Investigation of the damping wiggler effect and application on the PAL fourth-generation storage ring.

An investigation of the damping wiggler effect to reduce the emittance in the Pohang Accelerator Laboratory (PAL), a fourth-generation storage ring (4GSR) that uses a multi-bend achromat, is presented. A 4GSR lattice which has reduced emittance and increased dynamic aperture to amplify the synergy with two existing light sources (PLS-II and PAL-XFEL) at PAL is described.

Demonstration of a ring-FEL as an EUV lithography tool.

This paper presents the required structure and function of a ring-FEL as a radiation source for extreme ultraviolet radiation lithography (EUVL). A 100 m-long straight section that conducts an extremely low emittance beam from a fourth-generation storage ring can increase the average power at 13.5 nm wavelength to up to 1 kW without degrading the beam in the rest of the ring. Here, simulation results for a ring-FEL as a EUVL source are described.

Association between time to treatment and functional outcomes according to the Diffusion-Weighted Imaging Alberta Stroke Program Early Computed Tomography Score in endovascular stroke therapy.

BACKGROUND AND PURPOSE: The rate at which the chance of a good outcome of endovascular stroke therapy (EVT) decays with time when eligible patients are selected by baseline diffusion-weighted magnetic resonance imaging (DWI-MRI) and whether ischaemic core size affects this rate remain to be investigated. METHODS: This study analyses a prospective multicentre registry of stroke patients treated with EVT based on pretreatment DWI-MRI that was categorized into three groups: small [Diffusion-Weighted Imaging Alberta Stroke Program Early Computed Tomography Score (DWI-ASPECTS)] (8-10), moderate (5-7) and large (<5) cores. The main outcome was a good outcome at 90 days (modified Rankin Scale 0-2). The interaction between onset-to-groin puncture time (OTP) and DWI-ASPECTS categories regarding functional outcomes was investigated. RESULTS: Ultimately, 985 patients (age 69 ± 11 years; male 55%) were analysed. Potential interaction effects between the DWI-ASPECTS categories and OTP on a good outcome at 90 days were observed (Pinteraction  = 0.06). Every 60-min delay in OTP was associated with a 16% reduced likelihood of a good outcome at 90 days amongst patients with large cores, although no associations were observed amongst patients with small to moderate cores. Interestingly, the adjusted rates of a good outcome at 90 days steeply declined between 65 and 213 min of OTP and then remained smooth throughout 24 h of OTP (Pnonlinearity  = 0.15). CONCLUSIONS: Our study showed that the probability of a good outcome after EVT nonlinearly decreased, with a steeper decline at earlier OTP than at later OTP. Discrepant effects of OTP on functional outcomes by baseline DWI-ASPECTS categories were observed. Thus, different strategies for EVT based on time and ischaemic core size are warranted.

Seizures in patients with acute pesticide intoxication, with a focus on glufosinate ammonium.

The incidence and clinical aspects of seizures remain to be elucidated in patients with acute pesticide intoxication. The present study included subjects who ingested pesticide with the intention of committing suicide and were treated at Soonchunhyang University Hospital (Cheonan, Korea) between January 2011 and December 2014. We analyzed the incidence and characterized the type and frequency of seizure, from the medical records of 464 patients with acute pesticide intoxication, according to the pesticide class. The effect of seizure on the clinical outcome was assessed. The incidence of seizure was 31.5% in patients who ingested glufosinate ammonium {2-amino-4-[hydroxyl (methyl) phosphinoyl] butyrate; ammonium DL-homoalanin-4-yl (methyl) phosphinate}, followed by those who ingested pyrethroid (5.9%) or glycine derivatives (5.4%). All of the seizures developed between 12 and 24 h of pesticide ingestion and had ceased by 72 h after seizure initiation, following treatment with antiseizure medication. Generalized tonic-clonic seizures were the most commonly observed (85.7% of the cases). Multivariable logistic regression analysis showed that the effect of seizure on mortality was not statistically significant. In conclusion, glufosinate ammonium herbicide is the most common seizurogenic pesticide class. Seizure itself was not a risk factor for mortality in patients with acute glufosinate ammonium intoxication.

Femtosecond charge and molecular dynamics of I-containing organic molecules induced by intense X-ray free-electron laser pulses.

We studied the electronic and nuclear dynamics of I-containing organic molecules induced by intense hard X-ray pulses at the XFEL facility SACLA in Japan. The interaction with the intense XFEL pulse causes absorption of multiple X-ray photons by the iodine atom, which results in the creation of many electronic vacancies (positive charges) via the sequential electronic relaxation in the iodine, followed by intramolecular charge redistribution. In a previous study we investigated the subsequent fragmentation by Coulomb explosion of the simplest I-substituted hydrocarbon, iodomethane (CH3I). We carried out three-dimensional momentum correlation measurements of the atomic ions created via Coulomb explosion of the molecule and found that a classical Coulomb explosion model including charge evolution (CCE-CE model), which accounts for the concerted dynamics of nuclear motion and charge creation/charge redistribution, reproduces well the observed momentum correlation maps of fragment ions emitted after XFEL irradiation. Then we extended the study to 5-iodouracil (C4H3IN2O2, 5-IU), which is a more complex molecule of biological relevance, and confirmed that, in both CH3I and 5-IU, the charge build-up takes about 10 fs, while the charge is redistributed among atoms within only a few fs. We also adopted a self-consistent charge density-functional based tight-binding (SCC-DFTB) method to treat the fragmentations of highly charged 5-IU ions created by XFEL pulses. Our SCC-DFTB modeling reproduces well the experimental and CCE-CE results. We have also investigated the influence of the nuclear dynamics on the charge redistribution (charge transfer) using nonadiabatic quantum-mechanical molecular dynamics (NAQMD) simulation. The time scale of the charge transfer from the iodine atomic site to the uracil ring induced by nuclear motion turned out to be only ∼5 fs, indicating that, besides the molecular Auger decay in which molecular orbitals delocalized over the iodine site and the uracil ring are involved, the nuclear dynamics also play a role for ultrafast charge redistribution. The present study illustrates that the CCE-CE model as well as the SCC-DFTB method can be used for reconstructing the positions of atoms in motion, in combination with the momentum correlation measurement of the atomic ions created via XFEL-induced Coulomb explosion of molecules.

Top-up operation at Pohang Light Source-II.

After three years of upgrading work, PLS-II (S. Shin, Commissioning of the PLS-II, JINST, January 2013) is now successfully operating. The top-up operation of the 3 GeV linear accelerator had to be delayed because of some challenges encountered, and PLS-II was run in decay mode at the beginning in March 2012. The main difficulties encountered in the top-up operation of PLS-II are different levels between the linear accelerator and the storage ring, the 14 narrow gap in-vacuum undulators in operation, and the full energy injection by 3 GeV linear accelerator. Large vertical emittance and energy jitter of the linac were the major obstacles that called for careful control of injected beam to reduce beam loss in the storage ring during injection. The following measures were taken to resolve these problems: (1) The high resolution Libera BPM (see http://www.i-tech.si) was implemented to measure the beam trajectory and energy. (2) Three slit systems were installed to filter the beam edge. (3) De-Qing circuit was applied to the modulator system to improve the energy stability of injected beam. As a result, the radiation by beam loss during injection is reduced drastically, and the top-up mode has been successfully operating since 19th March 2013. In this paper, we describe the experimental results of the PLS-II top-up operation and the improvement plan.

Cleavage of BCR-ABL transcripts at the T315I point mutation by DNAzyme promotes apoptotic cell death in imatinib-resistant BCR-ABL leukemic cells.

The BCR-ABL fusion transcript encodes the BCR-ABL tyrosine kinase (TK), which causes chronic myelogenous leukemia (CML). Although the TK inhibitor imatinib mesylate, which targets the BCR-ABL protein, has been proven to be effective in controlling leukemic growth, imatinib resistance has been observed with disease relapse because of point mutations in the ABL gene that inhibit imatinib efficacy. In this study, we designed oligodeoxyribozymes (DNAzymes) that specifically target and cleave both the junction sequence and the site of the point mutation (T315I), conferring imatinib resistance in BCR-ABL mRNA. DNAzymes significantly induced apoptosis and inhibited proliferation in wild-type and T315I-mutant BCR-ABL-positive cells. Selective cleavage of T315I-mutant ABL mRNA by DNAzyme (T315I Dz) led to cell cycle arrest in G0/G1 phase, with induction of caspase-3/-7 in imatinib-resistant BCR-ABL-positive cells harboring the T315I mutation. Moreover, cotreatment with the DNAzyme targeting the T315I mutation and imatinib resulted in enhanced inhibition of proliferation and induction of apoptosis in T315I leukemic cells as compared with imatinib alone, thereby antagonizing imatinib resistance in CML cells bearing T315I-mutant BCR-ABL. Therefore, cleavage of T315I-mutant ABL mRNA by DNAzyme combined with imatinib treatment may be an alternative approach to overcoming imatinib resistance in leukemic cells.

SVCT-2 in breast cancer acts as an indicator for L-ascorbate treatment.

L-ascorbate (L-ascorbic acid, vitamin C) clearly has an inhibitory effect on cancer cells. However, the mechanism underlying differential sensitivity of cancer cells from same tissue to L-ascorbate is yet to be clarified. Here, we demonstrate that L-ascorbate has a selective killing effect, which is influenced by sodium-dependent vitamin C transporter 2 (SVCT-2) in human breast cancer cells. Treatment of human breast cancer cells with L-ascorbate differentially induced cell death, dependent on the SVCT-2 protein level. Moreover, knockdown of endogenous SVCT-2 via RNA interference in breast cancer cells expressing high levels of the protein induced resistance to L-ascorbate treatment, whereas transfection with SVCT-2 expression plasmids led to enhanced L-ascorbate chemosensitivity. Surprisingly, tumor regression by L-ascorbate administration in mice bearing tumor cell xenograft also corresponded to the SVCT-2 protein level. Interestingly, SVCT-2 expression was absent or weak in normal tissues, but strongly detected in tumor samples obtained from breast cancer patients. In addition, enhanced chemosensitivity to L-ascorbate occurred as a result of caspase-independent autophagy, which was mediated by beclin-1 and LC3 II. In addition, treatment with N-acetyl-L-cysteine, a reactive oxygen species (ROS) scavenger, suppressed the induction of beclin-1 and LC3 II, implying that the differential SVCT-2 protein-dependent L-ascorbate uptake was attributable to intracellular ROS induced by L-ascorbate, subsequently leading to autophagy. These results suggest that functional SVCT-2 sensitizes breast cancer cells to autophagic damage by increasing the L-ascorbate concentration and intracellular ROS production and furthermore, SVCT-2 in breast cancer may act as an indicator for commencing L-ascorbate treatment.

Right-to-left shunts as a cause of juxtacortical spots in patients with migraine.

BACKGROUNDS: Juxtacortical spots on fluid-attenuated inversion recovery (FLAIR) images can be frequently detected in patients with migraine. However, the origins of the cerebral lesions (including juxtacortical spots on FLAIR images) found in the previous studies are not known. We sought to investigate the association between juxtacortical spots on FLAIR images and right-to-left shunt (RLS) in migraine patients. METHODS: Juxtacortical spots on FLAIR images were arbitrarily defined as small areas of hyperintensities in the juxtacortex and cortico-subcortical junction. The presence of RLS was examined by a transcranial Dopper (TCD) with the agitated saline test. The degree of RLS was categorized into four grades according to the number of microemboli: no shunt, <10 microbubbles (MB), >10 MB single spots pattern, and >10 MB shower/curtain pattern. We compared the results for migraine patients (n = 49) with those for healthy controls (n = 49). RESULTS: Juxtacortical spots on FLAIR images occurred in 38/98 subjects; of them, 27/49 (55.1%) had migraines and 11/49 (22.2%) were healthy controls (P = 0.002). The independent factors associated with juxtacortical spots on FLAIR images were female, migraine patients, and RLS by multivariate analysis. In migraine patients, RLS was independently associated with juxtacortical spots on FLAIR images. CONCLUSION: Our results suggest that juxtacortical spots on FLAIR images were frequently found in migraine patients and might be associated with the presence of RLS in those patients. Further studies are needed to assess whether juxtacortical spots have clinical implications in patients with migraine.

Biotribological investigation of a multi-tube foot for traction generation in a medical microrobot.

In recent years, efforts to develop microrobots for medical applications have been expanding. One of the key design issues in such microrobots is to attain adequate frictional interaction between the robotic foot and the organ tissue. In particular, it is important to generate the necessary frictional force without damaging the tissue. In this work, a design for the robotic foot was proposed on the basis of the frictional behaviour of a tube structure. Fundamental experiments were initially performed to understand the biotribological behaviour of the tube and rod structures. The design was then modified to a multi-tube structure to achieve adequate frictional behaviour. Biotribological investigation of a multi-tube foot in contact with a small intestine specimen of a pig was conducted using a pin-on-reciprocator type biotribotester. It was found that there is an optimum number and arrangement of the tubes for generating high frictional force. Experimental results showed that a nine-tube foot had the highest initial friction coefficient of about 1.5. The major frictional mechanism was determined to be interlocking between the tubes and the surface structures of the intestine specimen. The results of this work will aid the optimum design of frictional surface for medical microrobots and other biological devices.

Analytical model development for the prediction of the frictional resistance of a capsule endoscope inside an intestine.

For the purpose of optimizing the design of the locomotion mechanism as well as the body shape of a self-propelled capsule endoscope, an analytical model for the prediction of frictional resistance of the capsule moving inside the small intestine was first developed. The model was developed by considering the contact geometry and viscoelasticity of the intestine, based on the experimental investigations on the material properties of the intestine and the friction of the capsule inside the small intestine. In order to verify the model and to investigate the distributions of various stress components applied to the capsule, finite element (FE) analyses were carried out. The comparison of the frictional resistance between the predicted and the experimental values suggested that the proposed model could predict the frictional force of the capsule with reasonable accuracy. Also, the FE analysis results of various stress components revealed the stress relaxation of the intestine and explained that such stress relaxation characteristics of the intestine resulted in lower frictional force as the speed of the capsule decreased. These results suggested that the frontal shape of the capsule was critical to the design of the capsule with desired frictional performance. It was shown that the proposed model can provide quantitative estimation of the frictional resistance of the capsule under various moving conditions inside the intestine. The model is expected to be useful in the design optimization of the capsule locomotion inside the intestine.

Crystal structure of Bacillus subtilis YckF: structural and functional evolution.

The crystal structure of the YckF protein from Bacillus subtilis was determined with MAD phasing and refined at 1.95A resolution. YckF forms a tight tetramer both in crystals and in solution. Conservation of such oligomerization in other phosphate sugar isomerases indicates that the crystallographically observed tetramer is physiologically relevant. The structure of YckF was compared to with its ortholog from Methanococcus jannaschii, MJ1247. Both of these proteins have phosphate hexulose isomerase activity, although neither of the organisms can utilize methane or methanol as source of energy and/or carbon. Extensive sequence and structural similarities with MJ1247 and with the isomerase domain of glucosamine-6-phosphate synthase from Escherichia coli allowed us to group residues contributing to substrate binding or catalysis. Few notable differences among these structures suggest possible cooperativity of the four active sites of the tetramer. Phylogenetic relationships between obligatory and facultative methylotrophs along with B. subtilis and E. coli provide clues about the possible evolution of genes as they loose their physiological importance.

Frictional resistance characteristics of a capsule inside the intestine for microendoscope design.

The design of the capsule body for a self-propelled endoscope is important from the frictional resistance point of view. The motivation of this work was to gain a better understanding of the effect of capsule shape on the frictional resistance of the capsule inside a small intestine. Special experimental set-ups were built to investigate the frictional resistance of the capsule and the viscoelastic deformation characteristics of the small intestine specimen of a pig. Tests were performed with capsules of various shapes and dimensions. Experimental data showed that a smooth cylindrical capsule geometry resulted in the least frictional resistance due to the shape and relatively small surface area. Also, it was found that the variation of frictional resistance of the capsule was closely related to the local change in the viscoelastic property of the intestine due to the heterogeneity of the internal structure of the intestine.

The 2003 Carl A Moyer Award: real-time metabolic monitors, ischemia-reperfusion, titration endpoints, and ultraprecise burn resuscitation.

Real-time metabolic monitoring of varied vascular beds provides the raw data necessary to conduct ultraprecise burn shock resuscitation based on second-by-second assessment of regional tissue perfusion. It also illustrates shortcomings of current clinical practices. Arterial base deficit was continuously monitored during 11 clinical resuscitations of patients suffering burn shock using a Paratrend monitor. Separately, in a 30% TBSA rat burn model (N = 70), three Paratrend monitors simultaneously recorded arterial blood gas and tissue pCO2 of the burn wound and colonic mucosa during resuscitation at 0, 2, 4, 6, and 8 ml/kg/%TBSA. Paratrend data were analyzed in conjunction with previously reported laser Doppler images of actual burn wound capillary perfusion. With current clinical therapy, continuous monitoring of arterial base deficit revealed repetitive cycles of resolution/worsening/resolution during burn shock resuscitation. In the rat model, tissue pCO2 in both burn wounds and splanchnic circulation differed depending on the rate of fluid resuscitation (P <.01 between sham and 0 ml/kg/%TBSA and between 2 ml/kg/%TBSA and 4 ml/kg/%TBSA). Burn wound pCO2 values correlated well with laser Doppler determination of actual capillary perfusion (rho = -.48, P <.01). The following conclusions were reached: 1). Gratuitous and repetitive ischemia-reperfusion-ischemia cycles plague current clinical therapy as demonstrated by numerous "false starts" in the resolution of arterial base deficit; 2). in a rat model, real-time monitoring of burn wound and splanchnic pCO2 demonstrate a dose-response relationship with rate of fluid administration; and 3). burn wound and splanchnic pCO2 are highly correlated with direct measurement of burn wound capillary perfusion by laser Doppler imager. Either technique can serve as a resuscitation endpoint for real-time feedback-controlled ultraprecise resuscitation.

Single-site mutations induce 3D domain swapping in the B1 domain of protein L from Peptostreptococcus magnus.

BACKGROUND: Thermodynamic and kinetic studies of the Protein L B1 domain (Ppl) suggest a folding pathway in which, during the folding transition, the first beta hairpin is formed while the second beta hairpin and the alpha helix are largely unstructured. The same mutations in the two beta turns have opposite effects on the folding and unfolding rates. Three of the four residues composing the second beta turn in Ppl have consecutive positive phi angles, indicating strain in the second beta turn. RESULTS: We have determined the crystal structures of the beta turn mutants G55A, K54G, and G15A, as well as a core mutant, V49A, in order to investigate how backbone strain affects the overall structure of Ppl. Perturbation of the hydrophobic interactions at the closed interface by the V49A mutation triggered the domain swapping of the C-terminal beta strand that relieved the strain in the second beta turn. Interestingly, the asymmetric unit of V49A contains two monomers and one domain-swapped dimer. The G55A mutation escalated the strain in the second beta turn, and this increased strain shifted the equilibrium toward the domain-swapped dimer. The K54G structure revealed that the increased stability is due to the reduction of strain in the second beta turn, while the G15A structure showed that increased strain alone is insufficient to trigger domain swapping. CONCLUSIONS: Domain swapping in Ppl is determined by the balance of two opposing components of the free energy. One is the strain in the second beta turn that favors the dimer, and the other is the entropic cost of dimer formation that favors the monomer. A single-site mutation can disrupt this balance and trigger domain swapping.

Conversion of monomeric protein L to an obligate dimer by computational protein design.

Protein L consists of a single alpha-helix packed on a four-stranded beta-sheet formed by two symmetrically opposed beta-hairpins. We use a computer-based protein design procedure to stabilize a domain-swapped dimer of protein L in which the second beta-turn straightens and the C-terminal strand inserts into the beta-sheet of the partner. The designed obligate dimer contains three mutations (A52V, N53P, and G55A) and has a dissociation constant of approximately 700 pM, which is comparable to the dissociation constant of many naturally occurring protein dimers. The structure of the dimer has been determined by x-ray crystallography and is close to the in silico model.

Sensory dermatomal representation in the medial lemniscus.

BACKGROUND: Restricted sensory deficits along the somatotopic topography of the medial lemniscus rarely develop in medial medullary infarction. We describe a patient with medial medullary infarction who presented with dermatomal sensory deficits caused by a medial lemniscal lesion. CASE DESCRIPTION: A 58-year-old man presented with sudden right-sided hemiparesis and paresthesia. He had noticed the paresthesia below the level of the right L5 dermatome, where his vibration and position senses were mildly diminished. His paresthesia was more severe over the right calf and foot. Magnetic resonance images of the brain showed an acute small infarct in the medial-ventral portion of the left rostral medulla oblongata. A nerve conduction study and electromyography showed no abnormalities. At follow-up, the patient's motor and sensory deficits had improved considerably. CONCLUSIONS: The patient showed lemniscal sensory deficits below the right L5 dermatome that were caused by the partial involvement of the medial lemniscus. These findings suggest that lemniscal sensory dermatomal representation is preserved at least up to the level of the medulla oblongata.