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The molecular basis of mullerian aplasia, also known as Mayer-Rokitansky-Kuster Hauser (MRKH) or congenital absence of the uterus and vagina, is largely unknown. We applied a multifaceted genetic approach to studying the pathogenesis of MRKH including exome sequencing of trios and duos, genome sequencing of families, qPCR, RT-PCR, and Sanger sequencing to detect intragenic deletions, insertions, splice variants, single nucleotide variants, and rearrangements in 132 persons with MRKH. We identified two heterozygous variants in ZNHIT3 localized to a commonly involved CNV region at chromosome 17q12 in two different families with MRKH. One is a frameshift, truncating variant that is predicted to interfere with steroid hormone binding of the LxxLL sequence of the C-terminal region. The second variant is a double missense/stopgain variant. Both variants impair protein expression in vitro. In addition, four more probands with MRKH harbored the stopgain variant without the nearby missense variant. In total, 6/132 (4.5%) of patients studied, including five with associated anomalies (type 2 MRKH), had ZNHIT3 variants that impair function in vitro. Our findings implicate ZNHIT3 as an important gene associated with MRKH within the 17q12 CNV region., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Chromatin organization is essential for maintaining cell-fate trajectories and developmental programs. Here, we find that disruption of H3K36 methylation dramatically impairs normal epithelial differentiation and development, which promotes increased cellular plasticity and enrichment of alternative cell fates. Specifically, we observe a striking increase in the aberrant generation of excessive epithelial glandular tissues, including hypertrophic salivary, sebaceous, and meibomian glands, as well as enhanced squamous tumorigenesis. These phenotypic and gene expression manifestations are associated with loss of H3K36me2 and rewiring of repressive H3K27me3, changes we also observe in human patients with glandular hyperplasia. Collectively, these results have identified a critical role for H3K36 methylation in both in vivo epithelial cell-fate decisions and the prevention of squamous carcinogenesis and suggest that H3K36 methylation modulation may offer new avenues for the treatment of numerous common disorders driven by altered glandular function, which collectively affect large segments of the human population., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

N6 -methyladenosine (m 6 A) is the most abundant modification on messenger RNAs (mRNAs) and is catalyzed by methyltransferase-like protein 3 (Mettl3). To understand the role of m 6 A in a self-renewing somatic tissue, we deleted Mettl3 in epidermal progenitors in vivo. Mice lacking Mettl3 demonstrate marked features of dysfunctional development and self-renewal, including a loss of hair follicle morphogenesis and impaired cell adhesion and polarity associated with oral ulcerations. We show that Mettl3 promotes the m 6 A-mediated degradation of mRNAs encoding critical histone modifying enzymes. Depletion of Mettl3 results in the loss of m 6 A on these mRNAs and increases their expression and associated modifications, resulting in widespread gene expression abnormalities that mirror the gross phenotypic abnormalities. Collectively, these results have identified an additional layer of gene regulation within epithelial tissues, revealing an essential role for m 6 A in the regulation of chromatin modifiers, and underscoring a critical role for Mettl3-catalyzed m 6 A in proper epithelial development and self-renewal.

Hund's rule coupling (J) has attracted much attention recently for its role in the description of the novel quantum phases of multi-orbital materials. Depending on the orbital occupancy, J can lead to various intriguing phases. However, experimental confirmation of the orbital occupancy dependency has been difficult as controlling the orbital degrees of freedom normally accompanies chemical inhomogeneities. Here, we demonstrate a method to investigate the role of orbital occupancy in J related phenomena without inducing inhomogeneities. By growing SrRuO 3 monolayers on various substrates with symmetry-preserving interlayers, we gradually tune the crystal field splitting and thus the orbital degeneracy of the Ru t 2g orbitals. It effectively varies the orbital occupancies of two-dimensional (2D) ruthenates. Via in-situ angle-resolved photoemission spectroscopy, we observe a progressive metal-insulator transition (MIT). It is found that the MIT occurs with orbital differentiation: concurrent opening of a band insulating gap in the d xy band and a Mott gap in the d xz/yz bands. Our study provides an effective experimental method for investigation of orbital-selective phenomena in multi-orbital materials., (© 2023. The Author(s).)

Cracking has been recognized as a major obstacle degrading material properties, including structural stability, electrical conductivity, and thermal conductivity. Recently, there have been several reports on the nanosized cracks (nanocracks), particularly in the insulating oxides. In this work, we comprehensively investigate how nanocracks affect the physical properties of metallic SrRuO 3 (SRO) thin films. We grow SRO/SrTiO 3 (STO) bilayers on KTaO 3 (KTO) (001) substrates, which provide +1.7% tensile strain if the SRO layer is grown epitaxially. However, the SRO/STO bilayers suffer from the generation and propagation of nanocracks, and then, the strain becomes inhomogeneously relaxed. As the thickness increases, the nanocracks in the SRO layer become percolated, and its dc conductivity approaches zero. Notably, we observe an enhancement of the local optical conductivity near the nanocrack region using scanning-type near-field optical microscopy. This enhancement is attributed to the strain relaxation near the nanocracks. Our work indicates that nanocracks can be utilized as promising platforms for investigating local emergent phenomena related to strain effects.

Interfaces between dissimilar correlated oxides can offer devices with versatile functionalities, and great efforts have been made to manipulate interfacial electronic phases. However, realizing such phases is often hampered by the inability to directly access the electronic structure information; most correlated interfacial phenomena appear within a few atomic layers from the interface. Here, atomic-scale epitaxy and photoemission spectroscopy are utilized to realize the interface control of correlated electronic phases in atomic-scale ruthenate-titanate heterostructures. While bulk SrRuO 3 is a ferromagnetic metal, the heterointerfaces exclusively generate three distinct correlated phases in the single-atomic-layer limit. The theoretical analysis reveals that atomic-scale structural proximity effects yield Fermi liquid, Hund metal, and Mott insulator phases in the quantum-confined SrRuO 3 . These results highlight the extensive interfacial tunability of electronic phases, hitherto hidden in the atomically thin correlated heterostructure. Moreover, this experimental platform suggests a way to control interfacial electronic phases of various correlated materials., (© 2023 The Authors. Advanced Materials published by Wiley-VCH GmbH.)

The oxide interfaces between materials with different structural symmetries have been actively studied due to their novel physical properties. However, the investigation of intriguing interfacial phenomena caused by the oxygen octahedral tilt (OOT) proximity effect has not been fully exploited, as there is still no clear understanding of what determines the proximity length and what the underlying control mechanism is. Here, we achieved scalability of the OOT proximity effect in SrRuO 3 (SRO) by epitaxial strain near the SRO/SrTiO 3 heterointerface. We demonstrated that the OOT proximity length scale of SRO is extended from 4 unit cells to 14 unit cells by employing advanced scanning transmission electron microscopy. We also suggest that this variation may originate from changes in phonon dispersions due to electron-phonon coupling in SRO. This study will provide in-depth insights into the structural gradients of correlated systems and facilitate potential device applications.

Antiferromagnetic (AFM) materials are attracting tremendous attention due to their spintronic applications and associated novel topological phenomena. However, detecting and identifying the spin configurations in AFM materials are quite challenging due to the absence of net magnetization. Herein, we report the practicality of utilizing the planar Hall effect (PHE) to detect and distinguish "cluster magnetic multipoles" in AFM Nd 2 Ir 2 O 7 (NIO-227) fully strained films. By imposing compressive strain on the spin structure of NIO-227, we artificially induced cluster magnetic multipoles, namely dipoles and A 2 - and T 1 -octupoles. Importantly, under magnetic field rotation, each magnetic multipole exhibits distinctive harmonics of the PHE oscillation. Moreover, the planar Hall conductivity has a nonlinear magnetic field dependence, which can be attributed to the magnetic response of the cluster magnetic octupoles. Our work provides a strategy for identifying cluster magnetic multipoles in AFM systems and would promote octupole-based AFM spintronics., (© 2022. The Author(s).)

Sagnac interferometry is advantageous in measuring time-reversal-symmetry breaking effects in ferromagnetic and antiferromagnetic materials as it suppresses time-reversal symmetric birefringent effects that are ubiquitous and often overwhelming in optical detection systems. When its sensitivity is limited only by the amplifier noise in the photo-detector, one needs to optimize the optical power that returns to the detector. We demonstrate an experimental scheme that maximizes the returning optical power in a Sagnac interferometry when detecting the magneto-optic effect in ultrathin films. In this scheme, the optical beam bearing the Faraday effect on a thin film is reflected at a second surface coated with a highly reflective gold film. The gold film increases the returned optical power by a factor of 4-5. For a normal-incidence Sagnac interferometer, this scheme yields an increase in the signal-to-noise ratio by the same factor. For an oblique-incidence Sagnac interferometer, this scheme should yield an increase in the signal-to-noise ratio by a factor of 20-25. For illustration, this scheme is used to measure magnetization curves and Kerr rotation images of 4.5-unit-cell thick SrRuO 3 (001) grown on SrTiO 3 (001).

Recent evidence suggests that the disruption of gene expression by alterations in DNA, RNA, and histone methylation may be critical contributors to the pathogenesis of keratinocyte cancers (KCs), made up of basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC), which collectively outnumber all other human cancers combined. While it is clear that methylation modifiers are frequently dysregulated in KCs, the underlying molecular and mechanistic changes are only beginning to be understood. Intriguingly, it has recently emerged that there is extensive cross-talk amongst these distinct methylation processes. Here, we summarize and synthesize the latest findings in this space and highlight how these discoveries may uncover novel therapeutic approaches for these ubiquitous cancers.

Ruddlesden-Popper (RP) phases ( A n +1 B n O 3 n +1 , n = 1, 2,···) have attracted intensive research with diverse functionalities for device applications. However, the realization of a high-quality RP-phase film is hindered by the formation of out-of-phase boundaries (OPBs) that occur at terrace edges, originating from lattice mismatch in the c -axis direction with the A ' B 'O 3 ( n = ∞) substrate. Here, using strontium ruthenate RP-phase Sr 2 RuO 4 ( n = 1) as a model system, an experimental approach for suppressing OPBs was developed. By tuning the growth parameters, the Sr 3 Ru 2 O 7 ( n = 2) phase was formed in a controlled manner near the film-substrate interface. This higher-order RP-phase then blocked the subsequent formation of OPBs, resulting in nearly defect-free Sr 2 RuO 4 layer at the upper region of the film. Consequently, the Sr 2 RuO 4 thin films exhibited superconductivity up to 1.15 K, which is the highest among Sr 2 RuO 4 films grown by pulsed laser deposition. This work paves the way for synthesizing pristine RP-phase heterostructures and exploring their unique physical properties.

Shiga toxin-producing Escherichia coli (STEC) strains are important food-borne pathogens that can be transmitted through the consumption of food products derived from pigs. Moreover, antimicrobial resistance in STEC has been a matter of increasing concern. The aim of this study was to investigate the prevalence and antimicrobial characteristics of STEC isolates from pork in Korea. We isolated 131 isolates of E. coli from 334 pork samples collected from slaughterhouses and retail markets from 2008 to 2009. Among the 131 isolates, 6 (4.58%) were confirmed to belong to 6 different serotypes of STEC. All six STEC isolates contained stx1 and eaeA virulence genes, and four of them additionally carried the hly gene. The minimum inhibitory concentration (MIC) of 15 antibiotics (amoxicillin/clavulanic acid, ampicillin, cephalothin, cefoxitin, ceftiofur, gentamicin, neomycin, streptomycin, nalidixic acid, ciprofloxacin, colistin, chloramphenicol, florfenicol, tetracycline and sulfamethoxazole/trimethoprim) toward the STEC isolates was determined. As a result, three strains were associated with high MICs for florfenicol and chloramphenicol (64 μg/mL). Furthermore, all three strains were found to contain the florfenicol-resistant gene ( floR ) but not the chloramphenicol-resistant gene ( cat ). Sequence alignment and BLAST analysis of the polymerase chain reaction products of the floR gene indicated that they contained sequences with homology to the floR gene of E. coli or Salmonella enterica serovar, Heidelberg. This is the first report on the detection of floR in STEC isolated from pork obtained from retail markets in Korea.

The recent observation of the anomalous Hall effect (AHE) without notable magnetization in antiferromagnets has suggested that ferromagnetic ordering is not a necessary condition. Thus, recent theoretical studies have proposed that higher-rank magnetic multipoles formed by clusters of spins (cluster multipoles) can generate the AHE without magnetization. Despite such an intriguing proposal, controlling the unconventional AHE by inducing these cluster multipoles has not been investigated. Here, we demonstrate that strain can manipulate the hidden Berry curvature effect by inducing the higher-rank cluster multipoles in spin-orbit-coupled antiferromagnets. Observing the large AHE on fully strained antiferromagnetic Nd 2 Ir 2 O 7 thin films, we prove that strain-induced cluster T 1 -octupoles are the only source of observed AHE. Our results provide a previously unidentified pathway for generating the unconventional AHE via strain-induced magnetic structures and establish a platform for exploring undiscovered topological phenomena via strain in correlated materials., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

Dielectrics have long been considered as unsuitable for pure electrical switches; under weak electric fields, they show extremely low conductivity, whereas under strong fields, they suffer from irreversible damage. Here, we show that flexoelectricity enables damage-free exposure of dielectrics to strong electric fields, leading to reversible switching between electrical states-insulating and conducting. Applying strain gradients with an atomic force microscope tip polarizes an ultrathin film of an archetypal dielectric SrTiO 3 via flexoelectricity, which in turn generates non-destructive, strong electrostatic fields. When the applied strain gradient exceeds a certain value, SrTiO 3 suddenly becomes highly conductive, yielding at least around a 10 8 -fold decrease in room-temperature resistivity. We explain this phenomenon, which we call the colossal flexoresistance, based on the abrupt increase in the tunneling conductance of ultrathin SrTiO 3 under strain gradients. Our work extends the scope of electrical control in solids, and inspires further exploration of dielectric responses to strong electromechanical fields.

In quantum matters hosting electron-electron correlation and spin-orbit coupling, spatial inhomogeneities, arising from competing ground states, can be essential for understanding exotic topological properties. A prominent example is Hall anomalies observed in SrRuO 3 films, which were interpreted in terms of either magnetic skyrmion-induced topological Hall effect or inhomogeneous anomalous Hall effect (AHE). To clarify this ambiguity, we systematically investigated the evolution of AHE with controllable inhomogeneities in SrRuO 3 film thickness ( t SRO ). By exploiting the step-flow growth of SrRuO 3 films, we induced a microscopically ordered stripe pattern with one-unit-cell differences in t SRO . The associated spatial distribution of momentum-space Berry curvatures enables a two-channel AHE with hump-like Hall anomalies, which can be continuously engineered according to non-integer t SRO . We further microscopically characterized the stripe-like ferromagnetic domains and two-step magnetic switching behavior in the inhomogeneous SrRuO 3 film. These unique features can be utilized to identify the two-channel AHE model and understand its microscopic origin.

A 9-year-old female with Trisomy 21 with complex craniovertebral instability causing severe cervicomedullary compression underwent occipitocervical fusion. This paper will discuss the anaesthetic management and highlight the use of the Narcotrend monitor not only as a depth of consciousness monitor but more importantly as a tool to detect surgery-induced cerebral hypoperfusion by monitoring the right and left cerebral hemispheres independently and simultaneously., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

The metal-insulator transition (MIT) in transition-metal-oxide is fertile ground for exploring intriguing physics and potential device applications. Here, an atomic-scale MIT triggered by surface termination conversion in SrRuO 3 ultrathin films is reported. Uniform and effective termination engineering at the SrRuO 3 (001) surface can be realized via a self-limiting water-leaching process. As the surface termination converts from SrO to RuO 2 , a highly insulating and nonferromagnetic phase emerges within the topmost SrRuO 3 monolayer. Such a spatially confined MIT is corroborated by systematic characterizations on electrical transport, magnetism, and scanning tunneling spectroscopy. Density functional theory calculations and X-ray linear dichroism further suggest that the surface termination conversion breaks the local octahedral symmetry of the crystal field. The resultant modulation in 4d orbital occupancy stabilizes a nonferromagnetic insulating surface state. This work introduces a new paradigm to stimulate and tune exotic functionalities of oxide heterostructures with atomic precision., (© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Self-renewing somatic tissues depend upon the proper balance of chromatin-modifying enzymes to coordinate progenitor cell maintenance and differentiation, disruption of which can promote carcinogenesis. As a result, drugs targeting the epigenome hold significant therapeutic potential. The histone demethylase, LSD1 (KDM1A), is overexpressed in numerous cancers, including epithelial cancers; however, its role in the skin is virtually unknown. Here we show that LSD1 directly represses master epithelial transcription factors that promote differentiation. LSD1 inhibitors block both LSD1 binding to chromatin and its catalytic activity, driving significant increases in H3K4 methylation and gene transcription of these fate-determining transcription factors. This leads to both premature epidermal differentiation and the repression of squamous cell carcinoma. Together these data highlight both LSD1's role in maintaining the epidermal progenitor state and the potential of LSD1 inhibitors for the treatment of keratinocyte cancers, which collectively outnumber all other cancers combined., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Hypothalamic gonadotropin releasing hormone (GnRH) is crucial for the proper function of the hypothalamic-pituitary-gonadal (HPG) axis, subsequent puberty, and reproduction. When GnRH neuron migration or GnRH regulation is impaired, hypogonadotropic hypogonadism results. Mutations in the gene for nasal embryonic luteinizing hormone-releasing factor (NELF) have been identified in GnRH-deficient humans. NELF is a predominantly nuclear protein that may participate in gene transcription, but the genes NELF regulates are unknown. To address this question, RNA was extracted from NLT GnRH neuronal cells following either stable Nelf knockdown or scrambled control and subjected to cDNA arrays. Transcription factors and cell migration gene expression was altered most commonly. Members of the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway, including Stat1, Stat2, Stat5a, Jak2, Irf7 and Irf9, were significantly down regulated as assessed by RT-qPCR. Protein levels of STAT1, phospho-STAT1, and JAK2 were reduced, but the protein level of phospho-JAK2 was not. These findings suggest a role for NELF in the regulation of the JAK/STAT signaling pathway, which have important functions in GnRH neurons., (Copyright © 2017. Published by Elsevier B.V.)

Aim: Nonalcoholic hepatic fat accumulation has been hypothesized to be associated with alterations in gut microbiota composition, although mechanistic explanations for this link are largely insufficient. The aim of this study was to elucidate the microbiota-driven mechanisms involved in the development of nonalcoholic hepatic steatosis., Methods and Results: Ob/ob mice and their wild-type lean control mice were fed an AIN-93G diet for 12 weeks. Faecal microbiota composition, faecal bile acid (BA) profile and intestinal and hepatic markers of BA metabolism were analysed. Ob/ob mice had significantly less faecal taurine-conjugated BAs compared to their lean controls. The proportions of butyrate-producing bacteria were lower in ob/ob mice compared to those in lean mice. Intestinal expression of farnesoid X receptor (FXR) mRNA was significantly higher, whereas hepatic expression of cholesterol-7α-hydroxylase 1 (CYP7A1) and small heterodimer partner (SHP) were significantly lower in ob/ob mice compared to those in control mice., Conclusion: Microbiota-associated BAs deconjugation may induce nonalcoholic fatty liver disease (NAFLD) by activating intestinal FXR signalling and blocking hepatic FXR-SHP pathway, thereby accelerating fat synthesis., Significance and Impact of the Study: We provided evidences that changes in the gut microbiota and their metabolites can alter the profile of BAs, thereby providing a mechanism by which an altered microbiota profile contributes to the development of NAFLD., (© 2016 The Society for Applied Microbiology.)

Aims: MicroRNAs (miRs) have been shown to play important roles in tumour progression. Their expression pattern can be useful for cancer classification. However, little is known about miRs in mammary phyllodes tumours (PT)., Methods and Results: In this study, polymerase chain reaction (PCR)-based miR profiling was performed in a small PT cohort to identify deregulated miRs in malignant PT. The purported roles and targets of these miRs were further validated. Unsupervised clustering of miR expression profiling segregated PT into different grades, implicating the miR profile in PT classification. Among the deregulated miRs, miR-21, miR-335 and miR-155 were validated to be higher in malignant than in lower-grade PT in the independent cohort by quantitative PCR (qPCR) (P ≤ 0.032). Their expression correlated with some of the malignant histological features, including high stromal cellularity, nuclear pleomorphism and mitosis. Subsequent analysis of their downstream proteins, namely PTEN for miR-21/miR-155 and Rb for miR-335, also showed an independent significant negative association between miR and protein expression., Conclusions: Differential expression of miRs in PT could be useful in diagnosis and grading of PT. Their deregulated expression, together with the altered downstream targets, implicated their active involvement in PT malignant transformation., (© 2015 John Wiley & Sons Ltd.)

In this study, the prevalence of Shiga toxin-producing Escherichia coli (STEC) was investigated among raw meat or meat products from slaughterhouses and retail markets in South Korea, and their potential for antibiotic resistance and virulence was further analyzed. A total of 912 raw meats, including beef, pork, and chicken, were collected from 2008 to 2009. E. coli strains were frequently isolated in chicken meats (176/233, 75.9%), beef (102/217, 42.3%), and pork (109/235, 39.2%). Putative STEC isolates were further categorized, based on the presence or absence of the Shiga toxin (stx) genes, followed by standard O-serotyping. Polymerase chain reaction assays were used to detect the previously defined virulence genes in STEC, including Shiga toxins 1 and Shiga toxin 2 (stx1 and 2), enterohemolysin (ehxA), intimin (eaeA), STEC autoagglutination adhesion (saa), and subtilase cytotoxin (subAB). All carried both stx1 and eae genes, but none of them had the stx2, saa, or subAB genes. Six (50.0%) STEC isolates possessed the ehxA gene, which is known to be encoded by the 60-megadalton virulence plasmid. Our antibiogram profiling demonstrated that some STEC strains, particularly pork and chicken isolates, displayed a multiple drug-resistance phenotype. RPLA analysis revealed that all the stx1-positive STEC isolates produced Stx1 only at the undetectable level. Altogether, these results imply that the locus of enterocyte and effacement (LEE)-positive strains STEC are predominant among raw meats or meat products from slaughterhouses or retail markets in Korea.

Puberty and reproduction require proper signaling of the hypothalamic-pituitary-gonadal axis controlled by gonadotropin-releasing hormone (GnRH) neurons, which arise in the olfactory placode region and migrate along olfactory axons to the hypothalamus. Factors adversely affecting GnRH neuron specification, migration, and function lead to delayed puberty and infertility. Nasal embryonic luteinizing hormone-releasing factor (NELF) is a predominantly nuclear protein. NELF mutations have been demonstrated in patients with hypogonadotropic hypogonadism, but biallelic mutations are rare and heterozygous NELF mutations typically co-exist with mutations in another gene. Our previous studies in immortalized GnRH neurons supported a role for NELF in GnRH neuron migration. To better understand the physiology of NELF, a homozygous Nelf knockout (KO) mouse model was generated. Our findings indicate that female Nelf KO mice have delayed vaginal opening but no delay in time to first estrus, decreased uterine weight, and reduced GnRH neuron number. In contrast, male mice were normal at puberty. Both sexes of mice had impaired fertility manifested as reduced mean litter size. These data support that NELF has important reproductive functions. The milder than expected phenotype of KO mice also recapitulates the human phenotype since heterozygous NELF mutations usually require an additional mutation in a second gene to result in hypogonadotropic hypogonadism., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

NELF, a protein identified in migratory GnRH neurons, is predominantly nuclear and alternatively spliced. However, specific NELF splice variants expressed in immortalized GnRH neuronal cell lines from mouse and human are not known. RNA from migratory (GN11 and NLT) and postmigratory (GT1-7) cells in mouse, and (FNCB4-hTERT) cells in human was subjected to RT-PCR. RT-PCR products were cloned, electrophoresed on denaturing gradient gels and sequenced. In addition, quantitative RT-PCR was performed using variant-specific primers. Western blot and immunofluorescence using confocal microscopy were performed for selected variants. Nelf variant 2 (v2), which contains a nuclear localization signal (NLS), was the predominant variant in all mouse and human GnRH neurons. Variants without a NLS (v3 in mouse; v4 in human) were identified. In mouse, v2 protein expression was nuclear, while v3 was non-nuclear. In mouse GnRH neurons, six Nelf splice variant transcripts were identified, including three previously unreported variants. In human, four NELF variant transcripts were observed. In both mouse and human, nuclear and non-nuclear variant transcript and protein were identified, explaining variable NELF cellular localization., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

The identity of 45 Hanwo and 47 imported beef (non-Hanwoo) samples from USA and Australia were verified using the microsatellite (MS) marker and single nucleotide polymorphism (SNP) methods. Samples were collected from 19 supermarkets located in the city of Seoul and Gyeonggi province, South Korea, from 2009 to 2011. As a result, we obtained a 100% concordance rate between the MS and SNP methods for identifying Hanwoo and non-Hanwoo beef. The MS method presented a 95% higher individual discriminating value for Hanwoo (97.8%) than for non-Hanwoo (61.7%) beef. For further comparison of the MS and SNP methods, blood samples were collected and tested from 54 Hanwoo × Holstein crossbred cattle (first, second, and third generations). By using the SNP and MS methods, we correctly identified all of the first-generation crossbred cattle as non-Hanwoo; in addition, among the second and third generation crossbreds, the ratio identified as Hanwoo was 20% and 10%, respectively. The MS method used in our study provides more information, but requires sophisticated techniques during each experimental process. By contrast, the SNP method is simple and has a lower error rate. Our results suggest that the MS and SNP methods are useful for discriminating Hanwoo from non-Hanwoo breeds.

Oncogenic Ras mutations are rare in gastric cancer, indicating that other mechanisms may be responsible for aberrant Ras activation in this type of cancer. Ezrin is critical to Ras activation by remodeling cortical actin cy-toskeleton. In this study, we aimed to illustrate the relevance and regulation of ezrin in gastric cancer. Ezrin was upregulated in gastric cancer cells. Ezrin siRNA inhibited Ras activation, cell growth and cell migration. Ezrin overex-pression was correlated with a poor outcome of gastric cancer patients (n=150, p<0.01). Cox regression analysis revealed a significant value of ezrin expression in prognosis prediction of gastric cancer (relative risk: 2.37, 95% confidence interval: 1.24-4.56, p<0.01). MiR-204, which was predicted to target ezrin, was downregulated in gastric cancer cells and gastric carcinomas (n=22, p<0.01). MiR-204 inhibited ezrin expression, Ras activation, cell growth and cell migration. Importantly, miR-204 suppressed the expression of luciferase controlled by wild-type but not mutated ezrin 3'-UTR. In conclusion, ezrin is important to Ras activation in gastric cancer. Its upregulation is an independent prognosis prediction factor for gastric cancer. By contributing to ezrin upregulation, miR-204 downregulation represents a novel mechanism for aberrant Ras activation in gastric carcinogenesis.

The effect of NBM incorporation in PLA nanofibers on their mechanical properties and the differentiation and mineralization of osteoblasts was studied. At 20% NBM, the Young's modulus of the nanofibers was 37.78 +/- 4.23, significantly larger than that of pure PLA nanofibers. MC3T3-E1 pre-osteoblasts attached to both types of nanofibers and developed full osteogenic phenotypes. A profound effect of NBM on the mineralization of MC3T3-E1 pre-osteoblasts was confirmed, suggesting that NBM/PLA composite nanofibers exhibit properties similar to those of the native collagen-rich mineralized bone matrix, and could therefore serve as a temporary substrate for facilitating the differentiation and mineralization of bone-forming cells.

Tissue engineering has become an alternative method to traditional surgical treatments for the repair of bone defects, and an appropriate scaffold supporting bone formation is a key element in this approach. In the present study, nanofibrous organic and inorganic composite scaffolds containing nano-sized demineralized bone powders (DBPs) with biodegradable poly(L-lactide) (PLA) were developed using an electrospinning process for engineering bone. To assess their biocompatibility, in vitro osteogenic differentiation of human mandible-derived mesenchymal stem cells (hMSCs) cultured on PLA or PLA/DBP composite nanofiber scaffolds were examined. The mineralization of hMSCs cultured with osteogenic supplements on the PLA/DBP nanofiber scaffolds was remarkably greater than on the PLA nanofiber scaffold during the first 14 days of culture but reached the same level after 21 days. The in vivo osteoconductive effect of PLA/DBP nanofibrous scaffolds was further investigated using rats with critical-sized skull defects. Micro-computerized tomography revealed that a greater amount of newly formed bone extended across the defect area in PLA/DBP scaffolds than in the nonimplant and PLA scaffolds 12 weeks after implantation and that the defect size was almost 90% smaller. Therefore, PLA/DBP composite nanofiber scaffolds may serve as a favorable matrix for the regeneration of bone tissue.

The production of nanofibrous PLA/HA composite scaffolds is described. The morphological, mechanical, surface, and thermal properties of the composites were extensively investigated. The results show that the mixture of PLA and HA formed smooth nanofibers without lumps. The incorporation of HA increased the mechanical strength of the nanofibers and changed the morphology, increasing the mean fiber diameter and pore size. Surface and internal properties confirmed that HA was homogeneously distributed inside the nanofibers and oriented towards their surface. The nanofiber composites allowed the adhesion and proliferation of pre-osteoblasts for up to 3 weeks.

Protein tyrosine phosphatase 1B plays a major role in the negative regulation of insulin signaling, and this establishes protein tyrosine phosphatase 1B as an attractive therapeutic target for diabetes. Bioassay-guided fractionation of the EtOAc-soluble extract of the seeds of Psoralea corylifolia afforded two protein tyrosine phosphatase 1B inhibitory compounds, psoralidin (1) and bakuchiol (2), along with inactive corylin. Compounds 1 and 2 inhibited PTP1B activity in a dose-dependent manner, displaying IC50 values of 9.4 +/- 0.5 microM and 20.8 +/- 1.9 microM, respectively.

Activity-guided fractionation of the EtOAc and MeOH extract of the leaves of Syringa dilatata NAKAI furnished one free radical scavenger, the secoiridoid glucoside oleuropein together with ligstroside and an iridoid glucoside, syringopicroside. Oleuropein interacted with the stable free radical, 1,1-diphenyl-2-picrylhydrazyl (DPPH), and showed an IC(50) value of 40.4 microM. L-Ascorbic acid as a positive control showed an IC(50) value of 50.3 microM., (Copyright 2003 John Wiley & Sons, Ltd.)

Translocations involving the MLL gene on the chromosome 11 (11q23) are frequently observed in acute leukaemia. The detection of this genetic change has a unique significance as a result of its implication of poor prognosis. To reveal the utility of fluorescence in situ hybridization (FISH) in detecting the MLL translocation, we analysed 289 consecutive Korean patients (children and adults) with acute leukaemias using both conventional cytogenetic analysis (CC) and FISH, placing an emphasis on the result discrepancies. Twenty-two of 289 patients (7.6%) had the 11q23/MLL translocation. In nine of 22 patients (41%), only FISH detected the translocation. In eight of these 22 patients, a total of 19 follow-up examinations were performed, of which FISH detected a significant level of leukaemic cells harbouring the MLL translocation in five patients (26%) without cytogenetic evidence. In addition to the MLL translocation, FISH detected submicroscopic amplification, partial deletion of the MLL gene and trisomy 11 in 12 patients without cytogenetic evidence. In summary, up to 41% of the MLL translocations at initial work-up and 26% during follow-up were detected by FISH without cytogenetic evidence. Thus, we recommend that MLL FISH should be performed in the diagnosis and monitoring of acute leukaemias in combination with CC.

Chemical investigation of the EtOH extract of Morus alba L. (Moraceae), as guided by free radical scavenging activity, furnished 5,7-dihydroxycoumarin 7-methyl ether (1), two prenylflavones, cudraflavone B (2) and cudraflavone C (3), and oxyresveratrol (4). Compounds 1 and 4 showed superoxide scavenging effects with the IC(50) values of 19.1 +/- 3.6 and 3.81 +/- 0.5 microM, respectively. Compound 4 exhibited a DPPH free radical scavenging effect (IC(50) = 23.4 +/- 1.5 microM). Compounds 2 and 4 showed hepatoprotective effects with EC(50) values of 10.3 +/- 0.42 and 32.3 +/- 2.62 micro, respectively, on tacrine-induced cytotoxicity in human liver-derived Hep G2 cells.

A predominance of total or partial chromosomal losses and the rarity of translocations are characteristics of myelodysplastic syndrome (MDS), and 5q,-5, -7 and +8 are known to be the most predominant chromosomal changes. To investigate whether the incidence and the pattern of chromosomal changes in MDS varies by location in Korea, we reviewed the cytogenetic results of 205 MDS cases from three medical centers. Distribution of MDS subtypes and the incidence of chromosomal aberration (44.8%) of MDS in Korea were similar to those found in other countries, however, their patterns were different. Translocations (40.4%) predominated over partial or total deletions (36.3%) in Korea. The most common abnormalities in MDS were trisomy 8, trisomy 1q, -5/5q-, and -7/7q-, which occurred in 18(19.5%), 14(15.2%), 12(13.0%), and 11(11.9%) patients, respectively. It is of note that trisomy 1q, which is rarely reported in hematologic malignancies, was the second most common change associated with MDS in Korea, and that structural anomalies of chromosomes 1(19.6%) exceeded that of chromosome 5(15.2%). The most common sole anomalies were trisomy 8(7.6%) and 14(78%) of 18 cases with chromosome 1 anomalies accompanied by other chromosomal abnormalities, suggesting that the changes of chromosome 1 may be evolutionary events rather than sporadic events. In conclusion, trisomy 1q and trisomy 8 predominate in Korean MDS, suggesting the likelihood of ethnic differences.

To evaluate the immature eggs of Paragonimus westermani as a source of diagnostic antigen, about a million eggs which were excreted by 104 adult worms were collected; their saline extract (soluble egg antigen; PwSEA) was prepared. The specific IgG and IgM antibody levels were observed in experimental dog paragonimiasis by micro-ELISA, using PwSEA as well as whole worm extract of 12 week-old P. westermani (PwWWE). The protein composition of the PwSEA was observed by disc-PAGE. The results could be summarized as follows: Specific IgG antibody to PwSEA began to increase on 8 weeks after the experimental infection; it maintained its high level until the observation period of 13 weeks. The levels of IgM antibody to PwSEA, however, did not show any significant change. Specific IgG antibody to PwWWE began to increase earlier from 2 weeks after the infection and continued to increase until the observation period of 13 weeks. Its level was much higher than that to PwSEA. Specific IgM antibody to PwWWE increased temporarily during 2-8 weeks after the infection. By disc-PAGE, PwSEA showed 2 protein bands of very low motility. The bands of PwSEA corresponded to the first and second bands in the electrophoretic pattern of PwWWE of the 12 week-old worms. The above results indicated that the PwSEA induced antibody production in dog paragonimiasis but its antigenicity was weaker than PwWWE to be used as a diagnostic antigen.