Stochastic chromatin packing of 3D mitotic chromosomes revealed by coherent X-rays.

DNA molecules are atomic-scale information storage molecules that promote reliable information transfer via fault-free repetitions of replications and transcriptions. Remarkable accuracy of compacting a few-meters-long DNA into a micrometer-scale object, and the reverse, makes the chromosome one of the most intriguing structures from both physical and biological viewpoints. However, its three-dimensional (3D) structure remains elusive with challenges in observing native structures of specimens at tens-of-nanometers resolution. Here, using cryogenic coherent X-ray diffraction imaging, we succeeded in obtaining nanoscale 3D structures of metaphase chromosomes that exhibited a random distribution of electron density without characteristics of high-order folding structures. Scaling analysis of the chromosomes, compared with a model structure having the same density profile as the experimental results, has discovered the fractal nature of density distributions. Quantitative 3D density maps, corroborated by molecular dynamics simulations, reveal that internal structures of chromosomes conform to diffusion-limited aggregation behavior, which indicates that 3D chromatin packing occurs via stochastic processes.

Ultrafast Energy Transfer Process in Confined Gold Nanospheres Revealed by Femtosecond X-ray Imaging and Diffraction.

Femtosecond laser pulses drive nonequilibrium phase transitions via reaction paths hidden in thermal equilibrium. This stimulates interest to understand photoinduced ultrafast melting processes, which remains incomplete due to challenges in resolving accompanied kinetics at the relevant space-time resolution. Here, by newly establishing a multiplexing femtosecond X-ray probe, we have successfully revealed ultrafast energy transfer processes in confined Au nanospheres. Real-time images of electron density distributions with the corresponding lattice structures elucidate that the energy transfer begins with subpicosecond melting at the specimen boundary earlier than the lattice thermalization, and proceeds by forming voids. Two temperature molecular dynamics simulations uncovered the presence of both heterogeneous melting with the melting front propagation from surface and grain boundaries and homogeneous melting with random melting seeds and nanoscale voids. Supported by experimental and theoretical results, we provide a comprehensive atomic-scale picture that accounts for the ultrafast laser-induced melting and evaporation kinetics.

Oxidation-induced three-dimensional morphological changes in Ni nanoparticles observed by coherent X-ray diffraction imaging.

Three-dimensional structures of Ni nanoparticles undergoing significant morphological changes on oxidation were observed non-destructively using coherent X-ray diffraction imaging. The Ni particles were oxidized into Ni1O1 while forming pores of various sizes internally. For each Ni nanoparticle, one large void was identified at a lower corner near the interface with the substrate. The porosity of the internal region of the agglomerated Ni oxide was about 38.4%. Regions of high NiO density were mostly observed at the outer crust of the oxide or at the boundary with the large voids. This research expands our understanding of general catalytic reactions with direct observation of oxidation-induced nanoscale morphological changes.

Characterizing the intrinsic properties of individual XFEL pulses via single-particle diffraction.

With each single X-ray pulse having its own characteristics, understanding the individual property of each X-ray free-electron laser (XFEL) pulse is essential for its applications in probing and manipulating specimens as well as in diagnosing the lasing performance. Intensive research using XFEL radiation over the last several years has introduced techniques to characterize the femtosecond XFEL pulses, but a simple characterization scheme, while not requiring ad hoc assumptions, to address multiple aspects of XFEL radiation via a single data collection process is scant. Here, it is shown that single-particle diffraction patterns collected using single XFEL pulses can provide information about the incident photon flux and coherence property simultaneously, and the X-ray beam profile is inferred. The proposed scheme is highly adaptable to most experimental configurations, and will become an essential approach to understanding single X-ray pulses.

High Resolution Full-Aperture ISAR Processing through Modified Doppler History Based Motion Compensation.

A high resolution inverse synthetic aperture radar (ISAR) technique is presented using modified Doppler history based motion compensation. To this purpose, a novel wideband ISAR system is developed that accommodates parametric processing over extended aperture length. The proposed method is derived from an ISAR-to-SAR approach that makes use of high resolution spotlight SAR and sub-aperture recombination. It is dedicated to wide aperture ISAR imaging and exhibits robust performance against unstable targets having non-linear motions. We demonstrate that the Doppler histories of the full aperture ISAR echoes from disturbed targets are efficiently retrieved with good fitting models. Experiments have been conducted on real aircraft targets and the feasibility of the full aperture ISAR processing is verified through the acquisition of high resolution ISAR imagery.

A Multicenter Study Investigating Empathy and Burnout Characteristics in Medical Residents with Various Specialties.

We assessed empathy in medical residents, including factors modifying empathy and the relationship between empathy and burnout. Participants (n = 317 residents, response rate = 42%) from 4 university hospitals completed a socio-demographic questionnaire, the Jefferson Scale of Empathy (Health Professional version, Korean edition), and the Maslach Burnout Inventory (MBI). Participants were classified by medical specialty: "people-oriented specialty" (POS group) or "technology-oriented specialty" (TOS group), with more women in the POS than in the TOS group, χ(2) = 14.12, P < 0.001. Being female, married, and having children were factors related to higher empathy (gender, t = -2.129, P = 0.034; marriage, t = -2.078, P = 0.038; children, t = 2.86, P = 0.005). Within specialty group, POS residents showed higher empathy scores in the fourth as compared to the first year, F = 3.166, P = 0.026. Comparing POS and TOS groups by year, fourth year POS residents had significantly higher scores than did fourth year TOS residents, t = 3.349, P = 0.002. There were negative correlations between empathy scores and 2 MBI subscales, emotional exhaustion (EE) and depersonalization (DP). Additionally, first year POS residents had higher DP scores than did first year TOS residents, t = 2.183, P = 0.031. We suggest that factors important for empathy are type of medical specialty, marriage, siblings, and children. Burnout state may be related to decreasing empathy.

Methylphenidate-osmotic-controlled release oral delivery system treatment reduces parenting stress in parents of children and adolescents with attention-deficit/hyperactivity disorder.

OBJECTIVE: The aim of the current study was to investigate the effect of methylphenidate-osmotic release oral delivery system (MPH-OROS) treatment on parenting stress in parents of children and adolescents with attention-deficit/hyperactivity disorder (ADHD). METHODS: Four hundred and ninety-five children and adolescents (391 boys and 104 girls), aged 7 to 18 years who met the Diagnostic and Statistical Manual of Mental Disorders, fourth edition criteria for ADHD, were recruited at 48 psychiatric outpatient clinics across South Korea. Children's symptoms, parenting stress, and parental depression were assessed at baseline, week 4, and week 8 of MPH-OROS treatment using the Korean version of the DuPaul's ADHD Rating Scale (ARS), the Beck's Depression Inventory (BDI), and the Parenting Stress Index, Short Form (PSI-SF). RESULTS: We found significantly decreased scores of ARS, parental BDI, and PSI-SF from baseline to week 4 and from week 4 to week 8. Also, there were positive correlations among baseline PSI-SF, ARS, and BDI scores. The changes in BDI and ARS scores were significantly associated with the PSI score changes, accounting for 20.1% and 10.0%, respectively. CONCLUSIONS: We suggest that the increased parenting stress and depression in parents of children and adolescents with ADHD can be improved following the treatment with MPH-OROS.

Observing femtosecond orbital dynamics in ultrafast Ge melting with time-resolved resonant X-ray scattering.

Photoinduced nonequilibrium phase transitions have stimulated interest in the dynamic interactions between electrons and crystalline ions, which have long been overlooked within the Born-Oppenheimer approximation. Ultrafast melting before lattice thermalization prompted researchers to revisit this issue to understand ultrafast photoinduced weakening of the crystal bonding. However, the absence of direct evidence demonstrating the role of orbital dynamics in lattice disorder leaves it elusive. By performing time-resolved resonant X-ray scattering with an X-ray free-electron laser, we directly monitored the ultrafast dynamics of bonding orbitals of Ge to drive photoinduced melting. Increased photoexcitation of bonding electrons amplifies the orbital disturbance to expedite the lattice disorder approaching the sub-picosecond scale of the nonthermal regime. The lattice disorder time shows strong nonlinear dependence on the laser fluence with a crossover behavior from thermal-driven to nonthermal-dominant kinetics, which is also verified by ab initio and two-temperature molecular dynamics simulations. This study elucidates the impact of bonding orbitals on lattice stability with a unifying interpretation on photoinduced melting.

High-Throughput 3D Ensemble Characterization of Individual Core-Shell Nanoparticles with X-ray Free Electron Laser Single-Particle Imaging.

The structures as building blocks for designing functional nanomaterials have fueled the development of versatile nanoprobes to understand local structures of noncrystalline specimens. Progress in analyzing structures of individual specimens with atomic scale accuracy has been notable recently. In most cases, however, only a limited number of specimens are inspected lacking statistics to represent the systems with structural inhomogeneity. Here, by employing single-particle imaging with X-ray free electron lasers and algorithms for multiple-model 3D imaging, we succeeded in investigating several thousand specimens in a couple of hours and identified intrinsic heterogeneities with 3D structures. Quantitative analysis has unveiled 3D morphology, facet indices, and elastic strain. The 3D elastic energy distribution is further corroborated by molecular dynamics simulations to gain mechanical insight at the atomic level. This work establishes a route to high-throughput characterization of individual specimens in large ensembles, hence overcoming statistical deficiency while providing quantitative information at the nanoscale.

Inducing thermodynamically blocked atomic ordering via strongly driven nonequilibrium kinetics.

Ultrafast light-matter interactions enable inducing exotic material phases by promoting access to kinetic processes blocked in equilibrium. Despite potential opportunities, actively using nonequilibrium kinetics for material discovery is limited by the poor understanding on intermediate states of driven systems. Here, using single-pulse time-resolved imaging with x-ray free-electron lasers, we found intermediate states of photoexcited bismuth nanoparticles that showed kinetically reversed surface ordering during ultrafast melting. This entropy-lowering reaction was further investigated by molecular dynamics simulations to reveal that observed kinetics were thermodynamically buried in equilibrium, which emphasized the critical role of electron-mediated ultrafast free-energy modification in inducing exotic material phases. This study demonstrated that ultrafast photoexcitations of electrons provide an efficient strategy to induce hidden material phases by overcoming thermodynamic barriers via nonequilibrium reaction pathways.

Stable Silicon Anode for Lithium-Ion Batteries through Covalent Bond Formation with a Binder via Esterification.

Silicon (Si) is considered to be one of the most promising anode candidates for next-generation lithium-ion batteries because of its high theoretical specific capacity and low discharge potential. However, its poor cyclability, caused by tremendous volume change during cycling, prevents commercial use of the Si anode. Herein, we demonstrate a high-performance Si anode produced via covalent bond formation between a commercially available Si nanopowder and a linear polymeric binder through an esterification reaction. For efficient ester bonding, polyacrylic acid, composed of -COOH groups, is selected as the binder, Si is treated with piranha solution to produce abundant -OH groups on its surface, and sodium hypophosphite is employed as a catalyst. The as-fabricated electrode exhibits excellent high rate capability and long cycle stability, delivering a high capacity of 1500 mA h g-1 after 500 cycles at a high current density of 1000 mA g-1 by effectively restraining the susceptible sliding of the binder, stabilizing the solid electrolyte interface layer, preventing the electrode delamination, and suppressing the Si aggregation. Furthermore, a full cell is fabricated with as-fabricated Si as an anode and commercially available LiNi0.6Mn0.2Co0.2O2 as a cathode, and its electrochemical properties are investigated for the possibility of practical use.

A P2-type Na0.7(Ni0.6Co0.2Mn0.2)O2 cathode with excellent cyclability and rate capability for sodium ion batteries.

A new P2-type Na0.7(Ni0.6Co0.2Mn0.2)O2 was prepared via co-precipitation and its electrochemical properties as a cathode for sodium ion batteries were compared with those of O3-type Na(Ni0.6Co0.2Mn0.2)O2, focusing on phase stability and cycling performance. The P2-type delivered a high capacity of 108 mA h g-1 after 300 cycles at 2C.

Direct observation of picosecond melting and disintegration of metallic nanoparticles.

Despite more than a century of study, the fundamental mechanisms behind solid melting remain elusive at the nanoscale. Ultrafast phenomena in materials irradiated by intense femtosecond laser pulses have revived the interest in unveiling the puzzling processes of melting transitions. However, direct experimental validation of various microscopic models is limited due to the difficulty of imaging the internal structures of materials undergoing ultrafast and irreversible transitions. Here we overcome this challenge through time-resolved single-shot diffractive imaging using X-ray free electron laser pulses. Images of single Au nanoparticles show heterogeneous melting at the surface followed by density fluctuation deep inside the particle, which is directionally correlated to the polarization of the pumping laser. Observation of this directionality links the non-thermal electronic excitation to the thermal lattice melting, which is further verified by molecular dynamics simulations. This work provides direct evidence to the understanding of irreversible melting with an unprecedented spatiotemporal resolution.

[Quality characteristics and nonclinical/clinical profiles of Etanercept BS SC [MA]].

Etanercept is a dimeric genetic recombinant glycoprotein consisting of Fc domain of human Immunoglobulin G1 and the extracellular domain of human tumor necrosis factor (TNF) receptor type II. Etanercept exerts therapeutic effects on inflammatory diseases such as rheumatoid arthritis and juvenile idiopathic arthritis by neutralizing biological activities of TNFα/Lymphotoxin (LT) α. Mochida Pharmaceutical and LG Chem have developed syringe, pen, and vial products of Etanercept BS (biosimilar) as the first biosimilar of Enbrel in Japan. The active ingredient of those products "Etanercept biosimilar 1" has the identical primary structure to that of Enbrel. The development of the Etanercept BS, including evaluations of quality attributes, nonclinical and clinical studies was performed in accordance with "Policies on Assurance of Quality, Safety and Efficacy of Biosimilars". The quality attributes of Etanercept BS were similar to those of Enbrel, and the binding affinities to TNFα/LTα, TNFα neutralizing activity, nonclinical pharmacokinetics and toxicological profiles of Etanercept BS were comparable to Enbrel. Additionally, the pharmacokinetic profile and efficacy of Etanercept BS were equivalent to those of Enbrel and there was no clinically significant difference in safety profiles between them in Phase I and Phase III clinical studies. The marketing approval application of the Etanercept BS with the same indications as Enbrel filed by Mochida Pharmaceutical was approved in January 2018 and the products will be launched by Ayumi Pharmaceutical in the near future. The Etanercept BS, which is as highly effective as Enbrel is expected to make beneficial therapies more easily accessible to patients.

Imaging the magnetic structures of artificial quasicrystal magnets using resonant coherent diffraction of circularly polarized X-rays.

Unraveling nanoscale spin structures has long been an important activity addressing various scientific interests, that are also readily adaptable to technological applications. This has invigorated the development of versatile nanoprobes suitable for imaging specimens under native conditions. Here we have demonstrated the resonant coherent diffraction of an artificial quasicrystal magnet with circularly polarized X-rays. The nanoscale magnetic structure was revealed from X-ray speckle patterns by comparing with micromagnetic simulations, as a step toward understanding the intricate relationship between the chemical and spin structures in an aperiodic quasicrystal lattice. Femtosecond X-ray pulses from free electron lasers are expected to immediately extend the current work to nanoscale structure investigations of ultrafast spin dynamics, surpassing the present spatio-temporal resolution.

Additive effects of neurofeedback on the treatment of ADHD: A randomized controlled study.

Neurofeedback (NF) has been identified as a "possibly efficacious" treatment in current evidence-based reviews; therefore, more research is needed to determine its effects. The current study examined the potential additive effect of NF for children diagnosed with ADHD beginning a medication trial first. Thirty-six children (6-12 years) with a DSM-IV-TR diagnosis of ADHD were randomly assigned to an NF with medication (NF condition) or a medication only condition. Children in the NF group attended 20 twice-weekly sessions. Outcome measures included individual cognitive performance scores (ADS, K-WISC-III), ADHD rating scores completed by their parents (ARS, CRS) and brainwave indices of left and right hemispheres before and after NF treatment. Significant additive treatment effect in any of the symptom variables was found and a reduction of theta waves in both the right and left hemispheres was recorded in NF condition participants. However our randomized controlled study could not demonstrate superior effects of combined NF on intelligent functioning compared to the medication treatment only. This study suggested any possible evidence of positive and additive treatment effects of NF on brainwaves and ADHD symptomatology.

Interferon regulatory factor-1 (IRF-1) is a mediator for interferon-gamma induced attenuation of telomerase activity and human telomerase reverse transcriptase (hTERT) expression.

Constitutive activation of the telomerase is a key step in the development of human cancers. Interferon-gamma (IFN-gamma) signaling induces growth arrest in many tumors through multiple regulatory mechanisms. In this study, we show that IFN-gamma signaling represses telomerase activity and human telomerase reverse transcriptase (hTERT) transcription, and suggest that this signaling is mediated by IRF-1. Ectopic expression of IRF-1 attenuated hTERT promoter activity. Murine embryonic fibroblasts (MEFs) genetically deficient in IRF-1 (IRF-1(-/-)) showed an elevated level (>15 times) of hTERT promoter activity as compared to the hTERT promoter activity of wild-type MEFs. The telomerase activity and hTERT expression in IRF-1(-/-) MEFs were downregulated by IRF-1 transfection. Interestingly, less extent of telomerase repression was observed in HPV E6 and E7 negative, p53 mutant HT-3 cells than in HPV 18 E6 and E7 positive HeLa cells (intact p53). These findings provide evidence that IRF-1 is a potential mediator of IFN-gamma-induced attenuation of telomerase activity and hTERT expression.

Characterization of N alpha-acetyl methionyl human growth hormone formed during expression in Saccharomyces cerevisiae with liquid chromatography and mass spectrometry.

We found a new variant of human growth hormone (hGH) from the recombinant hGH expression process in Saccharomyces cerevisiae. The variant was identified as N(alpha)-acetyl methionyl hGH which may be formed by N(alpha)-acetylation of met-hGH during the intracellular expression of hGH in S. cerevisiae. The variant was isolated from manufacturing process of LG Life Sciences' hGH product. The variant was subjected to trypsin digestion and RP-HPLC analysis, resulting in a delayed retention time and an increased mass (173 Da) of T1 tryptic peptide. The amino acid composition and amino acid sequence of the peptide showed the same result with T1 peptide of met-hGH except the N-terminal modification on methionine in the variant peptide. With collision induced dissociation (CID) experiments of the variant T1 tryptic peptide, we found the sequence and the a(1) fragment of N-terminal residue matched with those of acetyl-methionyl hGH. Within our production process, we produce the methionyl hGH first and then use the aminopeptidase to cut the N-terminal methionine. So the acetylation may inhibit the aminopeptidase to remove methionine and produces N(alpha)-acetyl methionyl hGH. And the biological activity of the variant was comparable to one of the unmodified hGH when tested by rat weight gain bioassay.

Oriented film growth of Ba(1-x)Sr(x)TiO3 dielectrics on glass substrates using 2D nanosheet seed layer.

An approach to fabricate Ba0.5Sr0.5TiO3 (BST) films with a preferred orientation on a glass substrate by pulsed laser deposition was developed. To ensure a preferred crystallographic orientation, we utilized a molecularly thin Ca2Nb3O10 perovskite nanosheet as a seed layer and successfully fabricated BST films with a nearly perfect (100)-axis orientation. The 100 nm films after annealing at 450 °C in air showed a good dielectric performance (ε(r) > 400), which was comparable to the ε(r) value of epitaxially grown films with the same thickness. These results indicate that the nanosheet seed layer plays a crucial role in controlled film growth, realizing a nearly intrinsic performance of BST.

Clinical features of pathologic childhood aerophagia: early recognition and essential diagnostic criteria.

OBJECTIVE: This study investigated the early recognition and diagnosis of pathologic childhood aerophagia to avoid unnecessary diagnostic approaches and serious complications. METHODS: Between 1995 and 2003, data from 42 consecutive patients with pathologic childhood aerophagia, aged 2 to 16 years, were reviewed. An esophageal air sign was defined as an abnormal air shadow on the proximal esophagus adjacent to the trachea on a full-inflated chest radiograph. RESULTS: Of the 42 patients, the chief complaints were abdominal distention (52.4%), recurrent abdominal pain syndrome (21.4%), chronic diarrhea (11.9%), acute abdominal pain (7.1%) and others (7.2%). Mean symptom duration before diagnosis was 10.6 months (range, 1 to 60 months), and it exceeded 12 months for 16 (38.1%) patients. The clinical features common to all patients were abdominal distention that increased progressively during the day, increased flatus on sleep, increased bowel sound on auscultation and an air-distended stomach with increased gas in the small and large bowel by radiography. Visible or audible air swallowing (26.2%) and repetitive belching (9.5%) were also noted. Esophageal air sign was observed in 76.2% of the patients and in 9.7% of the controls (P=0.0001). The subgroups of pathologic childhood aerophagia divided by underlying associations were pathologic childhood aerophagia without severe mental retardation (76.2%), which consisted of psychological stresses and uncertain condition, and pathologic childhood aerophagia with severe mental retardation (23.8%). CONCLUSIONS: The common manifestations of pathologic childhood aerophagia may be its essential diagnostic criteria, and esophageal air sign may be useful for the early recognition of pathologic childhood aerophagia. Our observations show that the diagnostic clinical profiles suggested by Rome II criteria should be detailed and made clearer if they are to serve as diagnostic criteria for pathologic childhood aerophagia.