Unveiling the Electronic Structure of Grain Boundaries in Anatase with Electron Microscopy and First-Principles Modeling.

Polycrystalline anatase titanium dioxide has drawn great interest, because of its potential applications in high-efficiency photovoltaics and photocatalysts. There has been speculation on the electronic properties of grain boundaries but little direct evidence, because grain boundaries in anatase are challenging to probe experimentally and to model. We present a combined experimental and theoretical study of anatase grain boundaries that have been fabricated by epitaxial growth on a bicrystalline substrate, allowing accurate atomic-scale models to be determined. The electronic structure in the vicinity of stoichiometric grain boundaries is relatively benign to device performance but segregation of oxygen vacancies introduces barriers to electron transport, because of the development of a space charge region. An intrinsically oxygen-deficient boundary exhibits charge trapping consistent with electron energy loss spectroscopy measurements. We discuss strategies for the synthesis of polycrystalline anatase in order to minimize the formation of such deleterious grain boundaries.

Conserving terrestrial linkages that connect natural landscapes of the Korean Peninsula.

Human-induced land degradation fragments natural ecosystems, hinders ecological processes, and threatens biodiversity. Maintaining or restoring ecological flows across landscapes through landscape linkages may provide a solution. Here, we identify a peninsula-wide ecological connectivity network for the Korean Peninsula using two linkage mapping models. We found three major north-south axes of connectivity traversing the Demilitarized Zone (DMZ), which emerged as an important east-west linkage. Only 7% of the highest-ranked connections are currently secured by protected areas. We found 120 linkages in North and South Korea that are intersected by road networks consisting of motorways and trunk roads under both models. These locations should be the focus of immediate attention for conservation planners, as well as 274 and 1130 additional road-impacted linkages under one model or the other. The results can be used for policy support, and potentially as a basis for the two countries to engage in discussions about ecosystem health and climate change adaptation. The approach presented here can also be efficiently used to assess and map natural landscape linkages.

Comprehensive lysine acetylomes emerging from bacteria to humans.

Recent proteomic studies reveal that 5-10% of mammalian and bacterial proteins undergo lysine acetylation, a post-translational modification that adds an acetyl group to the ɛ-amino group of lysine residues. Many of these proteins are not canonical targets, such as histones and transcription factors, suggesting that this modification plays a much wider role than previously appreciated. These studies also suggest that lysine acetylomes are at least comparable with (if not larger than) phosphoproteomes. Although many of the newly identified acetylation events still require validation, they constitute an important framework for further research and the development of new drugs useful in treating a variety of pathologies. Herein, we summarize these proteomic studies and highlight recent reports linking lysine acetylation to heterochromatin assembly, sister chromatid cohesion, cytoskeleton dynamics, autophagy, receptor signaling, RNA processing and metabolic control.

Retropharyngeal lymph node metastasis in 54 patients with oropharyngeal squamous cell carcinoma who underwent surgery-based treatment.

BACKGROUND: This study aimed to determine the incidence, risk factors, and prognostic significance of retropharyngeal lymph node (RPLN) metastasis from malignancies of the oropharynx. METHODS: The study retrospectively analyzed 54 patients with oropharyngeal squamous cell carcinoma who underwent primary surgery-based treatment. Most of the patients had advanced stage (stage 3 or 4, 96.3 %) oropharyngeal cancer. Surgery alone was performed for 14 patients. Postoperative radiotherapy was administered to 14 patients and chemoradiation to 26 patients. Genotyping and detection of human papillomavirus (HPV) was available for 52 patients. RESULTS: Using pathologic analysis, RPLN metastasis was confirmed in 22 subjects. The patients with RPLN metastasis had a significantly lower disease-specific survival rate than the non-RPLN metastasis group (54.5 vs 75 %; p = 0.05). The pN+ (RPLN) yield of these cases was 18/22 (81.8 %) for cN+ (RPLN) versus 4/32 (7.4 %) for cN0 (RPLN). Multivariate analysis identified the independent factors associated with RPLN metastasis as radiographically positive retropharyngeal node (p = 0.012; odds ratio [OR] 53.920) and posterior pharyngeal wall invasion (p = 0.021; OR 33.014). A high-risk HPV-positive result was not significantly correlated with RPLN metastasis. CONCLUSIONS: Elective RPLN dissection should be considered for patients with advanced neck and primary tumor, particularly those with posterior pharyngeal wall invasion.

Mice lacking α-tubulin acetyltransferase 1 are viable but display α-tubulin acetylation deficiency and dentate gyrus distortion.

α-Tubulin acetylation at Lys-40, located on the luminal side of microtubules, has been widely studied and used as a marker for stable microtubules in the cilia and other subcellular structures, but the functional consequences remain perplexing. Recent studies have shown that Mec-17 and its paralog are responsible for α-tubulin acetylation in Caenorhabditis elegans. There is one such protein known as Atat1 (α-tubulin acetyltransferase 1) per higher organism. Zebrafish Atat1 appears to govern embryo development, raising the intriguing possibility that Atat1 is also critical for development in mammals. In addition to Atat1, three other mammalian acetyltransferases, ARD1-NAT1, ELP3, and GCN5, have been shown to acetylate α-tubulin in vitro, so an important question is how these four enzymes contribute to the acetylation in vivo. We demonstrate here that Atat1 is a major α-tubulin acetyltransferase in mice. It is widely expressed in mouse embryos and tissues. Although Atat1-null animals display no overt phenotypes, α-tubulin acetylation is lost in sperm flagella and the dentate gyrus is slightly deformed. Furthermore, human ATAT1 colocalizes on bundled microtubules with doublecortin. These results thus suggest that mouse Atat1 may regulate advanced functions such as learning and memory, thereby shedding novel light on the physiological roles of α-tubulin acetylation in mammals.

Dephosphorylation at a conserved SP motif governs cAMP sensitivity and nuclear localization of class IIa histone deacetylases.

Histone deacetylase 4 (HDAC4) and its paralogs, HDAC5, -7, and -9 (all members of class IIa), possess multiple phosphorylation sites crucial for 14-3-3 binding and subsequent nuclear export. cAMP signaling stimulates nuclear import of HDAC4 and HDAC5, but the underlying mechanisms remain to be elucidated. Here we show that cAMP potentiates nuclear localization of HDAC9. Mutation of an SP motif conserved in HDAC4, -5, and -9 prevents cAMP-stimulated nuclear localization. Unexpectedly, this treatment inhibits phosphorylation at the SP motif, indicating an inverse relationship between the phosphorylation event and nuclear import. Consistent with this, leptomycin B-induced nuclear import and adrenocorticotropic hormone (ACTH) treatment result in the dephosphorylation at the motif. Moreover, the modification synergizes with phosphorylation at a nearby site, and similar kinetics was observed for both phosphorylation events during myoblast and adipocyte differentiation. These results thus unravel a previously unrecognized mechanism whereby cAMP promotes dephosphorylation and differentially regulates multisite phosphorylation and the nuclear localization of class IIa HDACs.

The tumor suppressor kinase LKB1 activates the downstream kinases SIK2 and SIK3 to stimulate nuclear export of class IIa histone deacetylases.

Histone deacetylases 4 (HDAC4), -5, -7, and -9 form class IIa within the HDAC superfamily and regulate diverse physiological and pathological cellular programs. With conserved motifs for phosphorylation-dependent 14-3-3 binding, these deacetylases serve as novel signal transducers that are able to modulate histone acetylation and gene expression in response to extracellular cues. Here, we report that in a PKA-sensitive manner the tumor suppressor kinase LKB1 acts through salt-inducible kinase 2 (SIK2) and SIK3 to promote nucleocytoplasmic trafficking of class IIa HDACs. Both SIK2 and SIK3 phosphorylate the deacetylases at the conserved motifs and stimulate 14-3-3 binding. SIK2 activates MEF2-dependent transcription and relieves repression of myogenesis by the deacetylases. Distinct from SIK2, SIK3 induces nuclear export of the deacetylases independent of kinase activity and 14-3-3 binding. These findings highlight the difference among members of the SIK family and indicate that LKB1-dependent SIK activation constitutes an important signaling module upstream from class IIa deacetylases for regulating cellular programs controlled by MEF2 and other transcription factors.

Clinical characteristics of spontaneous cholesteatoma of the external auditory canal in children comparing with cholesteatoma in adults.

The purpose of this study was to investigate the characteristics of external auditory canal cholesteatoma (EACC) in children through evaluation of the clinical and radiologic features as well as treatment outcomes. The clinical records were retrospectively reviewed for children under 15 years of age diagnosed with spontaneous EACC between March 2004 and December 2011. The clinical data of adults diagnosed with spontaneous EACC during the same period were evaluated to compare with EACC in children. Eight patients (3 males and 5 females) with pediatric EACC and 18 patients (7 males and 11 females, 20 ears) with adult EACC were included within the boundary of the study. The mean ages were 12.4 years (age range 9-15) for pediatric EACC and 49.8 years (age range 29-79) for adult EACC patients. Follow-up periods ranged from 8 to 86 months (mean 32.5 ± 8.62) in pediatric EACC and from 6 to 72 months (mean 22.2 ± 5.36) in adult EACC. Pediatric EACC, showed involvement most commonly in the posterior wall, while the inferior wall was most commonly involved in adult EACC. Pediatric EACC tended to show a more focal involvement and was not as extensive as adult EACC. Extension into the adjacent structures was similar in both groups, but bony destruction was more common in the adult group. Two children and eight adult patients were treated with surgery, but four adult cases needed more extensive surgical treatment because their disease was widely spread to included areas such as the mastoid segment of facial nerve and the temporomandibular joint. Six pediatric cases treated with conservative management showed no progression of disease on physical examination at the last visit, but two cases of adults progressed and required canaloplasty. Pediatric EACC shows less aggressive behavior compared to adult EACC. Adequate management may work better in pediatric than in adult EACC, even though the treatment modality is conservative management.

GPC-100, a novel CXCR4 antagonist, improves in vivo hematopoietic cell mobilization when combined with propranolol.

Autologous Stem Cell Transplant (ASCT) is increasingly used to treat hematological malignancies. A key requisite for ASCT is mobilization of hematopoietic stem cells into peripheral blood, where they are collected by apheresis and stored for later transplantation. However, success is often hindered by poor mobilization due to factors including prior treatments. The combination of G-CSF and GPC-100, a small molecule antagonist of CXCR4, showed potential in a multiple myeloma clinical trial for sufficient and rapid collection of CD34+ stem cells, compared to the historical results from the standards of care, G-CSF alone or G-CSF with plerixafor, also a CXCR4 antagonist. In the present study, we show that GPC-100 has high affinity towards the chemokine receptor CXCR4, and it potently inhibits ß-arrestin recruitment, calcium flux and cell migration mediated by its ligand CXCL12. Proximity Ligation Assay revealed that in native cell systems with endogenous receptor expression, CXCR4 co-localizes with the beta-2 adrenergic receptor (ß2AR). Co-treatment with CXCL12 and the ß2AR agonist epinephrine synergistically increases ß-arrestin recruitment to CXCR4 and calcium flux. This increase is blocked by the co-treatment with GPC-100 and propranolol, a non-selective beta-adrenergic blocker, indicating a functional synergy. In mice, GPC-100 mobilized more white blood cells into peripheral blood compared to plerixafor. GPC-100 induced mobilization was further amplified by propranolol pretreatment and was comparable to mobilization by G-CSF. Addition of propranolol to the G-CSF and GPC-100 combination resulted in greater stem cell mobilization than the G-CSF and plerixafor combination. Together, our studies suggest that the combination of GPC-100 and propranolol is a novel strategy for stem cell mobilization and support the current clinical trial in multiple myeloma registered as NCT05561751 at www.clinicaltrials.gov.

Habitat suitability and connectivity modeling predict genetic population structure and priority control areas for invasive nutria (Myocastor coypus) in a temperate river basin.

The nutria (Myocastor coypus), also known as the coypu, is a semi-aquatic, invasive rodent native to South America that causes damage to natural riverine and wetland habitats in many parts of the world, including South Korea. Understanding habitat use, connectivity, and gene flow of nutria populations is critical for the sound management of local and regional ecosystems. Here, we assessed habitat suitability and connectivity in relation to the genetic structure of nutria populations in the Nakdong River Basin of South Korea. A total of 321 nutria occurrence sites and seven environmental variables were used to perform ensemble habitat suitability modeling using five species distribution models (SDMs), including boosted regression trees, maximum entropy model, random forest, generalized linear model, and multivariate adaptive regression splines. Using graph and circuit theory approaches, we assessed the population gene flow and current flow betweenness centrality (CFBC) of suitable habitats derived from the ensemble SDM. All SDMs performed well with a range of test AUC values from 0.962 to 0.970 (mean = 0.966) with true skill statistic values over 0.8. The minimum temperature of the coldest month, mean temperature of the warmest quarter, precipitation of the driest quarter, and distance from water bodies were important predictors in nutria habitat modeling. Nutria population gene flow was significantly correlated with the least-cost path distance on a cost resistance surface based on ensemble habitat suitability modeling and roads (Mantel's r = 0.60, p < 0.05). Finally, the CFBC positively correlated with the genetic diversity of nutria populations was used to identify priority control areas. Habitat suitability and connectivity modeling not only revealed environmental conditions and areas that support the survival and spread of nutrias, but also improved our understanding of the animals' genetic population structure, thereby indicating priority areas to target for eradication.

K-acetylation and its enzymes: overview and new developments.

Lysine (K) acetylation refers to transfer of the acetyl moiety from acetyl-CoA to the ε-amino group of a lysine residue. This is posttranslational and reversible, with its level dynamically maintained by lysine acetyltransferases (KATs) and deacetylases (KDACs). Traditionally, eukaryotic KDACs have been referred to as HDACs (histone deacetylases). Recent proteomic studies have revealed that hundreds of bacterial proteins and thousands of eukaryotic proteins contain acetyl-lysine (AcK) residues, indicating that K-acetylomes are comparable to phosphoproteomes. The current challenges are to assign enzymes that execute specific acetylation events, to determine the impact of these events, and to relate this modification to other posttranslational modifications, cell signaling networks, and pathophysiology under different cellular and developmental contexts. In this chapter, we provide a brief overview about the acetylomes, KATs, HDACs, AcK-recognizing protein domains, and acetylation-modulating therapeutics, and emphasize the latest developments in related areas. The remaining chapters of the book focus on and cover various aspects of HDACs (both the Rpd3/Hda1 and sirtuin families), which shall provide novel insights into how to utilize these enzymes for developing a new generation of HDAC-related therapeutics.

Antibacterial Activity and Multi-Targeting Mechanism of Dehydrocorydaline From Corydalis turtschaninovii Bess. Against Listeria monocytogenes.

Listeria monocytogenes is a foodborne pathogen, with relatively low incidence but high case-fatality. Phytochemicals have been recognized as a promising antimicrobial agent as an alternative to synthetic chemicals due to their safety and high efficacy with multi-target sites. This study identified and characterized a novel antibacterial agent, dehydrocorydaline, in the Corydalis turschaninovii rhizome using HPLC-LTQ-Orbitrap-HRMS, and its antibacterial effect with lowest MIC (1 mg/mL) and MBC (2 mg/mL) values. In addition, an in vitro growth kinetic assay, cytoplasmic nucleic acid and protein leakage assay, and observation of morphological changes in bacterial cells supported the strong antibacterial activity. Dehydrocorydaline also displayed effective inhibitory effects on biofilm formation and bacterial motility. In order to investigate the potential antibacterial mechanism of action of dehydrocorydaline against L. monocytogenes, label-free quantitative proteomics was used, demonstrating that dehydrocorydaline has multiple targets for combating L. monocytogenes including dysregulation of carbohydrate metabolism, suppression of cell wall synthesis, and inhibition of bacterial motility. Overall, this study demonstrated that dehydrocorydaline has potential as a natural and effective antibacterial agent with multi-target sites in pathogenic bacteria, and provides the basis for development of a new class of antibacterial agent.

Anisotropic Electrical Conductivity of Oxygen-Deficient Tungsten Oxide Films with Epitaxially Stabilized 1D Atomic Defect Tunnels.

Materials having an anisotropic crystal structure often exhibit anisotropy in the electrical conductivity. Compared to complex transition-metal oxides (TMOs), simple TMOs rarely show large anisotropic electrical conductivity due to their simple crystal structure. Here, we focus on the anisotropy in the electrical conductivity of a simple TMO, oxygen-deficient tungsten oxide (WOx) with an anisotropic crystal structure. We fabricated several WOx films by the pulsed laser deposition technique on the lattice-matched (110)-oriented LaAlO3 substrate under a controlled oxygen atmosphere. The crystallographic analyses of the WOx films revealed that highly dense atomic defect tunnels were aligned one-dimensionally (1D) along [001] LaAlO3. The electrical conductivity along the 1D atomic defect tunnels was ∼5 times larger than that across the tunnels. The present approach, introduction of 1D atomic defect tunnels, might be useful to design simple TMOs exhibiting anisotropic electrical conductivity.

Solid-State Electrochemical Switch of Superconductor-Metal-Insulators.

Controlling the oxygen content can manipulate the electrical conductivity of transition metal oxides (TMOs). Although the superconductor-metal-insulator transition is useful for functional devices, an electrical path must be developed to manipulate the oxygen deficiency (δ) while maintaining the solid state. YBa2Cu3O7-δ (YBCO, 0 ≤ δ ≤ 1) is a high transition temperature (Tc) TMO that can be modulated from a superconductor (Tc ≈ 92 K when δ = 0) to an insulator (δ ≈ 1). Here, we show a simple and efficient way to manipulate δ in YBCO films using a solid-state electrochemical redox treatment. Applying a negative voltage injects oxide ions to the YBCO films, increasing Tc. Employing a positive voltage suppresses the superconducting transition and modulates the electrical conductivity. The present results demonstrate that the superconductor-metal-insulator transition of YBCO is modulated electrochemically in the solid state, opening possibilities of superconducting oxide-based device applications.

Large-Scale Screening of 239 Traditional Chinese Medicinal Plant Extracts for Their Antibacterial Activities against Multidrug-Resistant Staphylococcus aureus and Cytotoxic Activities.

Novel alternative antibacterial compounds have been persistently explored from plants as natural sources to overcome antibiotic resistance leading to serious foodborne bacterial illnesses. In this study, the ethanolic extracts from 239 traditional Chinese medicinal plants (TCMP)' materials were screened to discover promising candidates that have strong antibacterial properties against multidrug-resistant Staphylococcus (S.) aureus and low cytotoxicity. The results revealed that 74 extracts exhibited good antibacterial activities (diameter of inhibition zone (DIZ) ≥ 15 mm). Furthermore, 18 extracts (DIZ ≥ 20 mm) were determined their minimum inhibitory concentrations (MIC) and minimum bactericide concentrations (MBC), ranging from 0.1 to 12.5 mg/mL and 0.78 to 25 mg/mL, respectively. In addition, most of the 18 extracts showed relatively low cytotoxicity (a median lethal concentration (LC50) >100 µg/mL). The 18 extracts were further determined to estimate possible correlation of their phenolic contents with antibacterial activity, and the results did not show any significant correlation. In conclusion, this study selected out some promising antibacterial TCMP extracts with low cytotoxicity, including Rhus chinensis Mill., Ilex rotunda Thunb., Leontice kiangnanensis P.L.Chiu, Oroxylum indicum Vent., Isatis tinctorial L., Terminalia chebula Retz., Acacia catechu (L.f.) Willd., Spatholobus suberectus Dunn, Rabdosia rubescens (Hemsl.) H.Hara, Salvia miltiorrhiza Bunge, Fraxinus fallax Lingelsh, Coptis chinensis Franch., Agrimonia Pilosa Ledeb., and Phellodendron chinense C.K.Schneid.

A spatial approach to climate-resilient infrastructure in coastal social-ecological systems: The case of dumbeong in Goseong County, South Korea.

Sustainable landscape planning and management of coastal habitats has become an integral part of the global agenda due to anthroprogenic pressures and climate change-induced events. As an example of human-engineered infrastructure that enhances the sustainability and resilience of coastal social-ecological systems (SES), we have presented the dumbeong system, a farmer-engineered and managed irrigation system based on Korean traditional ecological knowledge. We analyzed the spatial relationship of dumbeongs with coastal landscape attributes and droughts in Goseong County in South Korea. We used generalized linear models (GLMs) to examine the effects of land cover and recent (2001-2010) standardized precipitation index (SPI) on the abundance of dumbeongs. Then, we projected near future (2020-2050) changes in the SPI-based drought risk for the dumbeong system using representative concentration pathway (RCP) climate scenarios. We found that forest and marine water areas have positive relations with dumbeong abundance, whereas SPI has a negative relation, indicating that the dumbeongs are more abundant in areas close to sea water and forests, and with higher incidences of drought. Derived climate change scenarios show that the study region will experience higher incidence of drought. Our findings provide empirical evidence for the dumbeong system as an effective community designed and driven adaptive response to local hydrological processes and climatic conditions, and as climate-resilient infrastructure that strengthens sustainability and resilience of coastal SES. Based on our findings, we provide recommendations for sustainable landscape management and optimal use of the dumbeong system in coastal regions.

Author Correction: An ADAMTS Sol narae is required for cell survival in Drosophila.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Assessment of the Molecular Mechanism of Action of SB3, a Trastuzumab Biosimilar.

BACKGROUND: SB3, a biosimilar of Herceptin® (trastuzumab, hereinafter referred to as reference product) is currently approved in the EU, Korea, Australia, the USA, and Brazil for the treatment of human epidermal growth factor receptor (HER) 2-positive early and metastatic breast cancer and HER2-positive metastatic gastric cancer. Previously, the biological similarity of SB3 to EU- or US-sourced reference product was assessed using various cell-based and binding assays. OBJECTIVE: In this paper, as a part of its similarity assessment, SB3 was evaluated for additional characteristics related to its molecular mechanism of action (MoA). METHODS: For extracellular effects of SB3, HER2-overexpressing cancer cell lines were used to assess expression of surface HER2, shedding of the extracellular domain of HER2, and antibody-dependent cell-mediated phagocytosis (ADCP) activity. For intracellular effects, Akt phosphorylation and vascular endothelial growth factor (VEGF) release were assessed. Additionally, in vitro docetaxel or pertuzumab combination experiments were performed for further characterization; anti-proliferation, HER2/HER3 dimerization inhibition, apoptosis, and antibody-dependent cell-mediated cytotoxicity (ADCC) assays were used. RESULTS: It was confirmed that SB3 is highly similar to the reference products on quality attributes related to extracellular/intracellular efficacy. This similarity was also confirmed during combination studies with docetaxel and pertuzumab. CONCLUSION: Overall, the equivalence of SB3 with reference product in MoA-related qualities in in vitro mono- and combination therapy experiments may support clinical bioequivalence of the two substances.

ADAMTS Sol narae cleaves extracellular Wingless to generate a novel active form that regulates cell proliferation in Drosophila.

Wnt/ Wingless (Wg) is essential for embryonic development and adult homeostasis in all metazoans, but the mechanisms by which secreted Wnt/Wg is processed remain largely unknown. A Drosophila Sol narae (Sona) is a member of A Disintegrin And Metalloprotease with ThromboSpondin motif (ADAMTS) family, and positively regulates Wg signaling by promoting Wg secretion. Here we report that Sona and Wg are secreted by both conventional Golgi and exosomal transports, and Sona cleaves extracellular Wg at the two specific sites, leading to the generation of N-terminal domain (NTD) and C-terminal domain (CTD) fragments. The cleaved forms of extracellular Wg were detected in the extracellular region of fly wing discs, and its level was substantially reduced in sona mutants. Transient overexpression of Wg-CTD increased wing size while prolonged overexpression caused lethality and developmental defects. In contrast, Wg-NTD did not induce any phenotype. Moreover, the wing defects and lethality induced by sona RNAi were considerably rescued by Wg-CTD, indicating that a main function of extracellular Sona is the generation of Wg-CTD. Wg-CTD stabilized cytoplasmic Armadillo (Arm) and had genetic interactions with components of canonical Wg signaling. Wg-CTD also induced Wg downstream targets such as Distal-less (Dll) and Vestigial (Vg). Most importantly, Cyclin D (Cyc D) was induced by Wg-CTD but not by full-length Wg. Because Sona also induces Cyc D in a cell non-autonomous manner, Wg-CTD generated by Sona in the extracellular region activates a subset of Wg signaling whose major function is the regulation of cell proliferation.