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Background: Obsession and delusion are theoretically distinct from each other in terms of reality testing. Despite such phenomenological distinction, no extant studies have examined the identification of common and distinct neural correlates of obsession and delusion by employing biologically grounded methods. Here, we investigated dimensional effects of obsession and delusion spanning across the traditional diagnostic boundaries reflected upon the resting-state functional connectivity (RSFC) using connectome-wide association studies (CWAS)., Methods: Our study sample comprised of 96 patients with obsessive-compulsive disorder, 75 patients with schizophrenia, and 65 healthy controls. A connectome-wide analysis was conducted to examine the relationship between obsession and delusion severity and RFSC using multivariate distance-based matrix regression., Results: Obsession was associated with the supplementary motor area, precentral gyrus, and superior parietal lobule, while delusion was associated with the precuneus. Follow-up seed-based RSFC and modularity analyses revealed that obsession was related to aberrant inter-network connectivity strength. Additional inter-network analyses demonstrated the association between obsession severity and inter-network connectivity between the frontoparietal control network and the dorsal attention network., Conclusions: Our CWAS study based on the Research Domain Criteria (RDoC) provides novel evidence for the circuit-level functional dysconnectivity associated with obsession and delusion severity across diagnostic boundaries. Further refinement and accumulation of biomarkers from studies embedded within the RDoC framework would provide useful information in treating individuals who have some obsession or delusion symptoms but cannot be identified by the category of clinical symptoms alone.

Malassezia is the most abundant genus in the fungal microflora found on human skin, and it is associated with various skin diseases. Among the 18 different species of Malassezia that have been identified to date, M. restricta and M. globosa are the most predominant fungal species found on human skin. Several studies have suggested a possible link between Malassezia and skin disorders. However, our knowledge on the physiology and pathogenesis of Malassezia in human body is still limited. Malassezia is unable to synthesize fatty acids; hence, it uptakes external fatty acids as a nutrient source for survival, a characteristic compensated by the secretion of lipases and degradation of sebum to produce and uptake external fatty acids. Although it has been reported that the activity of secreted lipases may contribute to pathogenesis of Malassezia , majority of the data were indirect evidences; therefore, enzymes' role in the pathogenesis of Malassezia infections is still largely unknown. This review focuses on the recent advances on Malassezia in the context of an emerging interest for lipases and summarizes the existing knowledge on Malassezia , diseases associated with the fungus, and the role of the reported lipases in its physiology and pathogenesis.

Despite their high potency, the widespread implementation of natural antimicrobial peptides is still challenging due to their low scalability and high hemolytic activities. Herein, we address these issues by employing a modular approach to mimic the key amino acid residues present in antimicrobial peptides, such as lysine, leucine, and serine, but on the highly biocompatible poly(ethylene glycol) (PEG) backbone. A series of these PEG-based peptides (PEGtides) were developed using functional epoxide monomers, corresponding to each key amino acid, with several possessing highly potent bactericidal activities and controlled selectivities, with respect to their hemolytic behavior. The critical role of the composition and the structure of the PEGtides in their selectivities was further supported by coarse-grained molecular dynamic simulations. This modular approach is anticipated to provide the design principles necessary for the future development of antimicrobial polymers.

Background: Studies have reported that opening wedge high tibial osteotomy (OWHTO) without bone grafting has outcomes that are similar to or even better than those of OWHTO with bone grafting, especially after use of a locking plate. However, a consensus on managing the gap after OWHTO has not been established., Purpose: To determine the degree of gap healing achieved without bone grafting, the factors associated with gap healing, and whether additional gap healing would be obtained after plate removal., Study Design: Cohort study; Level of evidence, 3., Methods: This retrospective study included 73 patients who underwent OWHTO without bone grafting between 2015 and 2018. Patients in the study were divided into 2 groups based on the correction angle: small correction group (<10°; SC group) and large correction group (≥10°; LC group). The locking plate used in OWHTO was removed at a mean of 13.5 months after surgery in 65 patients. Radiographic indexes were measured: gap filling height, gap vacancy ratio (GVR), and osteotomy filling index. The acceptable gap healing was defined as an osteotomy filling index ≥3. The factors related to gap healing around the osteotomy site were selected after multicollinearity analysis., Results: Although both groups achieved acceptable gap healing regardless of the correction angle, the SC group showed higher and earlier gap healing than did the LC group (gap healing rate 81.4% in the SC group vs 41.7% in the LC group at 3 months postoperatively). The GVR was 8.6% in the SC group and 15.3% in the LC group at 12 months after surgery ( P = .005). Both the amount of time that elapsed after surgery and the correction angle were associated with gap healing ( P < .05). Additional gap healing was observed after plate removal, as the GVR decreased 2.7% more in the patients with plate removal than in patients who did not have plate removal ( P = .012)., Conclusion: All patients achieved acceptable gap healing without bone graft. The degree of gap healing was higher in the SC group and increased over time. Gap healing was promoted after plate removal. Considering the results of this study, a bone graft is not necessary in routine OWHTO in terms of gap healing., Competing Interests: One or more of the authors has declared the following potential conflict of interest or source of funding: This study was supported by the Bio & Medical Technology Development Program of the National Research Foundation (NRF), funded by the Korean government (MSIT) (2017M3A9D8063538). AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto., (© The Author(s) 2021.)

Functional neuroimaging studies have implicated alterations in frontostriatal and frontoparietal circuits in obsessive-compulsive disorder (OCD) during various tasks. To date, however, brain activation for visuospatial function in conjunction with symptoms in OCD has not been comprehensively evaluated. To elucidate the relationship between neural activity, cognitive function, and obsessive-compulsive symptoms, we investigated regional brain activation during the performance of a visuospatial task in patients with OCD using functional magnetic resonance imaging (fMRI). Seventeen medication-free patients with OCD and 21 age-, sex-, and IQ-matched healthy controls participated in this study. Functional magnetic resonance imaging data were obtained while the subjects performed a mental rotation (MR) task. Brain activation during the task was compared between the two groups using a two-sample t -test. Voxel-wise whole-brain multiple regression analyses were also performed to examine the relationship between obsessive-compulsive symptom severity and neural activity during the task. The two groups did not differ in MR task performance. Both groups also showed similar task-related activation patterns in frontoparietal regions with no significant differences. Activation in the right dorsolateral prefrontal cortex in patients with OCD during the MR task was positively associated with their total Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) scores. This study identified the specific brain areas associated with the interaction between symptom severity and visuospatial cognitive function during an MR task in medication-free patients with OCD. These findings may serve as potential neuromodulation targets for OCD treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Oh, Jung, Kim, Shim and Kwon.)

The proper timing of flowering in response to environmental changes is critical for ensuring crop yields. FLOWERING LOCUS T ( FT ) homologs of the phosphatidylethanolamine-binding protein family play important roles as floral integrators in many crops. In soybean, we identified 17 genes of this family, and characterized biological functions in flowering for ten FT homologs. Overexpression of GmFT homologs in Arabidopsis revealed that a set of GmFT homologs, including GmFT2a/2b , GmFT3a/3b , and GmFT5a/5b , promoted flowering similar to FT ; in contrast, GmFT1a/1b , GmFT4 , and GmFT6 delayed flowering. Consistently, expressions of GmFT2a , GmFT2b , and GmFT5a were induced in soybean leaves in response to floral inductive short days, whereas expressions of GmFT1a and GmFT4 were induced in response to long days. Exon swapping analysis between floral activator GmFT2a and floral repressor GmFT4 revealed that the segment B region in the fourth exon is critical for their antagonistic functions. Finally, expression analysis of GmFT2a , GmFT5a , and GmFT4 in soybean accessions exhibiting various flowering times indicated that the mRNA levels of GmFT2a and GmFT5a were higher in early flowering accessions than in late-flowering accessions, while GmFT4 showed the opposite pattern. Moreover, the relative mRNA levels between GmFT2a / GmFT5a and GmFT4 was important in determining day length-dependent flowering in soybean accessions. Taken together, our results suggest that the functions of GmFT homologs have diversified into floral activators and floral repressors during soybean evolution, and the timing of flowering in response to changing day length is determined by modulating the activities of antagonistic GmFT homologs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Lee, Choi, Park, Jung, Chun, Baek, Cho, Jin, Park, No, Lim, Shim, Chung and Kim.)

Much attention is being devoted to the potential of marine sulfated polysaccharides as antiviral agents in preventing COVID-19. In this study, sulfated fucoidan and crude polysaccharides, extracted from six seaweed species (Undaria pinnatifida sporophyll, Laminaria japonica, Hizikia fusiforme, Sargassum horneri, Codium fragile, Porphyra tenera) and Haliotis discus hannai (abalone viscera), were screened for their inhibitory activity against SARS-CoV-2 virus entry. Most of them showed significant antiviral activities at an IC50 of 12~289 μg/mL against SARS-CoV-2 pseudovirus in HEK293/ACE2, except for P. tenera (IC50 > 1000 μg/mL). The crude polysaccharide of S. horneri showed the strongest antiviral activity, with an IC50 of 12 μg/mL, to prevent COVID-19 entry, and abalone viscera and H. fusiforme could also inhibit SARS-CoV-2 infection with an IC50 of 33 μg/mL and 47 μg/mL, respectively. The common properties of these crude polysaccharides, which have strong antiviral activity, are high molecular weight (>800 kDa), high total carbohydrate (62.7~99.1%), high fucose content (37.3~66.2%), and highly branched polysaccharides. These results indicated that the crude polysaccharides from seaweeds and abalone viscera can effectively inhibit SARS-CoV-2 entry.

Bioactivity-driven LC/MS-based phytochemical analysis of the root bark extract of Ulmus davidiana var. japonica led to the isolation of 10 compounds including a new coumarin glycoside derivative, ulmusakidian (1). The structure of the new compound was elucidated using extensive spectroscopic analyses via 1D and 2D NMR spectroscopic data interpretations, HR-ESIMS, and chemical transformation. The isolated compounds 1-10 were tested for their antifungal activity against human fungal pathogens Cryptococcus neoformans and Candida albicans. Compounds 9 and 10 showed antifungal activity against C. neoformans, with the lowest minimal inhibitory concentration (MIC) of 12.5-25.0 µg/mL, whereas none of the compounds showed antifungal activity against C. albicans., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

A suture is a ubiquitous medical device to hold wounded tissues together and support the healing process after surgery. Surgical sutures, having incomplete biocompatibility, often cause unwanted infections or serious secondary trauma to soft or fragile tissue. In this research, UV/ozone (UVO) irradiation or polystyrene sulfonate acid (PSS) dip-coating is used to achieve a fibronectin (FN)-coated absorbable suture system, in which the negatively charged moieties produced on the suture cause fibronectin to change from a soluble plasma form into a fibrous form, mimicking the actions of cellular fibronectin upon binding. The fibrous fibronectin coated on the suture can be exploited as an engineered interface to improve cellular migration and adhesion in the region around the wounded tissue while preventing the binding of infectious bacteria, thereby facilitating wound healing. Furthermore, the FN-coated suture is found to be associated with a lower friction between the suture and the wounded tissue, thus minimizing the occurrence of secondary wounds during surgery. It is believed that this surface modification can be universally applied to most kinds of sutures currently in use, implying that it may be a novel way to develop a highly effective and safer suture system for clinical applications., (© 2021 Wiley-VCH GmbH.)

Open-wedge high tibial osteotomy (OW-HTO) is an effective surgical intervention for medial-compartment knee osteoarthritis. However, the osteotomized gap might be a disadvantage in OW-HTO because it can cause problems such as delayed bone union or loss of correction. These issues can be minimized by using autologous bone graft in the osteotomized gap, which is known to be the fastest and most clinically satisfactory gap filler. The primary mechanical stability of the osteotomy site in OW-HTO is essential for early weight bearing after surgery. Therefore, we introduce the combination of a cylindrical autologous bone grafting technique and a metallic block insertion for faster bone union and better primary stability of the site in OW-HTO. We expect that the described procedure will enable early postoperative weight bearing and, thereby, allow an early return to normal function., (© 2020 by the Arthroscopy Association of North America. Published by Elsevier.)

The axial stiffness of DNA origami is determined as a function of key nanostructural characteristics. Different constructs of two-helix nanobeams with specified densities of nicks and Holliday junctions are synthesized and stretched by fluid flow. Implementing single particle tracking to extract force-displacement curves enables the measurement of DNA origami stiffness values at the enthalpic elasticity regime, i.e. for forces larger than 15 pN. Comparisons between ligated and nicked helices show that the latter exhibit nearly a two-fold decrease in axial stiffness. Numerical models that treat the DNA helices as elastic rods are used to evaluate the local loss of stiffness at the locations of nicks and Holliday junctions. It is shown that the models reproduce the experimental data accurately, indicating that both of these design characteristics yield a local stiffness two orders of magnitude smaller than the corresponding value of the intact double-helix. This local degradation in turn leads to a macroscopic loss of stiffness that is evaluated numerically for multi-helix DNA bundles., (© The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Background: The lipophilic yeasts Malassezia spp. are normally resident on the surface of the human body, and often associated with various skin diseases. Of the 18 known Malassezia spp., Malassezia restricta is the most predominantly identified Malassezia sp. found on the human skin. Malassezia possesses a large number of genes encoding lipases to degrade human sebum triglycerides into fatty acids, which are required not only for their growth, but also trigger skin diseases. Previously, we have shown that MrLIP5 (MRET&#95;0930), one of the 12 lipase genes in the genome of M. restricta , and is the most frequently expressed lipase gene in the scalp of patients with dandruff., Objective: In this study, we aimed to analyze the activity, stability, and expression of MrLip5, with particular focus on pH., Methods: We heterologously expressed MrLip5 in Escherichia coli , and purified and analyzed its activity and expression under different pH conditions., Results: We found that MrLip5 was most active and stable and highly expressed under alkaline conditions, which is similar to that of the diseased skin surface., Conclusion: Our results suggest that the activity and expression of MrLip5 are pH-dependent, and that this lipase may play an essential role at the M. restricta -host interface during disease progression., Competing Interests: CONFLICTS OF INTEREST: The authors have nothing to disclose., (Copyright © 2020 The Korean Dermatological Association and The Korean Society for Investigative Dermatology.)

Whether brain network connectivity during goal-directed planning in patients with obsessive-compulsive disorder (OCD) is abnormal and restored by treatment with selective serotonin reuptake inhibitors (SSRIs) remains unknown. This study investigated whether the disrupted network connectivity during the Tower of London (ToL) planning task in medication-free OCD patients could be restored by SSRI treatment. Seventeen medication-free OCD patients and 21 matched healthy controls (HCs) underwent functional magnetic resonance imaging (fMRI) while performing the ToL task at baseline and again after 16 weeks of SSRI treatment. Internetwork connectivity was compared across the groups and treatment statuses (pretreatment versus posttreatment). At baseline, compared with the HCs, the OCD patients showed lower internetwork connectivity between the dorsal attention network and the default-mode network during the ToL planning task. After 16 weeks of SSRI treatment, the OCD patients showed improved clinical symptoms accompanied by normalized network connectivity, although their improved behavioral performance in the ToL task did not reach that of the HCs. Our findings support the conceptualization of OCD as a network disease characterized by an imbalance between brain networks during goal-directed planning and suggest that internetwork connectivity may serve as an early biomarker of the effects of SSRIs on goal-directed planning.

The general practice of photodynamic therapy (PDT) comprises repeated multiple sessions, where photosensitizers are repeatedly administered prior to each operation of light irradiation. To address potential problems arising from the total overdose of photosensitizer by such repeated injections, we here introduce an internalizing RGD peptide (iRGD) derivative (Ppa-iRGDC-BK01) that self-aggregates into an injectable single-component supramolecular depot. Ppa-iRGDC-BK01 is designed as an in situ self-implantable photosensitizer so that it forms a depot by itself upon injection, and its molecular functions (cancer cell internalization and photosensitization) are activated by sustained release, tumor targeting, and tumor-selective proteolytic/reductive cleavage of the iRGD segment. The experimental and theoretical studies revealed that when exposed to body temperature, Ppa-iRGDC-BK01 undergoes thermally accelerated self-assembly to form a supramolecular depot through the hydrophobic interaction of the Ppa pendants and the reorganization of the interpeptide hydrogen bonding. It turned out that the self-aggregation of Ppa-iRGDC-BK01 into a depot exerts a multiple-quenching effect on the photosensitivity to effectively prevent nonspecific phototoxicity and protect it from photobleaching outside the tumor, while enabling autonomous tumor rephotosensitization by long sustained release, tumor accumulation, and intratumoral activation over time. We demonstrate that depot formation through a single peritumoral injection and subsequent quintuple laser irradiations at intervals resulted in complete eradication of the tumor. During the repeated PDT, depot-implanted normal tissues around the tumor exhibited no phototoxic damage under laser exposure. Our approach of single-component photosensitizing supramolecular depot, combined with a strategy of tumor-targeted therapeutic activation, would be a safer and more precise operation of PDT through a nonconventional protocol composed of one-time photosensitizer injection and multiple laser irradiations.

Social factors play a significant role in the health outcomes of those struggling with mental or physical health issues. People with mental illness experience more social stigmatization and receive less concern for their welfare than do those with physical illness. However, the cognitive and neural mechanisms by which such a bias in attitude arises remain unclear. This functional MRI study examined whether a lack of self-other similarity during mental state attribution affects perceivers' theory of mind and, subsequently, how they value a patient's welfare. During scanning, participants were asked to respond to an expression of caring and sympathetic concern from either their own perspective or while adopting the perspective of patients labeled physically ill or mentally ill. Participants reported that physically ill patients would share their affective responses to the situations, but mentally ill patients would not. Furthermore, mentalizing about physically ill patients was associated with increased activity in the ventromedial prefrontal cortex (vmPFC), a critical region for empathic concern and value-based decisions. In contrast, mentalizing about mentally ill patients preferentially engaged the dorsal anterior cingulate cortex (dACC) and anterior insula, regions previously implicated in empathic distress, in which activity correlated with individual differences in prejudice control. The findings indicate that a lack of perceived self-other similarity poses a challenge to the theory of mind and thus requires greater cognitive resources and neural computations. This might give rise to stereotyped beliefs about and prejudice against the mentally ill and failure to respond with appropriate empathy and care., (Copyright © 2020 Shin, Woo, Jung, Kim, Lee, Decety and Kwon.)

Based on high-resolution tandem mass spectrometry (HR-MS 2 ) and global natural products social molecular networking (GNPS), we found that plant-derived daidzein and genistein derivatives are polyhalogenated by termite-associated Actinomadura species RB99. MS-guided purification from extracts of bacteria grown under optimized conditions led to the isolation of eight polychlorinated isoflavones, including six unreported derivatives, and seven novel polybrominated derivatives, two of which showed antimicrobial activity.

Cells sense biophysical cues in the micro-environment and respond to the cues biochemically and biophysically. Proper responses from cells are critical to maintain the homeostasis in the body. Abnormal biophysical cues will cause pathological development in the cells; pathological or aging cells, on the other hand, can alter their micro-environment to become abnormal. In this minireview, we discuss four important biophysical cues of the micro-environment-stiffness, curvature, extracellular matrix (ECM) architecture and viscosity-in terms of their roles in health, aging, and diseases., (Copyright © 2020 by ASME.)

Most fungal viruses have been identified in plant pathogens, whereas the presence of viral particles in human-pathogenic fungi is less well studied. In the present study, we observed extrachromosomal double-stranded RNA (dsRNA) segments in various clinical isolates of Malassezia species. Malassezia is the most dominant fungal genus on the human skin surface, and species in this group are considered etiological factors of various skin diseases including dandruff, seborrheic dermatitis, and atopic dermatitis. We identified novel dsRNA segments, and our sequencing results revealed that the virus, named MrV40, belongs to the Totiviridae family and contains an additional satellite dsRNA segment encoding a novel protein. The transcriptome of virus-infected Malassezia restricta cells was compared to that of virus-cured cells, and the results showed that transcripts involved in ribosomal biosynthesis were downregulated and those involved in energy production and programmed cell death were upregulated. Moreover, transmission electron microscopy revealed significantly larger vacuoles in virus-infected M. restricta cells, indicating that MrV40 infection dramatically altered M. restricta physiology. Our analysis also revealed that viral nucleic acid from MrV40 induced a TLR3 (Toll-like receptor 3)-mediated inflammatory immune response in bone marrow-derived dendritic cells, suggesting that a viral element contributes to the pathogenicity of Malassezia IMPORTANCE Malassezia is the most dominant fungal genus on the human skin surface and is associated with various skin diseases including dandruff and seborrheic dermatitis. Among Malassezia species, Malassezia restricta is the most widely observed species on the human skin. In the current study, we identified a novel dsRNA virus, named MrV40, in M. restricta and characterized the sequence and structure of the viral genome along with an independent satellite dsRNA viral segment. Moreover, expression of genes involved in ribosomal synthesis and programmed cell death was altered, indicating that virus infection affected the physiology of the fungal host cells. Our data also showed that the viral nucleic acid from MrV40 induces a TLR3-mediated inflammatory immune response in bone marrow-derived dendritic cells, indicating that a viral element likely contributes to the pathogenicity of Malassezia This is the first study to identify and characterize a novel mycovirus in Malassezia ., (Copyright © 2020 Park et al.)

Mitochondria play a vital role in iron uptake and metabolism in pathogenic fungi, and also influence virulence and drug tolerance. However, the regulation of iron transport within the mitochondria of Cryptococcus neoformans , a causative agent of fungal meningoencephalitis in immunocompromised individuals, remains largely uncharacterized. In this study, we identified and functionally characterized Mrs3/4, a homolog of the Saccharomyces cerevisiae mitochondrial iron transporter, in C. neoformans var. grubii . A strain expressing an Mrs3/4-GFP fusion protein was generated, and the mitochondrial localization of the fusion protein was confirmed. Moreover, a mutant lacking the MRS3/4 gene was constructed; this mutant displayed significantly reduced mitochondrial iron and cellular heme accumulation. In addition, impaired mitochondrial iron-sulfur cluster metabolism and altered expression of genes required for iron uptake at the plasma membrane were observed in the mrs3/4 mutant, suggesting that Mrs3/4 is involved in iron import and metabolism in the mitochondria of C. neoformans . Using a murine model of cryptococcosis, we demonstrated that an mrs3/4 mutant is defective in survival and virulence. Taken together, our study suggests that Mrs3/4 is responsible for iron import in mitochondria and reveals a link between mitochondrial iron metabolism and the virulence of C. neoformans .

Rationale: One-lung ventilation (OLV) is essential for adequate visualization and exposure of the surgical site via a videoscopic approach. Although many instruments facilitating OLV are available, the choice is limited in pediatric patients., Patient Concerns: A 4-year-old female (weight: 18.6 kg, height: 100 cm) was admitted via our pediatric outpatient clinic because of recurrent hemoptysis, 2 weeks in duration. She had no medical or surgical history., Diagnosis: Contrast-enhanced computed tomography (CT) revealed a 4.5-cm-diameter mass in the left, lower lung lobe. She was diagnosed with a congenital pulmonary airway malformation (CPAM)., Interventions: She was scheduled for emergency lobectomy via video-assisted thoracoscopic surgery (VATS). To ensure successful VATS, OLV was essential. As our hospital lacked a small-diameter fiberoptic bronchoscope and a proper bronchial blocker, we decided to use single-lumen tube (SLT) with adult fiberoptic bronchoscope., Outcomes: We performed successful bronchoscopic-guided OLV using a SLT. We aligned the tube to the right upper lobar bronchus and Murphy eye to prevent obstruction of the right upper lobe bronchus. At the end of surgery, the endotracheal tube lumen had been narrowed by blood clots, we decided to exchange the tracheal tube. The tube was immediately exchanged. After re-intubation, the pulse oximetry (SpO2) then gradually increased., Lessons: Appropriate preparation and careful management should be considered to perform OLV in pediatric patients without significant complications.

Social comparison orientation (SCO), the tendency to compare oneself with others, is universal, varies widely across individuals, and predicts important life and health outcomes. However, the neural mechanism underlying individual differences in SCO is still not well-understood. In the present study, we identified intrinsic neural markers of SCO in healthy young adults (n = 42) using a multimodal neuroimaging approach that included diffusion tensor imaging and resting-state functional MRI data. We found that higher SCO was associated with weaker structural and functional connectivity (SC, FC) strengths between the ventral striatum and the medial prefrontal cortex, which are core regions of the brain reward network. Additionally, individual SCO was negatively associated with neural fluctuations in the intraparietal sulcus (IPS), part of the frontoparietal network, and positively with FC between the IPS and anterior insula/amygdala cluster. This finding was further confirmed by the observation of independently-defined, large-scale, inter-network FC between the frontoparietal network and cingulo-opercular network. Taken together, these results provide novel evidence for intrinsic functional and structural connectivity of the human brain associated with individual differences in SCO., (Copyright © 2020 Jung and Kim.)

We conducted systemic assessments on the toxicity of silicon dioxide (SiO 2 ) and titanium dioxide (TiO 2 ) nanoparticles using different forms of normal colon cells (CCD-18Co), in vivo and in human colon organoids. The in vivo acute oral toxicity data showed that the LD 50 values are greater than 2000 mg/kg for both the SiO 2 and TiO 2 nanoparticles; however, the SiO 2 and TiO 2 nanoparticles induced cytotoxicity in two-dimensional CCD-18Co cells and three-dimensional CCD-18Co spheroids and human colon organoids, with IC 50 values of 0.6, 0.8 and 0.3 mM for SiO 2 and 2.5, 1.1 and 12.5 mM for TiO 2 nanoparticles, respectively. The data suggest that, when SiO 2 and TiO 2 are in nanoparticle form, cytotoxicity is induced; thus, care should be taken with these materials.

Iron is essential for the growth of the human fungal pathogen Cryptococcus neoformans within the vertebrate host, and iron sensing contributes to the elaboration of key virulence factors, including the formation of the polysaccharide capsule. C. neoformans employs sophisticated iron acquisition and utilization systems governed by the transcription factors Cir1 and HapX. However, the details of the transcriptional regulatory networks that are governed by these transcription factors and connections to virulence remain to be defined. Here, we used chromatin immunoprecipitation followed by next-generation sequencing (ChIP-seq) and transcriptome analysis (RNA-seq) to identify genes directly regulated by Cir1 and/or HapX in response to iron availability. Overall, 40 and 100 genes were directly regulated by Cir1, and 171 and 12 genes were directly regulated by HapX, under iron-limited and replete conditions, respectively. More specifically, we found that Cir1 directly controls the expression of genes required for iron acquisition and metabolism, and indirectly governs capsule formation by regulating specific protein kinases, a regulatory connection not previously revealed. HapX regulates the genes responsible for iron-dependent pathways, particularly under iron-depleted conditions. By analyzing target genes directly bound by Cir1 and HapX, we predicted the binding motifs for the transcription factors and verified that the purified proteins bind these motifs in vitro Furthermore, several direct target genes were coordinately and reciprocally regulated by Cir1 and HapX, suggesting that these transcription factors play conserved roles in the response to iron availability. In addition, biochemical analyses revealed that Cir1 and HapX are iron-containing proteins, implying that the regulatory networks of Cir1 and HapX may be influenced by the incorporation of iron into these proteins. Taken together, our identification of the genome-wide transcriptional networks provides a detailed understanding of the iron-related regulatory landscape, establishes a new connection between Cir1 and kinases that regulate capsule, and underpins genetic and biochemical analyses that reveal iron-sensing mechanisms for Cir1 and HapX in C. neoformans ., (Copyright © 2020 by the Genetics Society of America.)

Aim: Insulin resistance is a metabolic state where insulin sensitivity is lower than normal condition and strongly related to type 2 diabetes. However, an in vitro model mimicking insulin resistance is rare and thus screening drugs for insulin resistance severely depends on an in vivo model. Here, to increase anti-diabetic drug selectivity for humans, 3D ADMSCs and macrophages were co-cultured with in-house fabricated co-culture plates., Material and Methods: 3D co-culture plates were designed to load ADMSCs and RAW264.7 cells containing hydrogels in separate wells while allowing cell-cell interaction with co-culturing media. Hydrogels were constructed using a 3D cell-printing system containing 20 mg/ml alginate, 0.5 mg/ml gelatin and 0.5 mg/ml type I collagen. Cells containing hydrogels in 3D co-culture plates were incubated for 10 min to allow stabilization before the experiment. 3D co-culture plates were incubated with the CaCl2 solution for 5 min to complete the cross linking of alginate hydrogel. Cells in 3D co-culture plates were cultured for up to 12 days depending on the experiment and wells containing adipocytes and macrophages were separated and used for assays., Results: KR-1, KR-2 and KR-3 compounds were applied during differentiation (12 days) in 3D co-cultured mouse 3T3-L1 adipocytes and 3D co-cultured human ADMSCs. Glucose uptake assay using 2-DG6P and 2-NBDG and western blot analysis were performed to investigate changes of insulin resistance in the 3D co-cultured model for interspecies selectivity of drug screening. KR-1 (mouse potent enantiomer) and KR-3 (racemic mixture) showed improvement of 2-DG and 2-NBDG uptake compared with KR-2 (human potent enantiomer) in 3D co-cultured 3T3-L1 adipocytes. In connection with insulin resistance in a 3D 3T3-L1 co-cultured model, KR-1 and KR-3 showed improvement of insulin sensitivity compared to KR-2 by markedly increasing GLUT4 expression. In contrast to the result of 3D co-cultured 3T3-L1 adipocytes, KR-1 failed to significantly improve 2-DG and 2-NBDG uptake in 3D co-cultured ADMSC adipocytes. Results of 2-NBDG accumulation and western blot analysis also showed that KR-2 and KR-3 improved insulin sensitivity relatively better than KR-1., Conclusions: Our 3D co-culture model with/without 3D co-culture plates can successfully mimic insulin resistance while allowing investigation of the effects of anti-obesity or anti-diabetic drugs on human or mouse co-culturing cell type. This 3D co-culture system may accelerate screening of drugs for insulin resistance depending on species., (© 2020 John Wiley & Sons Ltd.)

Investigation in posttraumatic stress disorder (PTSD) shows a negative association between patients' degrees of acceptance (the willingness to face unwanted private experiences while pursuing one's values and goals) and those of clinical symptom severity, suggesting that experiential acceptance is a protective factor of symptoms or an early indicator of resilience after trauma. However, neural mechanisms involved in the relationship between these two variables have yet to be elucidated. Thus, we here investigate whether there are neural mechanisms mediating such relationship using whole-brain voxel-level mediation analysis with seed-based resting-state functional connectivity (RSFC) maps generated by hippocampal subregion seeds in accident survivors (n = 33). We found that the correlation between patients' acceptance and symptom severity was mediated by the RSFC strength between left hippocampal body and left lateral occipital cortex adjacent to superior parietal cortex, the areas related to flashbacks. Our result provides novel evidence that hippocampal RSFC mediates the effect of experiential acceptance on posttraumatic stress symptom severity. If further refined and validated, the finding may aid to the identification of biomarkers to intervention and prevention programs for patients with PTSD., (Copyright © 2020 Jung and Kim.)

Pathogens must compete with hosts to acquire sufficient iron for proliferation during pathogenesis. The pathogenic fungus Cryptococcus neoformans is capable of acquiring iron from heme, the most abundant source in vertebrate hosts, although the mechanisms of heme sensing and acquisition are not entirely understood. In this study, we adopted a chromosomally encoded heme sensor developed for Saccharomyces cerevisiae to examine cytosolic heme levels in C. neoformans using fluorescence microscopy, fluorimetry, and flow cytometry. We validated the responsiveness of the sensor upon treatment with exogenous hemin, during proliferation in macrophages, and in strains defective for endocytosis. We then used the sensor to show that vacuolar and mitochondrial dysregulation and oxidative stress reduced the labile heme pool in the cytosol. Importantly, the sensor provided a tool to further demonstrate that the drugs artemisinin and metformin have heme-related activities and the potential to be repurposed for antifungal therapy. Overall, this study provides insights into heme sensing by C. neoformans and establishes a powerful tool to further investigate mechanisms of heme-iron acquisition in the context of fungal pathogenesis. IMPORTANCE Invasive fungal diseases are increasing in frequency, and new drug targets and antifungal drugs are needed to bolster therapy. The mechanisms by which pathogens obtain critical nutrients such as iron from heme during host colonization represent a promising target for therapy. In this study, we employed a fluorescent heme sensor to investigate heme homeostasis in Cryptococcus neoformans We demonstrated that endocytosis is a key aspect of heme acquisition and that vacuolar and mitochondrial functions are important in regulating the pool of available heme in cells. Stress generated by oxidative conditions impacts the heme pool, as do the drugs artemisinin and metformin; these drugs have heme-related activities and are in clinical use for malaria and diabetes, respectively. Overall, our study provides insights into mechanisms of fungal heme acquisition and demonstrates the utility of the heme sensor for drug characterization in support of new therapies for fungal diseases., (Copyright © 2020 Bairwa et al.)

Woodfordia uniflora is a flowering shrub unique to the Dhofar region of Oman and is used locally as a sedative and remedy for skin infection. However, no study to date has examined the pharmacological properties of this plant, and studies regarding phytochemicals present in W. uniflora are limited. Herein, phytochemical screening of the extract of W. uniflora was performed using LC/MS. Three new phenolic compounds, (±)-woodfordiamycin ( 1 ), woodfordic acid ( 2 ), and rhamnetin 3- O -(6″-galloyl)-β-d-glucopyranoside ( 3 ), together with 16 known compounds 4 - 19 , were isolated from the antifungal fraction of the extract. The structures of the new compounds were established by NMR and HR-MS data, and their absolute configurations were established using chemical transformations, including Mosher's method, comparison of experimental and calculated electronic circular dichroism data, and gauge-including atomic orbital NMR chemical shift calculations, followed by DP4+ analysis. The isolated compounds ( 1 - 19 ) were tested for antifungal activity against human fungal pathogens Cryptococcus neoformans and Candida albicans . Compounds (±) -1 and 8 showed antifungal activity against C. neoformans , with the lowest minimum inhibitory concentrations of 1.8-1.9 μM, which was ∼10-fold lower than that of the currently available antifungal drug fluconazole, while (±) -1 , 8 , and 19 showed antifungal activity against C. albicans .

Dry eye syndrome is the most common eye disease and it is caused by various reasons. As the balance of the tear film that protects the eyes is broken due to various causes, it becomes impossible to properly protect the eyes. In this study, the protective effects and underlying mechanisms of topical (E)-4-(2-(6-(2,6-dichloro-4-(trifluoromethyl)phenyl)-4-methyl-1,1-dioxido-1,2,6-thiadiazinan-2-yl)acetamido)adamantan-1-carboxamide (KR-67607), a novel selective 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) inhibitor, were investigated in benzalkonium chloride (BAC)-induced dry eye syndrome. BAC-treated rat eyes induced significant increases in ocular surface damage, decreased corneal thickness, corneal basement membrane destruction in the conjunctival epithelium, and expression of pro-inflammatory cytokines tumor necrosis factor-α and 11β-HSD1. These effects of BAC were reversed by topical KR-67607 treatment. Furthermore, KR-67607 decreased 4-hydroxynonenal expression and increased antioxidant and mucus secretion in BAC-treated rat eyes. Taken together, a novel selective 11β-HSD1 inhibitor can prevent BAC-induced dry eye syndrome by inhibiting pro-inflammatory cytokine and reactive oxygen species expression via the inhibition of both 11β-HSD1 activity and expression.

Purpose: To compare the radiological bone union rate after medial opening wedge high tibial osteotomy (MOW-HTO) and stabilization using a TomoFix™ plate (Synthes, Oberdorf, Switzerland) in three patient groups., Methods: Retrospective analysis of 137 knees that underwent MOW-HTO between January 2014 and January 2017 was using a TomoFix™ plate. Osteotomy gaps were filled with β-tricalcium phosphate (β-TCP) (group A), left unfilled (group B), and subject to autologous bone graft and β-TCP (group C). Radiological bone union using simple radiography was determined by a modified version of the Brosset et al. osteotomy filling index. Clinical outcomes were evaluated using the International Knee Documentation Committee (IKDC) and Lysholm score. Statistical analyses using the Chi-square and ANOVA tests were performed between the groups., Results: The mean time for radiological bone union was 8.3 ± 3.1 months in group A, 7.2 ± 3.2 in group B and 3.4 ± 1.5 in group C (p = 0.001). There was statistically significant faster bone union in Group C. If the opening distance was more than 10 mm, group A united in 8.6 ± 3.6 months, group B in 8.8 ± 3.4, and group C in 3.5 ± 1.7 (p = 0.001). IKDC and Lysholm knee scores improved significantly (p = 0.004 for IKDC and 0.001 for Lysholm knee scores) in group C when compared to groups A and B at sixth month follow-up. At final follow-up, there was no difference in IKDC and Lysholm knee scores. Less delayed union occurred in group C., Conclusions: MOW-HTO with autologous bone graft and β-TCP had the fastest radiological bone union and best clinical scores at 6 month follow-up., Level of Evidence: Retrospective comparative study, Level III.

Malassezia restricta is an opportunistic fungal pathogen on human skin; it is associated with various skin diseases, including seborrheic dermatitis and dandruff, which are usually treated using ketoconazole. In this study, we clinically isolated ketoconazole-resistant M. restricta strains (KCTC 27529 and KCTC 27550) from patients with dandruff. To understand the mechanisms of ketoconazole resistance in the isolates, their genomes were sequenced and compared with the susceptible reference strain M. restricta KCTC 27527. Using comparative genome analysis, we identified tandem multiplications of the genomic loci containing ATM1 and ERG11 homologs in M. restricta KCTC 27529 and KCTC 27550, respectively. Additionally, we found that the copy number increase of ATM1 and ERG11 is reflected in the increased expression of these genes; moreover, we observed that overexpression of these homologs caused ketoconazole resistance in a genetically tractable fungal pathogen, Cryptococcus neoformans . In addition to tandem multiplications of the genomic region containing the ATM1 homolog, the PDR5 homolog, which encodes the drug efflux pump protein was upregulated in M. restricta KCTC 27529 compared to the reference strain. Biochemical analysis confirmed that drug efflux was highly activated in M. restricta KCTC 27529, implying that upregulation of the PDR5 homolog may also contribute to ketoconazole resistance in the strain. Overall, our results suggest that multiplication of the genomic loci encoding genes involved in ergosterol synthesis, mitochondrial iron metabolism, and oxidative stress response and overexpression of the drug efflux pumps are the mechanisms underlying ketoconazole resistance in M. restricta ., (Copyright © 2020 Park, Cho, Lee and Jung.)

Introduction: The rotational alignment of femoral and tibial components is an important determinant of the success of Total Knee Arthroplasty (TKA). The optimal rotational position of the tibial component is still unclear. The purpose of this study was (1) to determine the pre-operative S-TEA (surgical-transepicondylar axis) derived tibialanteroposterior (AP) axis angle and postoperative tibial component axis angle using a "Bird's eye" high-definition CT image in TKA performed by Linker surgical technique; (2) to determine the femorotibial mismatch angle; and (3) to determine the optimal tibial component rotation in a well-aligned femoral and tibial components., Materials and Methods: 55 knees in 49 osteoarthritis patients who underwent primary TKA by Linker surgical technique were evaluated. Preoperative tibial AP axis angle, and the postoperative tibial component axis angle were measured. Rotational mismatch between femoral and tibial components was also measured., Results: The mean angle of the pre-operative tibial AP axis was 17.8° ± 4.0°, ranging from 4.3° to 25.4°. The mean angle of the post-operative tibial component axis was 16.2° ± 4.9°, ranging from 3.8° to 25.2°. The mean postoperative tibial component axis line was at 14.2% ± 11.9%., Conclusion: Because of the variability of pre-operative S-TEA derived tibial AP axis angle, the tibial component axis angle was also variable among the knees, but the two angles bore a strong correlation to each other. Based on our results, the optimal axis of the tibial component passes about halfway through the medial edge and medial one-third of the tibial tuberosity., Level of Evidence: Level II.

It is known cancer cells secrete cytokines inducing normal fibroblasts (NFs) to become carcinoma-associated fibroblasts (CAFs). However, it is not clear how the CAF-promoting cytokines can effectively navigate the dense ECM, a diffusion barrier, in the tumor microenvironment to reach NFs during the early stages of cancer development. In this study, we devised a 3D coculture system to investigate the possible mechanism of CAF induction at early stages of breast cancer. We found that in a force-dependent manner, ECM fibrils are radially aligned relative to the tumor spheroid. The fibril alignment enhances the diffusion of exosomes containing CAF-promoting cytokines towards NFs. Suppression of force generation or ECM remodeling abolishes the enhancement of exosome diffusion and the subsequent CAF induction. In summary, our finding suggests that early-stage, pre-metastatic cancer cells can generate high forces to align the ECM fibrils, thereby enhancing the diffusion of CAF-promoting exosomes to reach the stroma and induce CAFs., Competing Interests: Declaration of competing interest The authors declare no competing or financial interests., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: To evaluate the macular pigment optical density (MPOD) with age in the Korean population using the Macular Pigment Screener II (MPSII®)., Methods: One hundred and twenty-six eyes were retrospectively reviewed. MPOD was measured using MPSII®, which uses a heterochromatic flicker photometry method, and the estimated values were analyzed. Spearman's correlation test was used to evaluate correlations between MPOD and age. The association between MPOD and age was determined using a simple linear regression analysis. MPODs among the four groups were compared via the post hoc analysis with Bonferroni correction, MPODs between the age-related macular degeneration (AMD) group and aged-matched healthy subjects were compared via the Mann-Whitney U test. Other risk factors for AMD were identified via a logistic regression analysis., Results: Estimated MPOD decreased significantly with increasing age in the general population. In the simple regression analysis, a statistically significant linear regression model was observed, and the estimated values of MPOD decreased by ?0.005 as age increased by 1 year. Aged (> 50 years) showed lower MPOD than younger (30-49 years) subjects. But, in the healthy population, the estimated MPOD values exhibited a decreasing trend with age, but there were no significant differences according to age, after excluding patients with AMD. MPOD was significantly lower in patients with AMD than in aged healthy controls. Furthermore, hypertension, dyslipidemia, and smoking were identified as risk factors for AMD., Conclusion: MPOD measured with MPSII® reflects the MP density in healthy individuals and patients with dry AMD. Aging was not significantly associated with low MPOD in healthy population, but the presence of dry AMD was significantly associated with low MPOD. Then, low MPOD may be a risk factor for development of dry AMD. Furthermore, routine screening with MPS II® for ages 50 and older is thought to help detect early low MPOD and identify individuals who should take supplements., Competing Interests: The authors have no potential conflicts of interest of disclose., (© 2020 The Korean Academy of Medical Sciences.)

Introduction: A key obstacle in the creation of engineered cardiac tissues of clinically relevant sizes is limited diffusion of oxygen and nutrients. Thus, there is a need for organized vascularization within a three-dimensional (3D) tissue environment. Human induced pluripotent stem cell (hiPSC)-derived early vascular cells (EVCs) have shown to improve organization of vascular networks within hydrogels. We hypothesize that introduction of EVCs into 3D microtissue spheroids will lead to increased microvascular formation and improve spheroid formation. Methods: HiPSC-derived cardiomyocytes (CMs) were cocultured with human adult ventricular cardiac fibroblasts (FB) and either human umbilical vein endothelial cells (HUVECs) or hiPSC-derived EVCs for 72 h to form mixed cell spheroids. Three different groups of cell ratios were tested: Group 1 (control) consisted of CM:FB:HUVEC 70:15:15, Group 2 consisted of CM:FB:EVC 70:15:15, and Group 3 consisted of CM:FB:EVC 40:15:45. Vascularization, cell distribution, and cardiac function were investigated. Results: Improved microvasculature was found in EVC spheroids with new morphologies of endothelial organization not found in Group 1 spheroids. CMs were found in a core-shell type distribution in Group 1 spheroids, but more uniformly distributed in EVC spheroids. Contraction rate increased into Group 2 spheroids compared to Group 1 spheroids. Conclusion: The triculture of CM, FB, and EVC within a multicellular cardiac spheroid promotes microvascular formation and cardiac spheroid contraction.

The 11β-hydroxysteroiddehydrogenase type 1(11β-HSD1), acortisolregenerating enzyme that amplifies tissue glucocorticoidlevels, plays an important role in diabetes, obesity, and glaucoma and is recognized as a potential therapeutic target for various disease conditions. Moreover, a recent study demonstrated that selective 11β-HSD1 inhibitor can attenuate ischemic brain injury. This prompted us to optimize cyclic sulfamide derivative for aiming to treat ischemic brain injury. Among the synthesized compounds, 6e has an excellent in vitro activivity with an IC 50 value of 1 nM toward human and mouse 11β-HSD1 and showed good 11β-HSD1 inhibition in ex vivo study using brain tissue isolated from mice. Furthermore, in the transient middle cerebral artery occlusion model in mice, 6e treatment significantly attenuated infarct volume and neurological deficit following cerebral ischemia/reperfusion injury. Additionally, binding modes of 6e for human and mouse 11β-HSD1 were suggested., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The purposes of this study were to develop the Yonsei Face Database (YFace DB), consisting of both static and dynamic face stimuli for six basic emotions (happiness, sadness, anger, surprise, fear, and disgust), and to test its validity. The database includes selected pictures (static stimuli) and film clips (dynamic stimuli) of 74 models (50% female) aged between 19 and 40. Thousand four hundred and eighty selected pictures and film clips were assessed for the accuracy, intensity, and naturalness during the validation procedure by 221 undergraduate students. The overall accuracy of the pictures was 76%. Film clips had a higher accuracy, of 83%; the highest accuracy was observed in happiness and the lowest in fear across all conditions (static with mouth open or closed, or dynamic). The accuracy was higher in film clips across all emotions but happiness and disgust, while the naturalness was higher in the pictures than in film clips except for sadness and anger. The intensity varied the most across conditions and emotions. Significant gender effects were found in perception accuracy for both the gender of models and raters. Male raters perceived surprise more accurately in static stimuli with mouth open and in dynamic stimuli while female raters perceived fear more accurately in all conditions. Moreover, sadness and anger expressed in static stimuli with mouth open and fear expressed in dynamic stimuli were perceived more accurately when models were male. Disgust expressed in static stimuli with mouth open and dynamic stimuli, and fear expressed in static stimuli with mouth closed were perceived more accurately when models were female. The YFace DB is the largest Asian face database by far and the first to include both static and dynamic facial expression stimuli, and the current study can provide researchers with a wealth of information about the validity of each stimulus through the validation procedure., (Copyright © 2019 Chung, Kim, Jung and Kim.)

Background: Given that only a subgroup of patients with schizophrenia responds to first-line antipsychotic drugs, a key clinical question is what underlies treatment response. Observations that prefrontal activity correlates with striatal dopaminergic function, have led to the hypothesis that disrupted frontostriatal functional connectivity (FC) could be associated with altered dopaminergic function. Thus, the aim of this study was to investigate the relationship between frontostriatal FC and striatal dopamine synthesis capacity in patients with schizophrenia who had responded to first-line antipsychotic drug compared with those who had failed but responded to clozapine., Methods: Twenty-four symptomatically stable patients with schizophrenia were recruited from Seoul National University Hospital, 12 of which responded to first-line antipsychotic drugs (first-line AP group) and 12 under clozapine (clozapine group), along with 12 matched healthy controls. All participants underwent resting-state functional magnetic resonance imaging and [18F]DOPA PET scans., Results: No significant difference was found in the total PANSS score between the patient groups. Voxel-based analysis showed a significant correlation between frontal FC to the associative striatum and the influx rate constant of [18F]DOPA in the corresponding region in the first-line AP group. Region-of-interest analysis confirmed the result (control group: R2 = 0.019, p = 0.665; first-line AP group: R2 = 0.675, p < 0.001; clozapine group: R2 = 0.324, p = 0.054) and the correlation coefficients were significantly different between the groups., Conclusions: The relationship between striatal dopamine synthesis capacity and frontostriatal FC is different between responders to first-line treatment and clozapine treatment in schizophrenia, indicating that a different pathophysiology could underlie schizophrenia in patients who respond to first-line treatments relative to those who do not.

XAV939, a tankyrase inhibitor, exerts an anticancer effect in 3-dimensional (3D) cultured SW480 cells, however this is not exhibited in 2-dimensional (2D) cultured SW480 cells. In the current study, XAV939 induced a 3.7-fold increase in cellular apoptosis in 3D culture but not in the 2D culture. However, no significant changes were indicated in cell cycle distribution in the 2D or 3D culture. Based on the observation that protein expression, which was associated with the glycolytic pathway, was increased in the 3D culture, the effect of XAV939 on the patterns of glycolytic protein expression was assessed. XAV939 was revealed to decrease lactose dehydrogenase A (LDHA) expression in 3D cultured SW480 cells, but only exerted a small effect in the 2D culture. The coadministration of XAV939 with the LDHA inhibitor FX11 decreased proliferation in 3D cultured SW480 cells compared with the single administration of FX11, while there was no additive effect in the 2D culture. The lactate assay also indicated that XAV939 decreased lactate secretion in the 3D cell culture but not in the 2D culture. These results suggest that XAV939 exerts an anticancer effect through inhibition of LDHA in the 3D culture., (Copyright: © Kim et al.)

Glaucoma is one of the leading causes of preventable blindness, affecting > 2 million people in the United States. Recently, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitors were found to exert preventive effects against glaucoma. However, there is no evidence for the role of 11β-HSD1 inhibitors against glaucoma. Here, we developed a novel 11β-HSD1 inhibitor, (1R,2S,3S,5R,6S,7S)-6-(2-(6-(2,6-dichloro-4-(trifluoromethyl)phenyl)-4-methyl-1,1-dioxido-1,2,6-thiadiazinan-2-yl)acetamido)-adamantane-2-carboxamide (KR-67607) and showed its protective effects against ischemia-reperfusion-induced eye injury. We demonstrate that KR-67607 effectively reduced cortisol levels in mouse eyes and maintained the trabecular meshwork (TM) structure in the presence of transient ischemic stress. Furthermore, KR-67607 reversed the elevation of intra-ocular pressure (IOP), suggesting that the TM structure maintained by KR-67607 prevented the excessive rise in IOP that exacerbates glaucoma. KR-67607 was shown to have a higher specificity for 11β-HSD1 than carbenoxolone (CBX) in vitro. Moreover, KR-67607 reduced apoptosis and the structural disruption of TM cells. Antioxidation was the major protective pathway of KR-67607 against chemically-induced ischemia-reperfusion in TM cells and the glucocorticoid receptor (GR) was closely associated with this pathway. When TM cells undergo ischemic stress, GR is activated and then translocates to the cell nucleus where it interferes with Nrf-2-mediated antioxidant gene expression. However, when KR-67607 inhibited GR translocation, Nrf-2 was able to induce antioxidant gene transcription, which consequently, enhanced the antioxidant capacity of the cells. In conclusion, our current work describes a novel selective 11β-HSD1 inhibitor for glaucoma treatment and provides evidence of its physiological role in anti-oxidative pathways in the TM., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The Mkt1-Pbp1 complex promotes mating-type switching by regulating the translation of HO mRNA in Saccharomyces cerevisiae . Here, we performed in vivo immunoprecipitation assays and mass spectrometry analyses in the human fungal pathogen Cryptococcus neoformans to show that Pbp1, a poly(A)-binding protein-binding protein, interacts with Mkt1 containing a PIN like-domain. Association of Pbp1 with Mkt1 was confirmed by co-immunoprecipitation assays. Results of spot dilution growth assays showed that unlike pbp1 deletion mutant strains, mkt1 deletion mutant strains were not resistant to heat stress compared with wild-type. However, similar to the pbp1 deletion mutant strains, the mkt1 deletion mutants exhibited both, defective dikaryotic hyphal production and reduced pheromone gene ( MF α1) expression during mating. In addition, deletion of mkt1 caused attenuated virulence in a murine intranasal inhalation model. Taken together, our findings reveal that Mkt1 plays a crucial role in sexual reproduction and virulence in C. neoformans ., (Copyright © 2019 Son, Fu, Jung, Oh, Kwak, Cardenas, Heitman and Park.)

Fungal development is regulated by a variety of transcription factors in Aspergillus nidulans. Previous studies demonstrated that the NF-κB type velvet transcription factors regulate certain target genes that govern fungal differentiation and cellular metabolism. In this study, we characterize one of the VosA/VelB-inhibited developmental genes called vidA, which is predicted to encode a 581-amino acid protein with a C 2 H 2 zinc finger domain at the C-terminus. Levels of vidA mRNA are high during the early and middle phases of asexual development and decrease during the late phase of asexual development and asexual spore (conidium) formation. Deletion of either vosA or velB results in increased vidA mRNA accumulation in conidia, suggesting that vidA transcript accumulation in conidia is repressed by VosA and VelB. Phenotypic analysis demonstrated that deletion of vidA causes decreased colony growth, reduced production of asexual spores, and abnormal formation of sexual fruiting bodies. In addition, the vidA deletion mutant conidia contain more trehalose and β-glucan than wild type. Overall, these results suggest that VidA is a putative transcription factor that plays a key role in governing proper fungal growth, asexual and sexual development, and conidia formation in A. nidulans.

It has been demonstrated that geometry can affect cell behaviors. Though curvature-sensitive proteins at the nanoscale are studied, it is unclear how cells sense curvature at the cellular and multicellular levels. To characterize and determine the mechanisms of curvature-dependent cell behaviors, we grow cells on open channels of the 60-µm radius. We found that cortical F-actin is 1.2-fold more enriched in epithelial cells grown on the curved surface compared to the flat control. We observed that myosin activity is required to promote cortical F-actin formation. Furthermore, cell-cell contact was shown to be indispensable for curvature-dependent cortical actin assembly. Our results indicate that the actomyosin network coupled with adherens junctions is involved in curvature-sensing at the multi-cellular level.

Betaine derivatives are considered major ingredients of shampoos and are commonly used as antistatic and viscosity-increasing agents. Several studies have also suggested that betaine derivatives can be used as antimicrobial agents. However, the antifungal activity and mechanism of action of betaine derivatives have not yet been fully understood. In this study, we investigated the antifungal activity of six betaine derivatives against Malassezia restricta , which is the most frequently isolated fungus from the human skin and is implicated in the development of dandruff. We found that, among the six betaine derivatives, lauryl betaine showed the most potent antifungal activity. The mechanism of action of lauryl betaine was studied mainly using another phylogenetically close model fungal organism, Cryptococcus neoformans , because of a lack of available genetic manipulation and functional genomics tools for M. restricta . Our genome-wide reverse genetic screening method using the C. neoformans gene deletion mutant library showed that the mutants with mutations in genes for cell membrane synthesis and integrity, particularly ergosterol synthesis, are highly sensitive to lauryl betaine. Furthermore, transcriptome changes in both C. neoformans and M. restricta cells grown in the presence of lauryl betaine were analyzed and the results indicated that the compound mainly affected cell membrane synthesis, particularly ergosterol synthesis. Overall, our data demonstrated that lauryl betaine influences ergosterol synthesis in C. neoformans and that the compound exerts a similar mechanism of action on M. restricta .

Aims: There are many obstacles to overcome in the development of new drugs for metabolic diseases, including efficacy and toxicity problems in later stages of drug development. To overcome these problems and predict efficacy and toxicity in early stages, we constructed a new model of insulin resistance in terms of communication between 3T3-L1 adipocytes and RAW264.7 macrophages by three-dimensional (3D) culture., Results: In this study, results focused on the functional resemblance between 3D co-culture of adipocytes and macrophages and adipose tissue in diabetic mice. The 3D mono-culture preadipocytes showed good cell viability and induced cell differentiation to adipocytes, without cell confluence or cell-cell contact and interaction. The 3D co-cultured preadipocytes with RAW264.7 macrophages induced greater insulin resistance than two-dimensional and 3D mono-cultured adipocytes. Additionally, we demonstrated that 3D co-culture model had functional metabolic similarity to adipose tissue in diabetic mice. We utilized this 3D co-culture system to screen PPARγ antagonists that might have potential as therapeutic agents for diabetes as demonstrated by an in vivo assay., Conclusion: This in vitro 3D co-culture system could serve as a next-generation platform to accelerate the development of therapeutics for metabolic diseases., (© 2019 John Wiley & Sons Ltd.)

The draft genome sequence of Malassezia restricta KCTC 27527, a clinical isolate from a patient with dandruff, was previously reported. Using the PacBio Sequel platform, we completed and reannotated the genome of M. restricta KCTC 27527 for a better understanding of the genome of this fungus., (Copyright © 2019 Cho et al.)

Purpose: To evaluate clinical outcomes and radiographic changes in patellofemoral (PF) joint congruity between open wedge high tibial osteotomy (OWHTO) and hybrid closed wedge HTO (HCWHTO)., Methods: From 2011 to 2013, 36 knees in 31 patients who underwent OWHTO and 21 knees in 17 patients who underwent HCWHTO were evaluated in this retrospective study with a minimum 5-year follow-up. Radiological outcomes including hip-knee-ankle angle (HKA), femoral patellar height index (FPHI), preoperative PF osteoarthritis (OA) grade, medial and lateral joint spaces of the PF joint, and congruence angle were measured. Clinical parameters including the Knee injury and Osteoarthritis Outcome Score (KOOS) and the Oxford Knee Score (OKS) were also evaluated. Preoperative and final follow-up values for each procedure were compared in outcome analyses., Results: Mean preoperative HKA and the degree of PF-OA were significantly more severe for patients treated with HCWHTO compared with those treated with OWHTO (p = 0.001, p = 0.0001). Mean postoperative FPHI was significantly decreased with proximalization of the patella in HCWHTO (p = 0.01) but showed no significant change in OWHTO (n.s.). Regarding PF joint congruity after HCWHTO, lateral joint space and congruence angle were significantly improved (p = 0.0001, p = 0.005), while medial joint space was not significantly changed (n.s.). After OWHTO, congruence angle showed no significant difference (n.s.), but medial and lateral joint spaces were significantly decreased (p = 0.0001, p = 0.018). There were no significant differences in KOOS and OKS between the groups (n.s., n.s.)., Conclusions: Although degrees of varus knee and PF-OA were more severe in HCWHTO than those in OWHTO, HCWHTO led to improved PF joint congruity, and its mid-term clinical outcomes were equivalent to those of OWHTO. Therefore, in patients with varus knee combined with PF-OA preoperatively, HCWHTO is a more effective treatment than OWHTO., Level of Evidence: Therapeutic level III.

While recent studies have explored the maintenance of the effect of meditation on stress resilience, the underlying neural mechanisms have not yet been investigated. The present study conducted a highly controlled residential study of a 4-day meditation intervention to investigate the brain functional changes and long-term effects of meditation on mindfulness and resilience. Thirty participants in meditation practice and 17 participants in a relaxation retreat (control group) underwent magnetic resonance imaging scans at baseline and post-intervention and completed the Cognitive and Affective Mindfulness Scale (CAMS) and Resilience Quotient Test (RQT) at baseline, post-intervention, and the 3-month follow-up. All participants showed increased CAMS and RQT scores post-intervention, but only the meditation group sustained the enhancement after 3 months. Resting-state functional connectivity (rsFC) between the left rostral anterior cingulate cortex (rACC) and the dorsomedial prefrontal cortex (dmPFC), precuneus, and angular gyrus was significantly increased post-intervention in the meditation group compared with the relaxation group. The changes in rACC-dmPFC rsFC mediated the relationship between the changes in the CAMS and RQT scores and correlated with the changes in the RQT score both immediately and at 3 months post-intervention. Our findings suggest that increased rACC-dmPFC rsFC via meditation causes an immediate enhancement in resilience that is sustained. Since resilience is known to be associated with the preventative effect of various psychiatric disorders, the improvement in stress-related neural mechanisms may be beneficial to individuals at high clinical risk.

Background: Superficial fungal infections are one of the most common and burdensome skin problems affecting quality of life in patients. Various conventional antifungal agents have been used to treat fungal infections; however, various problems have been reported including drug interaction, drug resistance and low effectiveness. Efinaconazole is a novel antifungal agent, which has proven to be particularly effective against onychomycosis compared with conventional antifungal agents. However, the antifungal efficacy of Efinaconazole for specific strains has not been analysed., Objective: We conducted an in-vitro study to measure the antifungal activity of Efinaconazole against strains of Trichophyton rubrum, Trichophyton mentagrophytes and Candida albicans compared with widely-used antifungal drugs., Methods: We obtained strains of T. rubrum, T. mentagrophytes and C. albicans isolated from patients with onychomycosis and tinea pedis. The minimal inhibitory concentration (MIC) for various strains of fungal species was evaluated for the antifungal susceptibility test., Results: Efinaconazole showed a low MIC against almost strains of dermatophytes and C albicans and also presented low resistance, indicating high potency of efinaconazole for treatment of superficial fungal infections., Conclusion: Efinaconazole could be a comparable alternative to replace existing conventional agents., (© 2018 Blackwell Verlag GmbH.)

Sessile plants reprogram their metabolic and developmental processes during adaptation to prolonged environmental stresses. To understand the molecular mechanisms underlying adaptation of plant cells to saline stress, we established callus suspension cell cultures from Arabidopsis roots adapted to high salt for an extended period of time. Adapted cells exhibit enhanced salt tolerance compared with control cells. Moreover, acquired salt tolerance is maintained even after the stress is relieved, indicating the existence of a memory of acquired salt tolerance during mitotic cell divisions, known as mitotic stress memory. Metabolite profiling using 1H-nuclear magnetic resonance (NMR) spectroscopy revealed metabolic discrimination between control, salt-adapted and stress-memory cells. Compared with control cells, salt-adapted cells accumulated higher levels of sugars, amino acids and intermediary metabolites in the shikimate pathway, such as coniferin. Moreover, adapted cells acquired thicker cell walls with higher lignin contents, suggesting the importance of adjustments of physical properties during adaptation to elevated saline conditions. When stress-memory cells were reverted to normal growth conditions, the levels of metabolites again readjusted. Whereas most of the metabolic changes reverted to levels intermediate between salt-adapted and control cells, the amounts of sugars, alanine, γ-aminobutyric acid and acetate further increased in stress-memory cells, supporting a view of their roles in mitotic stress memory. Our results provide insights into the metabolic adjustment of plant root cells during adaptation to saline conditions as well as pointing to the function of mitotic memory in acquired salt tolerance., (� The Author 2018. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For permissions, please email: journals.permissions@oup.com.)