Observation of Skewed Electromagnetic Wakefields in an Asymmetric Structure Driven by Flat Electron Bunches.

Relativistic charged-particle beams that generate intense longitudinal fields in accelerating structures also inherently couple to transverse modes. The effects of this coupling may lead to beam breakup instability and thus must be countered to preserve beam quality in applications such as linear colliders. Beams with highly asymmetric transverse sizes (flat beams) have been shown to suppress the initial instability in slab-symmetric structures. However, as the coupling to transverse modes remains, this solution serves only to delay instability. In order to understand the hazards of transverse coupling in such a case, we describe here an experiment characterizing the transverse effects on a flat beam, traversing near a planar dielectric lined structure. The measurements reveal the emergence of a previously unobserved skew-quadrupolelike interaction when the beam is canted transversely, which is not present when the flat beam travels parallel to the dielectric surface. We deploy a multipole field fitting algorithm to reconstruct the projected transverse wakefields from the data. We generate the effective kick vector map using a simple two-particle theoretical model, with particle-in-cell simulations used to provide further insight for realistic particle distributions.

Fabrication of THz corrugated wakefield structure and its high power test.

We present overall process for developing terahertz (THz) corrugated structure and its beam-based measurement results. 0.2-THz corrugated structures were fabricated by die stamping method as the first step demonstration towards GW THz radiation source and GV/m THz wakefield accelerator. 150-[Formula: see text]m thick disks were produced from an OFHC (C10100) foil by stamping. Two types of disks were stacked alternately to form 46 mm structure with [Formula: see text] 170 corrugations. Custom assembly was designed to provide diffusion bonding with a high precision alignment of disks. The compliance of the fabricated structure have been verified through beam-based wakefield measurement at Argonne Wakefield Accelerator Facility. Both measured longitudinal and transverse wakefield showed good agreement with simulated wakefields. Measured peak gradients, 9.4 MV/m/nC for a long single bunch and 35.4 MV/m/nC for a four bunch trains, showed good agreement with the simulation.

Single Shot Characterization of High Transformer Ratio Wakefields in Nonlinear Plasma Acceleration.

Plasma wakefields can enable very high accelerating gradients for frontier high energy particle accelerators, in excess of 10 GeV/m. To overcome limits on single stage acceleration, specially shaped drive beams can be used in both linear and nonlinear plasma wakefield accelerators (PWFA), to increase the transformer ratio, implying that the drive beam deceleration is minimized relative to acceleration obtained in the wake. In this Letter, we report the results of a nonlinear PWFA, high transformer ratio experiment using high-charge, longitudinally asymmetric drive beams in a plasma cell. An emittance exchange process is used to generate variable drive current profiles, in conjunction with a long (multiple plasma wavelength) witness beam. The witness beam is energy modulated by the wakefield, yielding a response that contains detailed spectral information in a single-shot measurement. Using these methods, we generate a variety of beam profiles and characterize the wakefields, directly observing transformer ratios up to R=7.8. Furthermore, a spectrally based reconstruction technique, validated by 3D particle-in-cell simulations, is introduced to obtain the drive beam current profile from the decelerating wake data.

Whole-exome sequencing of cell-free DNA and circulating tumor cells in multiple myeloma.

Liquid biopsies including circulating tumor cells (CTCs) and cell-free DNA (cfDNA) have enabled minimally invasive characterization of many cancers, but are rarely analyzed together. Understanding the detectability and genomic concordance of CTCs and cfDNA may inform their use in guiding cancer precision medicine. Here, we report the detectability of cfDNA and CTCs in blood samples from 107 and 56 patients with multiple myeloma (MM), respectively. Using ultra-low pass whole-genome sequencing, we find both tumor fractions correlate with disease progression. Applying whole-exome sequencing (WES) to cfDNA, CTCs, and matched tumor biopsies, we find concordance in clonal somatic mutations (~99%) and copy number alterations (~81%) between liquid and tumor biopsies. Importantly, analyzing CTCs and cfDNA together enables cross-validation of mutations, uncovers mutations exclusive to either CTCs or cfDNA, and allows blood-based tumor profiling in a greater fraction of patients. Our study demonstrates the utility of analyzing both CTCs and cfDNA in MM.

Observation of High Transformer Ratio of Shaped Bunch Generated by an Emittance-Exchange Beam Line.

Collinear wakefield acceleration has been long established as a method capable of generating ultrahigh acceleration gradients. Because of the success on this front, recently, more efforts have shifted towards developing methods to raise the transformer ratio (TR). This figure of merit is defined as the ratio of the peak acceleration field behind the drive bunch to the peak deceleration field inside the drive bunch. TR is always less than 2 for temporally symmetric drive bunch distributions and therefore recent efforts have focused on generating asymmetric distributions to overcome this limitation. In this Letter, we report on using the emittance-exchange method to generate a shaped drive bunch to experimentally demonstrate a TR≈5 in a dielectric wakefield accelerator.

Precision Control of the Electron Longitudinal Bunch Shape Using an Emittance-Exchange Beam Line.

We report on the experimental generation of relativistic electron bunches with a tunable longitudinal bunch shape. A longitudinal bunch-shaping (LBS) beam line, consisting of a transverse mask followed by a transverse-to-longitudinal emittance exchange (EEX) beam line, is used to tailor the longitudinal bunch shape (or current profile) of the electron bunch. The mask shapes the bunch's horizontal profile, and the EEX beam line converts it to a corresponding longitudinal profile. The Argonne wakefield accelerator rf photoinjector delivers electron bunches into a LBS beam line to generate a variety of longitudinal bunch shapes. The quality of the longitudinal bunch shape is limited by various perturbations in the exchange process. We develop a simple method, based on the incident slope of the bunch, to significantly suppress the perturbations.

Interaction of an Ultrarelativistic Electron Bunch Train with a W-Band Accelerating Structure: High Power and High Gradient.

Electron beam interaction with high frequency structures (beyond microwave regime) has a great impact on future high energy frontier machines. We report on the generation of multimegawatt pulsed rf power at 91 GHz in a planar metallic accelerating structure driven by an ultrarelativistic electron bunch train. This slow-wave wakefield device can also be used for high gradient acceleration of electrons with a stable rf phase and amplitude which are controlled by manipulation of the bunch train. To achieve precise control of the rf pulse properties, a two-beam wakefield interferometry method was developed in which the rf pulse, due to the interference of the wakefields from the two bunches, was measured as a function of bunch separation. Measurements of the energy change of a trailing electron bunch as a function of the bunch separation confirmed the interferometry method.

TACC3 deregulates the DNA damage response and confers sensitivity to radiation and PARP inhibition.

Deregulation of the transforming acidic coiled-coil protein 3 (TACC3), an important factor in the centrosome-microtubule system, has been linked to a variety of human cancer types. We have recently reported on the oncogenic potential of TACC3; however, the molecular mechanisms by which TACC3 mediates oncogenic function remain to be elucidated. In this study, we show that high levels of TACC3 lead to the accumulation of DNA double-strand breaks (DSBs) and disrupt the normal cellular response to DNA damage, at least in part, by negatively regulating the expression of ataxia telangiectasia mutated (ATM) and the subsequent DNA damage response (DDR) signaling cascade. Cells expressing high levels of TACC3 display defective checkpoints and DSB-mediated homologous recombination (HR) and non-homologous end joining (NHEJ) repair systems, leading to genomic instability. Importantly, high levels of TACC3 confer cellular sensitization to radiation and poly(ADP-ribose) polymerase (PARP) inhibition. Overall, our findings provide critical information regarding the mechanisms by which TACC3 contributes to genomic instability, potentially leading to cancer development, and suggest a novel prognostic, diagnostic and therapeutic strategy for the treatment of cancer types expressing high levels of TACC3.

Tankyrase-1 function at telomeres and during mitosis is regulated by Polo-like kinase-1-mediated phosphorylation.

Telomere length is critical for chromosome stability that affects cell proliferation and survival. Telomere elongation by telomerase is inhibited by the telomeric protein, TRF1. Tankyrase-1 (TNKS1) poly(ADP-ribosyl)ates TRF1 and releases TRF1 from telomeres, thereby allowing access of telomerase to the telomeres. TNKS1-mediated poly(ADP-ribosyl)ation also appears to be crucial for regulating the mitotic cell cycle. In searching for proteins that interact with polo-like kinase-1 (Plk1) by using complex proteomics, we identified TNKS1 as a novel Plk1-binding protein. Here, we report that Plk1 forms a complex with TNKS1 in vitro and in vivo, and phosphorylates TNKS1. Phosphorylation of TNKS1 by Plk1 appears to increase TNKS1 stability and telomeric poly(ADP-ribose) polymerase (PARP) activity. By contrast, targeted inhibition of Plk1 or mutation of phosphorylation sites decreased the stability and PARP activity of TNKS1, leading to distort mitotic spindle-pole assembly and telomeric ends. Taken together, our results provide evidence of a novel molecular mechanism in which phosphorylation of TNKS1 by Plk1 may help regulate mitotic spindle assembly and promote telomeric chromatin maintenance.

Mitotic catastrophe is the predominant response to histone acetyltransferase depletion.

Histone acetylation induces chromatin opening by perturbing higher-order chromatin compaction and folding, suggesting that histone acetylation and deacetylation dynamics are central to chromosome condensation or decondensation. The condensation of chromosomes during mitosis is an essential prerequisite for successful chromosome segregation. In this study, we depleted three representative histone acetyltransferases (HATs; p300, CBP, and P/CAF) using shRNAs to explore their role in regulating mitotic progression and chromosome segregation. We showed that HAT depletion severely interfered with the normal timing of mitotic progression, and it reduced condensin subunit levels. The predominant response to HAT depletion, in both human primary and cancer cells, was a mitotic catastrophe following aberrant mitotic arrest. Alternatively, adaptation to HAT depletion, particularly in cancer cells, led to multinucleation and aneuploidy. Interestingly, mitotic catastrophe induced by HAT depletion appeared to be coupled to the signaling process of H2AX phosphorylation and foci formation, independently of DNA double-strand breaks and DNA damage. Taken together, our results provide novel molecular evidence that HAT proteins maintain mitotic chromatin assembly and integrity as a cellular determinant of mitotic cell death.

Subcutaneous hyalohyphomycosis due to Cephalotheca foveolata in an immunocompetent host.

We report the first case of subcutaneous hyalohyphomycosis caused by the genus Cephalotheca, which has not been reported to cause human infection. A 67-year-old immunocompetent farmer presented with a 10-year history of verrucous erythematous plaques on the right foot dorsum, great toe, heel and sole. Histopathology of the lesions revealed chronic granulomatous inflammation with numerous nonpigmented fungal spores in the dermis. Cultures of biopsy specimens on Sabouraud's dextrose agar for 2 weeks developed into yellowish brown, velvety colonies that subsequently turned black after 8 weeks because of the production of black cleistothecia indicating the teleomorph. On the basis of mycological features, scanning electron microscopic morphology and molecular analysis data, a new species of Cephalotheca was identified and designated Cephalotheca foveolata. Because there was no response to the antifungal agents administered, the patient was successfully treated by surgical excision with skin graft.

Fos expression after mating in noradrenergic cells of the A1 and A2 areas of the medulla is altered by adrenalectomy.

In the female rat, the integrity of the ventral noradrenergic bundle (VNAB) is necessary to carry stimuli from the uterine cervix and vagina to brain areas involved in mating-induced pseudopregnancy. Because adrenal hormones are known to alter noradrenergic function, we examined whether adrenalectomy altered mating-induced Fos expression in the A1 and A2 noradrenergic cell groups that project through the VNAB. Ovariectomized females were adrenalectomized (ADX) or sham-operated (Sham) and, 2 weeks after surgery, were given oestrogen and progesterone and mated. They received 15 intromissions, five intromissions or 15 mounts-without-intromission (mounts-only) from a male. Two hours after mating, rats were perfused and brains were collected; controls were perfused after being taken directly from their home cage. After immunocytochemical staining, Fos-immunoreactive (Fos-IR) and dopamine-beta-hydroxylase-immunoreactive (DBH-IR) cells and the percentage of DBH cells that were labelled with Fos (% DBH/Fos) were counted. In the A1 area, Fos-IR and percentage DBH/Fos were not affected by adrenalectomy. Although an overall effect of mating treatment was found for both measures, no specific mating treatment increased labelled cells above home cage levels. In the caudal, middle and rostral A2, 15 intromissions induced a significant increase in Fos-IR in Sham females above all other groups and a higher percentage of DBH/Fos in the middle and rostral A2 areas. ADX females showed no rise in either Fos-IR or percentage DBH/Fos after 15 intromissions. However, in the middle and rostral A2, ADX females showed significantly increased Fos-IR and percentage DBH/Fos after mounts-only treatment above Sham mounts-only females and all other ADX groups. These results demonstrate that adrenal hormones suppress activation of A2 cells to mounts-only stimuli but contribute to A2 activation in response to intromissions from males. The latter effect may result from stress associated with receipt of vaginocervical stimulation during mating.

Distribution in allele frequencies of predisposition-to-atopy genotypes in Chinese children.

Asthma is one of the most common chronic diseases in childhood; it is caused by a complex interaction between genetic factors and exposure to environmental allergens and irritants. Previous studies using the candidate gene approach showed that asthma was linked to a number of susceptibility genetic loci in Caucasian subjects. There are, however, only a few studies on asthma predisposition genes in the Chinese population. We studied the distribution of allele frequencies of I50V for the interleukin-4 receptor, two polymorphisms in intron 2 and exon 7 for the high-affinity IgE receptor (Fc epsilon RI-beta), R16G and E27Q for the beta(2)-adrenoceptor,and R275Q (824G/A) for CC chemokine receptor 3 in Chinese children.Seventy-six patients, with a mean age of 10.6 years, and 70 age- and sex-matched controls, were studied. Significantly more subjects in the asthma group had specific IgE antibodies against environmental allergens (P < 0.0001; odds ratio, 9.82). Genotyping of the six genetic markers showed that none of the six polymorphisms was associated with asthma in this cohort. The allele frequencies of I50V, R16G, and E27Q in our population were similar to those published for Asian subjects but not Caucasians. The R275Q substitution was a rare finding in our study and in the published reports. Our results demonstrate ethnic differences in polymorphisms of atopy candidate genes. Additional studies involving larger samples are required to investigate the association between asthma or atopy and the genotypes studied to date in Chinese children.

A polymorphism in the coding region of interleukin-13 gene is associated with atopy but not asthma in Chinese children.

BACKGROUND: Interleukin (IL)-13 is an important cytokine secreted from type 2 helper T lymphocytes. It is essential for modulating IgE synthesis by human B cells. Previous studies showed that polymorphisms in the IL-13 gene were associated with serum total IgE or allergic asthma. The relationship of this marker with sensitization to individual aeroallergens has not been evaluated. OBJECTIVE: We tested whether a polymorphism in the coding region of the IL-13 gene is associated with asthma and atopy in asthmatic children in Hong Kong. METHODS: We used restriction fragment length polymorphism to detect R130Q genotype in Chinese children with asthma and control subjects. Serum total IgE was measured by microparticle immunoassay and specific IgE to common aeroallergens was measured using fluorescent enzyme immunoassay. Pulmonary function studies were performed using spirometry. RESULTS: One hundred and fifty-seven patients and 54 control children were recruited. Their mean serum total IgE concentrations were 994 kIU/L and 473 kIU/L, respectively (P < 0.0001). Atopy as defined by > or = 1 positive RAST was found in 141 patients and 32 control children. The GlnGln form of the R130Q polymorphism in the IL-13 gene was associated with serum total IgE (P = 0.005) as well as specific IgE to Der p 1 (P = 0.021), mixed cockroaches (P = 0.03) and dog (P = 0.003) but not with physician-diagnosed asthma (P = 0.621). In addition, the R130Q polymorphism did not correlate with subjective or objective indicators of asthma severity in our patients. CONCLUSION: Our results suggest that the R130Q polymorphism of the IL-13 gene is associated with elevated serum total and allergen-specific IgE but not asthma in Chinese children.

Allergen sensitisation in asthmatic children: consecutive case series.

OBJECTIVE: To investigate the pattern of sensitisation to aero-allergens and food allergens among asthmatic children in Hong Kong, and to investigate any correlation between atopy and the severity of asthma. DESIGN: Consecutive case series. SETTING: Paediatric out-patient clinic of a university teaching hospital, Hong Kong. PARTICIPANTS: Two hundred and four consecutive children with physician-diagnosed asthma who attended from January 1999 through June 2000. MAIN OUTCOME MEASURES: Demographic data, questionnaire assessment of asthma control, spirometric evaluation, response to skin prick testing, eosinophil count, and total serum immunoglobulin E concentration. RESULTS: The median patient age was 8.2 years (range, 5.7-11.3 years), and the median 1-second forced expiratory volume was 95% of the predicted value. The median absolute eosinophil count in the peripheral blood was 0.48 x 10(9) /L and the ratio of total serum immunoglobulin E to the age-adjusted upper limit of the normal range was 2.7. Atopy, as defined by at least one positive response to skin prick testing, was found in 170 (83.3%) of the 204 patients. House dust mites were the most commonly sensitised aero-allergen (n=167; 81.9%). Sensitisation to food allergens was found in 47 (23.0%) of the patients. The self-reported frequency of asthmatic attacks was associated with a positive response to skin prick testing with animal allergens (P for trend = 0.001), whereas spirometric indices correlated with the degree of atopy and the presence of in vivo cockroach-specific immunoglobulin E. CONCLUSION: Sensitisation to indoor aero-allergens, as determined by skin prick testing, is prevalent among Chinese children with mild-to-moderate asthma, whereas sensitisation to food allergens is not. The severity of asthma is correlated with skin prick test responses to pet and cockroach allergens.

Case of sepsis caused by Bifidobacterium longum.

We report a case of sepsis caused by Bifidobacterium longum in a 19-year-old male who had developed high fever, jaundice, and hepatomegaly after acupuncture therapy with small gold needles. Anaerobic, non-spore-forming, gram-positive bacilli were isolated from his blood and finally identified as B. longum. He recovered completely after treatment with ticarcillin and metronidazole. To our knowledge, this is the first report of incidental sepsis caused by B. longum.

Hepatitis C virus E2 protein purified from mammalian cells is frequently recognized by E2-specific antibodies in patient sera.

The envelope protein of hepatitis C virus (HCV) is composed of two membrane-associated glycoproteins, E1 and E2. To obtain HCV E2 protein as a secretory form at a high level, we constructed a recombinant chinese hamster ovary (CHO) cell line expressing a C-terminal truncated E2 (E2t) fused to human growth hormone (hGH), CHO/hGHE2t. The hGHE2t fusion protein was purified from the culture supernatant using anti-hGH mAb affinity chromatography at approximately 80% purity. The purified hGHE2t protein appeared to be assembled into oligomers linked by intermolecular disulfide bond(s) when density gradient centrifugation and SDS-polyacrylamide gel electrophoresis were employed. When the purified fusion protein was used for testing its ability to bind to antibodies specific for HCV by enzyme-linked immunosorbent assay, the protein was recognized by antibodies in sera from 90% of HCV-positive patients. Treatment of hGHE2t protein by beta-mercaptoethanol, but not by heat and SDS, significantly reduced its reactivity to the antibodies of patient sera, suggesting that intermolecular and/or intramolecular disulfide bonds are important for its ability to recognize its specific antibody and that the E2 protein contains discontinuous antigenic epitope(s).

Alterations of p53 gene in primary gastric cancer tissues.

This study was conducted to investigate the p53 gene alterations in 25 surgically-resected gastric adenocarcinomas in the Korea Cancer Center Hospital by polymerase chain reaction single-strand conformation polymorphism analysis (PCR-SSCP) for exons 4-8 and immunohistochemical staining (IHCS) with anti-p53 antibody, DO-7. p53 mutations were detected in nine (36%) out of 25 cancer tissues by PCR-SSCP in exon 4-8: 0,1,1,6 and 1 mutations in exons 4,5,6,7 and 8, respectively. All tissues were also tested by IHCS, and positive staining was observed in 11 cases (44%). A discrepancy of the results between the two methods was observed in four cases. In one which showed positivity by PCR-SSCP a negative reaction by IHCS, the two base deletion was observed in exon 7. On the other hand, in three cases the mutation was detected only in IHCS but not in PCR-SSCP. The exact mechanism by which this discrepancy develops is not clear at present, although it may be due to the mutation of other exons not tested in this study or the relatively low sensitivity of the PCR-SSCP method. The incidence of p53 gene mutations was analysed according to pathologic stage and histological differentiation, but no significant difference was observed between the p53 alterations and these factors. By combined use of PCR-SSCP and IHCS, 48% of the 25 primary gastric cancer were considered to have mutations of the p53 gene. These results suggest that p53 mutation is not an infrequent event in primary gastric cancer and the p53 gene plays an important role in the carcinogenesis process of gastric cancer.