Cucurbit Genomics Database. The five putative watermelon PDLPs had two GNK2 domains and showed high sequence identities to AtPDLP5. Their mRNAs were expressed in three watermelon cultivars, PI189225, Au-Producer, and 920533. Each mRNA was differently expressed after infection of Colletotrichum orbiculare, Didymella bryoniae, and Pseudomonas syringae. In addition to pathogen infection, their expression patterns were altered when subjected to abiotic stresses (drought, salt, and cold) or salicylic acid treatment. Cla006974 mRNA was absent in the 920533 cultivar infected with D. bryoniae. Based on these findings, we propose that five putative watermelon PDLPs are involved in defense against fungal pathogens and abiotic stresses. In addition, Cla006974 could be useful as a marker for selecting Gummy stem blight-resistant cultivars via molecular screening.

Mutations in human ZIP14 have been linked to symptoms of the early onset of Parkinsonism and Dystonia. This phenotype is likely related to excess manganese accumulation in the CNS. The metal transporter ZIP14 (SLC39A14) is viewed primarily as a zinc transporter that is inducible via proinflammatory stimuli. In vitro evidence shows that ZIP14 can also transport manganese. To examine a role for ZIP14 in manganese homeostasis, we used Zip14 knock-out (KO) male and female mice to conduct comparative metabolic, imaging, and functional studies. Manganese accumulation was fourfold to fivefold higher in brains of Zip14 KO mice compared with young adult wild-type mice. There was less accumulation of subcutaneously administered 54Mn in the liver, gallbladder, and gastrointestinal tract of the KO mice, suggesting that manganese elimination is impaired with Zip14 ablation. Impaired elimination creates the opportunity for atypical manganese accumulation in tissues, including the brain. The intensity of MR images from brains of the Zip14 KO mice is indicative of major manganese accumulation. In agreement with excessive manganese accumulation was the impaired motor function observed in the Zip14 KO mice. These results also demonstrate that ZIP14 is not essential for manganese uptake by the brain. Nevertheless, the upregulation of signatures of brain injury observed in the Zip14 KO mice demonstrates that normal ZIP14 function is an essential factor required to prevent manganese-linked neurodegeneration.SIGNIFICANCE STATEMENT Manganese is an essential micronutrient. When acquired in excess, manganese accumulates in tissues of the CNS and is associated with neurodegenerative disease, particularly Parkinson-like syndrome and dystonia. Some members of the ZIP metal transporter family transport manganese. Using mutant mice deficient in the ZIP14 metal transporter, we have discovered that ZIP14 is essential for manganese elimination via the gastrointestinal tract, and a lack of ZIP14 results in manganese accumulation in critical tissues such as the brain, as measured by MRI, and produces signatures of brain injury and impaired motor function. Humans with altered ZIP14 function would lack this gatekeeper function of ZIP14 and therefore would be prone to manganese-related neurological diseases.

We study the intrinsic dissipation in nanomechanical resonators fabricated with synthetic singlecrystalline gold nanowires. Contrary to the etched nanostructures, the measured resonance frequencies and damping rates unambiguously demonstrate temperature dependence, as predicted by the standard two-level tunneling-state (TLS) theory. We compare the data to a model assuming a thin amorphous layer on the nanowire surface. The deduced TLS parameters are consistent with bulk poly(methyl methacrylate) (PMMA) data, confirming the presence of residual PMMA on the surface as the TLS host.

Inflammation and zinc dyshomeostasis are two common hallmarks of aging. A major zinc transporter ZIP14 (slc39a14) is upregulated by proinflammatory stimuli, e.g. interleukin-6. We have evaluated the influence of age on the Zip14 KO phenotype using wild-type (WT) and Zip14 knockout (KO) mice. Aging produced a major increase in serum IL-6 concentrations that was dramatically augmented in the Zip14 KO mice. In keeping with enhanced serum IL-6 concentrations, aging produced tissue-specific increases in zinc concentration of skeletal muscle and white adipose tissue. Metabolic endotoxemia produced by Zip14 ablation is maintained in aged KO mice. Muscle non-heme iron (NHI) was increased in aged WT mice but not in aged Zip14 KO mice demonstrating NHI uptake by muscle is ZIP14-dependent and increases with age. NF-κB and STAT3 activation was greater in aged mice, but was tissue specific and inversely related to tissue zinc. Micro-CT analysis revealed that Zip14 KO mice had markedly reduced trabecular bone that was greatly amplified with aging. These results demonstrate that the inflammation-responsive zinc transporter ZIP14 has phenotypic effects that are amplified with aging.

Glycogen synthase kinase-3 beta (GSK3β) kinase serves as a promising therapeutic target for the treatment of various human diseases, such as diabetes, obesity, and Alzheimer’s disease. In this study, we report lead GSK3β inhibitors identified using a fragment-linking strategy. Through the systematic exploration, a six-atom chain unit bearing the rigid double bond was found to be a suitable linker connecting two fragments, which enables favorable contacts with backbone groups of residues in the pockets. As a consequence, potent GSK3β inhibitor 9i was found with IC 50 values of 19 nM. The binding mode analysis indicates that the activities of the inhibitors appear to be achieved by the establishment of multiple hydrogen bonds and hydrophobic interactions in the ATP-binding site of GSK3β. The good biochemical potencies and structural uniqueness of the inhibitors support consideration in the further study to optimize the biological activity.

We investigate aggregation-induced emission (AIE) characters of bulk tetraphenylethene (TPE) derivatives with nonpolar and polar exterior chains. The bulk TPE derivatives with nonpolar dodecyl and polar di(ethylene oxide) chains are in liquid crystal (LC) and crystalline phases, respectively, at room temperature. The mobile LC character of the TPE derivatives in bulk is crucial for high AIE efficiency because the mobile LC character is effective in minimizing the number of undesirable nonemissive local sites in aggregates and inducing a homogeneous zigzag-stacked columnar structure with j-type coupled transition dipoles of the TPE derivatives. The mobile LC characteristics of AIE luminogens can be advantageous for highly efficient solid-state emission.

Activated microglia have been reported to play an important role in Parkinson’s disease (PD). A more rapid cognitive decline has been associated with deposits of β-amyloid. In this study, the aim was to evaluate the role of brain β-amyloid and its relationship with activated microglia in PD patients with normal and impaired cognition. We studied 17 PD patients with normal cognition (PDn), 12 PD patients with mild cognitive impairment (PD-MCI), and 12 healthy controls (HCs) with [11C] Pittsburgh compound B (PIB) to assess the impact of β-amyloid deposition in the brain on microglial activation evaluated using the translocator protein 18-kDa (TSPO) radioligand [18F]-FEPPA. [11C] PIB distribution volume ratio was measured in cortical and subcortical regions. [18F]-FEPPA total distribution volume values were compared for each brain region between groups to evaluate the effect of PIB positivity while adjusting for the TSPO rs6971 polymorphism. Factorial analysis of variance revealed a significant main effect of PIB positivity in the frontal lobe (F(1, 34) = 7.1, p = 0.012). Besides the frontal (p = 0.006) and temporal lobe (p = 0.001), the striatum (p = 0.018), the precuneus (p = 0.019), and the dorsolateral prefrontal cortex (p = 0.010) showed significant group × PIB positivity interaction effects. In these regions, PD-MCIs had significantly higher FEPPA VT if PIB-positive. Our results indicate an interaction between amyloid-β deposition and microglial activation in PD. Further investigations are necessary to evaluate if amyloid deposits cause neuroinflammation and further neurodegeneration or if increased microglia activation develops as a protective response.

This work investigated the extraction efficacy of phenolic acids on the potato and its byproducts. Also, the compositions of bioactive compounds and antioxidants were evaluated in various parts of the potato, such as the tuber, microtuber, peel, and flesh. The chemical constituents were quantified by HPLC analysis, and the highest levels of phenolics (88.99 mg/L) were obtained in acetone extracts from a micropropagated potato. The micropropagated potato demonstrated that notable phenolic compounds were mainly a bound form of phenolic acids including caffeic acid and vanillic acid. The micropropagated extracts using acetone showed the higher radical scavenging activity, 94.3% and 95.5% at 5 mg/mL in 1,1-diphenyl-2-picrylhydrazyl (DPPH) and 2,2′-azinobis-(3-ethylbenzothiazoline)-6-sulfonic acid (ABTS·+), respectively. In addition, the same extracts showed the highest (85.61%) β-carotene bleaching inhibition activity. A positive relationship existed between DPPH and either ABTS·+ (r = 0.58, p

BP10A is a novel two-herb medicine formula, consisting of Descurainiae sophia Semen and Peucedani praeruptorum Radix. This study was done to evaluate the antitumor efficacy of BP10A and its effect on the efficacy of the anticancer drugs oxaliplatin and irinotecan (CPT-11) in a colon tumor xenograft model. Chemical constituents from the ethanol extracts of BP10A were characterized with the ultra-performance liquid chromatography (UPLC) and each constituent was quantified with the UPLC-diode array detector method. Our study showed that BP10A exerted the cytotoxic effects in two colorectal cancer cell lines and its combination treatments with oxaliplatin or CPT-11 remarkably increased the in vitro cytotoxicity of each cancer drug assessed by the Ez-cytox assay. The in vivo antitumor activity of BP10A was evaluated in three colon cancer patient-derived tumor xenograft (PDTX) models with different genetic backgrounds. Oral administration with BP10A (250 and 500 mg/kg, daily) delayed tumor growth by 34–70% in the all PDTX models. Similarly, intraperitoneal injection of oxaliplatin (6 mg/kg) or CPT-11 (20 mg/kg) also suppressed tumor growth by 31.8–60.5% or by 24.3–50.4%, respectively. Furthermore, the combination treatment of BP10A with oxaliplatin or CPT-11 remarkably enhanced the antitumor activity of each anti-cancer drug and delayed tumor growth by 47.1–74.6% or by 74.4–82.9%, respectively. In accordance with the antitumor activity, the Ki-67 expression for tumor cell proliferation and the CD31 for angiogenesis were decreased, and TUNEL staining for tumor cell apoptosis was remarkably increased by the co-treatment of BP10A and the anticancer drugs as well as by each treatment of BP10A, oxaliplatin or CPT-11. Conclusively, BP10A has a strong tumor inhibitory effect against colon cancer and a synergistic effect with anticancer drugs, suggesting that BP10A could be considered as a good therapeutic candidate for the treatment of colon cancer.

A novel atomic layer deposition (ALD) that utilizes tertiary alkyl (tert-alkyl) halides as both growth activator and inhibitor is introduced and demonstrated for the deposition of a low resistive TiN film using TiCl4 and NH3. Among the alkyl halides, tert-butyl iodide is identified as a suitable material for both growth inhibition and growth activation without any incorporation of C impurity in the film. The electrical resistivity values of TiN thin films in activator-type and inhibitor-type ALD were significantly improved by 55% and 49%, respectively. The mechanism of the reduction in electrical resistivity is elucidated by means of theoretical approach and characterizations of TiN films. For activator-type ALD, tert-butyl iodide induces in situ ligand exchange with an adsorbed Ti precursor to form Ti–I bonds, leading to an increase in the reactivity with a NH3 reactant. For inhibitor-type ALD, the improvement of film conformality in a high aspect ratio (>22:1) substrate is exhibited. This study demonstrates that the effectiveness on the use of tert-alkyl halides in ALD deposition can serve as an important guideline for future studies of the growth activator and growth inhibitor to improve film properties, making the method widely applicable.

Bone marrow-derived progenitor cells are mobilized into the peripheral blood after acute myocardial injury and in chronic ischemic heart disease. However, the mechanisms responsible for this mobilization are poorly understood. We examined the relationship between plasma levels of bioactive lipids and number of circulating progenitor cells (CPCs) in patients (N = 437) undergoing elective or emergent cardiac catheterization. Plasma levels of sphingosine-1 phosphate (S1P) and ceramide-1 phosphate (C1P) were quantified using mass spectrometry. CPCs were assessed using flow cytometry. S1P levels correlated with the numbers of CD34+, CD34+/CD133+, and CD34+/CXCR4+ CPCs even after adjustment for potential confounding factors. However, no significant correlation was observed between C1P levels and CPC count. Plasma levels of S1P correlated with the number of CPCs in patients with coronary artery disease, suggesting an important mechanistic role for S1P in stem cell mobilization. The therapeutic effects of adjunctive S1P therapy to mobilize endogenous stem cells need to be investigated.

A systematic fragment-based de novo design procedure was developed and applied to discover new potent and selective inhibitors of glycogen synthase kinase-3 beta (GSK3β). Candidate inhibitors were generated to simultaneously maximize the biochemical potency and the specificity for GSK3β through three design steps: identification of the optimal molecular fragments for the three sub-binding regions, design of proper linking moieties to connect the fragmental building blocks, and final scoring of the generated molecules. By virtue of modifying the ligand hydration free energy term in the scoring function using hybrid scaled particle theory and the extended solvent-contact model, we identified several GSK3β inhibitors with biochemical potencies ranging from low nanomolar to picomolar levels. Among them, the two most potent inhibitors (12 and 27) are anticipated to serve as promising starting points of drug discovery for various diseases caused by GSK3β because of the high specificity for the inhibition of GSK3β.

Mushrooms have been previously investigated for their immune-modulating and anti-inflammatory properties. We examined whether the anti-inflammatory properties of Sarcodon aspratus ethanol extract (SAE) could elicit protective effects against dextran sulfate sodium (DSS)-induced colitis in vivo. Male C57/BL6 mice were randomly assigned to 1 of 4 treatment groups: control (CON; n = 8), DSS-treated (DSS; n = 9), DSS+SAE at 50 mg/kg BW (SAE50; n = 8), and DSS+SAE at 200 mg/kg BW groups (SAE200; n = 9). DSS treatment induced significant weight loss, which was significantly recovered by SAE200. Although SAE did not affect DSS-mediated reductions in colon length, it improved diarrhea and rectal bleeding induced by DSS. SAE at 200 mg/kg BW significantly attenuated IL-6 and enhanced IL-10 expression in mesenteric lymph nodes (MLN), and significantly reduced IL-6 levels in splenocytes. SAE200 also significantly attenuated DSS-induced increase in IL-6 and IL-1β, and reductions in IL-10 in colon tissue. High levels of SAE were also observed to significantly decrease inflammatory COX-2 expression that was upregulated by DSS in mice colon. These findings may have relevance for novel therapeutic strategies to mitigate inflammatory bowel disease-relevant inflammatory responses, via the direct and indirect anti-inflammatory activity of SAE. We also found that SAE harbors significant quantities of total fiber and β-glucan, suggesting a possible role for these components in protection against DSS-mediated colitis.

In the search for novel herbal-based anticancer agents, we isolated a new angular-type pyranocoumarin, (+)-cis-(3′S,4′S)-3′-angeloyl-4′-tigloylkhellactone (1) along with 12 pyranocoumarins (2–13), two furanocoumarins (14, 15), and a polyacetylene (16) were isolated from the roots of Peucedanum praeruptorum using chromatographic separation methods. The structures of the compounds were determined using spectroscopic analysis with nuclear magnetic resonance (NMR) and high-resolution-electrospray ionization-mass spectrometry (HR-ESI-MS). The multidrug-resistance (MDR) reversal and anti-inflammatory effects of all the isolated compounds were evaluated in human sarcoma MES-SA/Dx5 and lipopolysaccharide (LPS)-induced RAW 264.7 cells. Among the 16 tested compounds, two (2 and 16) downregulated nitric oxide (NO) production and five (1, 7, 8, 11, and 13) inhibited the efflux of drugs by MDR protein, indicating the reversal of MDR. Therefore, these compounds may be potential candidates for the development of effective agents against MDR forms of cancer.

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease localized to China, Japan, and Korea that is characterized by severe hemorrhage and a high fatality rate. Currently, no specific vaccine or treatment has been approved for this disease. To develop a therapeutic agent for SFTS, we isolated antibodies from a phage-displayed antibody library that was constructed from a patient who recovered from SFTS virus (SFTSV) infection. One antibody, designated as Ab10, was reactive to the Gn envelope glycoprotein of SFTSV and protected host cells and A129 mice from infection in both in vitro and in vivo experiments. Notably, Ab10 protected 80% of mice, even when injected 5 days after inoculation with a lethal dose of SFTSV. Using cross-linker assisted mass spectrometry and alanine scanning, we located the non-linear epitope of Ab10 on the Gn glycoprotein domain II and an unstructured stem region, suggesting that Ab10 may inhibit a conformational alteration that is critical for cell membrane fusion between the virus and host cell. Ab10 reacted to recombinant Gn glycoprotein in Gangwon/Korea/2012, HB28, and SD4 strains. Additionally, based on its epitope, we predict that Ab10 binds the Gn glycoprotein in 247 of 272 SFTSV isolates previously reported. Together, these data suggest that Ab10 has potential to be developed into a therapeutic agent that could protect against more than 90% of reported SFTSV isolates., Author summary Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease localized to China, Japan, and Korea. The tick-borne virus that causes SFTS has infected more than 5,000 humans, with a 6.4% to 20.9% fatality rate. Currently, there are no prophylactic or therapeutic measures against this virus. Historically, antibodies from patients who recovered from viral infection have been used to treat new patients, and commercially available antiviral monoclonal antibodies have been developed. Palivizumab was approved for the prophylaxis of respiratory syncytial virus (RSV) infection, and ibalizumab-uiyk was recently approved for the treatment of human immunodeficiency virus (HIV)-infected patients. To develop an antiviral monoclonal antibody for SFTS patients, we selected 10 antibodies from a patient who recovered from SFTS and found that one antibody potently inhibited SFTS viral infection both in vitro and in animal studies. We mapped the binding site of this antibody on the SFTS virus, which allowed us to predict that this antibody could bind 247 out of the 272 SFTS virus isolates reported to date. We anticipate that this antibody could be developed into a therapeutic treatment against SFTS.

Plants are exposed to various environmental stresses such as drought, cold, and high salinity during their sessile lifetime. The Late-Embryogenesis Abundant (LEA) proteins are involved in protection against different environmental stresses. LEA proteins have been classified into 7 groups based on sequence similarity and conserved domains. Among these groups, the functions of only group 1, 2 and 3 genes in regulating abiotic stress tolerance have been investigated. The productivity of watermelon (Citrullus lanatus), the most economically important cucurbitaceous crop, is affected by environmental stresses, but the functions of environmental stress-related genes in watermelon have not been reported yet. Therefore, abiotic and biotic stress-related research on watermelon is necessary. In this study, we selected Cl017745 (ClLEA3-1) as a representative group 3 LEA protein based on the watermelon database ( http://www.icugi.org ) and reported its expression patterns in response to diverse stresses and ABA treatment. Tissue-specific expression pattern of ClLEA3-1 was induced by dehydration, low-temperature, high-salinity, and abscisic acid (ABA) treatment, but expression of ClLEA3-1 was not increased by inoculation with a pathogen. Subcellular localization analysis showed that ClLEA3-1 was a cytosolic protein. Therefore, we recommend that ClLEA3-1 (Cl017745) can be used as an abiotic stress marker gene in watermelon.

We investigated self-assembled structures and aggregation mechanisms of tetraphenylethene (TPE) derivatives in a THF/water mixtures using time-resolved spectroscopic measurements and theoretical calculations. The TPE derivatives, with nonpolar aromatic core and nonpolar exterior dodecyl chains, form unidirectional ordered aggregates in the THF/water solvent mixture because of the effective ordered aggregation between nonpolar aromatic cores. The aggregation formation of the other TPE derivative with polar exterior di(ethylene oxide) chains is caused by an emulsion-driven amorphous aggregation without any obvious attractive intermolecular interaction. The different polarities of the exterior chains in the TPE derivatives and the emulsion formation in the THF/water mixture induce different aggregation mechanisms: unidirectional ordered versus emulsion-driven amorphous aggregates.