Applying Magnetic Curvature to MMS Data to Identify Thin Current Sheets Relative to Tail Reconnection.

Thin current sheets (TCSs) have been postulated to be a necessary precondition for reconnection onset. Magnetic reconnection X-lines in the magnetotail have been observed to be more common duskward of midnight. We take advantage of the MMS tetrahedral formation during the 2017-2020 MMS tail seasons to calculate the thickness of the cross-tail neutral sheet relative to ion gyroradius. While a similar technique was applied to Cluster data, current sheet thickness over a broader range of radial distances has not been robustly explored before this study. We compare our analysis to recent theories regarding mechanisms of tail current sheet thinning and to recent simulations. We find MMS spent more than twice as long in ion-scale TCSs in the pre-midnight sector than post-midnight, despite nearly even plasma sheet dwell time. The dawn-dusk asymmetry in the distribution of Ion Diffusion Regions, as previously reported in relation to regions of TCSs, is also analyzed.

Three dimensional reconstruction to visualize atrial fibrillation activation patterns on curved atrial geometry.

BACKGROUND: The rotational activation created by spiral waves may be a mechanism for atrial fibrillation (AF), yet it is unclear how activation patterns obtained from endocardial baskets are influenced by the 3D geometric curvature of the atrium or 'unfolding' into 2D maps. We develop algorithms that can visualize spiral waves and their tip locations on curved atrial geometries. We use these algorithms to quantify differences in AF maps and spiral tip locations between 3D basket reconstructions, projection onto 3D anatomical shells and unfolded 2D surfaces. METHODS: We tested our algorithms in N = 20 patients in whom AF was recorded from 64-pole baskets (Abbott, CA). Phase maps were generated by non-proprietary software to identify the tips of spiral waves, indicated by phase singularities. The number and density of spiral tips were compared in patient-specific 3D shells constructed from the basket, as well as 3D maps from clinical electroanatomic mapping systems and 2D maps. RESULTS: Patients (59.4±12.7 yrs, 60% M) showed 1.7±0.8 phase singularities/patient, in whom ablation terminated AF in 11/20 patients (55%). There was no difference in the location of phase singularities, between 3D curved surfaces and 2D unfolded surfaces, with a median correlation coefficient between phase singularity density maps of 0.985 (0.978-0.990). No significant impact was noted by phase singularities location in more curved regions or relative to the basket location (p>0.1). CONCLUSIONS: AF maps and phase singularities mapped by endocardial baskets are qualitatively and quantitatively similar whether calculated by 3D phase maps on patient-specific curved atrial geometries or in 2D. Phase maps on patient-specific geometries may be easier to interpret relative to critical structures for ablation planning.

Electrical Substrate Ablation for Refractory Ventricular Fibrillation: Results of the AVATAR Study.

[Figure: see text].

Comparing phase and electrographic flow mapping for persistent atrial fibrillation.

BACKGROUND: An increasing number of methods are being used to map atrial fibrillation (AF), yet the sensitivity of identifying potential localized AF sources of these novel methods are unclear. Here, we report a comparison of two approaches to map AF based upon (1) electrographic flow mapping and (2) phase mapping in a multicenter registry of patients in whom ablation terminated persistent AF. METHODS: Fifty-three consecutive patients with persistent AF in whom ablation terminated AF in an international multicenter registry were enrolled. Electrographic flow mapping (EGF) and phase mapping were applied to the multipolar simultaneous electrograms recorded from a 64-pole basket catheter in the chamber (left vs right atrium) where AF termination occurred. We analyzed if the mapping methods were able to detect localized sources at the AF termination site. We also analyzed global results of mapping AF for each method, patterns of activation of localized sources. RESULTS: Patients were 64.3 ± 9.4 years old and 69.8% were male. EGF and phase mapping identified localized sources at AF termination sites in 81% and 83% of the patients, respectively. Methods were complementary and in only n = 2 (3.7%) neither method identified a source. Globally, EGF identified more localized sources than phase mapping (5.3 ± 2.8 vs 1.8 ± 0.5, P < 0.001), with a higher prevalence of focal (compared to rotational) activation pattern (49% vs 2%, P < 0.01). CONCLUSIONS: EGF is a novel vectorial-based AF mapping method, which can detect sites of AF termination, agreeing with, and complementary to, an alternative AF mapping method using phase analysis.

Prevalence of the Novel Torque Teno Sus Virus Species k2b from Pigs in the United States and Lack of Association with Post-Weaning Multisystemic Wasting Syndrome or Mulberry Heart Disease.

The family Anelloviridae includes a number of viruses infecting humans (Torque teno viruses, TTV) and other animals including swine (Torque teno sus viruses, TTSuV). Two genetically distinct TTSuV species have been identified from swine thus far (TTSuV1 and TTSuVk2), although their definitive association with disease remains debatable. In 2012, a novel TTSuV species was identified from commercial swine serum and classified in the genus Kappatorquevirus as TTSuVk2b. The other Kappatorquevirus species, TTSuVk2a, has been associated with post-weaning multisystemic wasting syndrome (PMWS) when coinfected with porcine circovirus type 2 (PCV2). Therefore, in this study, we initially amplified a portion of TTSuVk2b ORF1 and, subsequently, assessed the molecular prevalence of the virus in pigs in the United States. A total of 127 serum and 115 tissue samples were obtained from pigs with PMWS or mulberry heart disease (MHD) in six states and tested by PCR for the presence of TTSuVk2b DNA. Approximately 27.6% of the serum and 21.7% of tissue samples tested positive for TTSuVk2b DNA, and the positive products were confirmed by sequencing. However, we did not detect a correlation between TTSuVk2b infection and PMWS or MHD. The near full-length genomic sequence of US TTSuVk2b was determined, and sequence analysis revealed that the US TTSuVk2b isolates were 95% identical to the TTSuVk2b isolate from Spain, with most of the variations clustering in ORF1. We conclude that the novel TTSuVk2b species is present in pigs in the United States and its potential association with a disease warrants further investigation.

The impact of endoscopic ultrasound findings on clinical decision making in Barrett's esophagus with high-grade dysplasia or early esophageal adenocarcinoma.

The clinical utility of endoscopic ultrasound (EUS) for staging patients with Barrett's esophagus and high-grade dysplasia (HGD) or intramucosal carcinoma (IMC) prior to endoscopic therapy is unclear. We performed a retrospective analysis of patients with HGD or IMC referred to an American medical center for endoscopic treatment between 2004 and 2010. All patients had pretreatment staging by EUS. We examined the frequency that EUS findings consistent with advanced disease (tumor invasion into the submucosa, lymph node involvement, or regional metastasis) led to a change in management. The analysis was stratified by nodularity and pre-EUS histology. We identified one hundred thirty-five patients with HGD (n = 106, 79%) or IMC (n = 29, 21%) had staging by EUS (79 non-nodular, 56 nodular). Pathologic lymph nodes or metastases were not found by EUS. There were no endosonographic abnormalities noted in any patient with non-nodular mucosa (0/79). Abnormal EUS findings were present in 8/56 patients (14%) with nodular neoplasia (five IMC, three HGD). Endoscopic mucosal resection was performed in 44 patients with a nodule, with 13% (6/44) having invasive cancer. In nodular neoplasia, the EUS and endoscopic mucosal resection were abnormal in 24% (5/21) and 40% (6/15) of those with IMC and 9% (3/35) and 0% (0/29) of those with HGD, respectively. In this study we found that EUS did not alter management in patients with non-nodular HGD or IMC. Because the diagnostic utility of EUS in subjects with non-nodular Barrett's esophagus is low, the value of performing endoscopic mucosal resection in this setting is questionable. For patients with nodular neoplasia, resection of the nodule with histological examination had greater utility than staging by EUS.

Copy number variation prevalence in known asthma genes and their impact on asthma susceptibility.

BACKGROUND: Genetic studies have identified numerous genes reproducibly associated with asthma, yet these studies have focussed almost entirely on single nucleotide polymorphisms (SNPs), and virtually ignored another highly prevalent form of genetic variation: Copy Number Variants (CNVs). OBJECTIVE: To survey the prevalence of CNVs in genes previously associated with asthma, and to assess whether CNVs represent the functional asthma-susceptibility variants at these loci. METHODS: We genotyped 383 asthmatic trios participating in the Childhood Asthma Management Program (CAMP) using a competitive genomic hybridization (CGH) array designed to interrogate 20 092 CNVs. To ensure comprehensive assessment of all potential asthma candidate genes, we purposely used liberal asthma gene inclusion criteria, resulting in consideration of 270 candidate genes previously implicated in asthma. We performed statistical testing using FBAT-CNV. RESULTS: Copy number variation in asthma candidate genes was prevalent, with 21% of tested genes residing near or within one of 69 CNVs. In six instances, the complete candidate gene sequence resides within the CNV boundaries. On average, asthmatic probands carried six asthma-candidate CNVs (range 1-29). However, the vast majority of identified CNVs were of rare frequency (< 5%) and were not statistically associated with asthma. Modest evidence for association with asthma was observed for 2 CNVs near NOS1 and SERPINA3. Linkage disequilibrium analysis suggests that CNV effects are unlikely to explain previously detected SNP associations with asthma. CONCLUSIONS AND CLINICAL RELEVANCE: Although a substantial proportion of asthma-susceptibility genes harbour polymorphic CNVs, the majority of these variants do not confer increased asthma risk. The lack of linkage disequilibrium (LD) between CNVs and asthma-associated SNPs suggests that these CNVs are unlikely to represent the functional variant responsible for most known asthma associations.

The interaction of glutathione S-transferase M1-null variants with tobacco smoke exposure and the development of childhood asthma.

BACKGROUND: The glutathione S-transferase M1 (GSTM1)-null variant is a common copy number variant associated with adverse pulmonary outcomes, including asthma and airflow obstruction, with evidence of important gene-by-environment interactions with exposures to oxidative stress. OBJECTIVE: To explore the joint interactive effects of GSTM1 copy number and tobacco smoke exposure on the development of asthma and asthma-related phenotypes in a family-based cohort of childhood asthmatics. METHODS: We performed quantitative PCR-based genotyping for GSTM1 copy number in children of self-reported white ancestry with mild to moderate asthma in the Childhood Asthma Management Program. Questionnaire data regarding intrauterine (IUS) and post-natal, longitudinal smoke exposure were available. We performed both family-based and population-based tests of association for the interaction between GSTM1 copy number and tobacco smoke exposure with asthma and asthma-related phenotypes. RESULTS: Associations of GSTM1-null variants with asthma (P=0.03), younger age of asthma symptom onset (P=0.03), and greater airflow obstruction (reduced forced expiratory volume in 1 s / forced vital capacity, P=0.01) were observed among the 50 children (10% of the cohort) with exposure to IUS. In contrast, no associations were observed between GSTM1-null variants and asthma-related phenotypes among children without IUS exposure. Presence of at least one copy of GSTM1 conferred protection. CONCLUSION: These findings support an important gene-by-environment interaction between two common factors: increased risk of asthma and asthma-related phenotypes conferred by GSTM1-null homozygosity in children is restricted to those with a history of IUS exposure.

Characterization of MspA, an immunogenic autotransporter protein that mediates adhesion to epithelial and endothelial cells in Neisseria meningitidis.

A novel putative autotransporter protein (NMB1998) was identified in the available genomic sequence of meningococcal strain MC58 (ET-5; ST-32). The mspA gene is absent from the genomic sequences of meningococcal strain Z2491 (ET-IV; ST-4) and the gonococcal strain FA1090. An orthologue is present in the meningococcal strain FAM18 (ET-37; ST-11), but the sequence contains a premature stop codon, suggesting that the protein may not be expressed in this strain. MspA is predicted to be a 157-kDa protein with low cysteine content, and it exhibits 36 and 33% identity to the meningococcal autotransporter proteins immunoglobulin A1 (IgA1) protease and App, respectively. Search of the Pfam database predicts the presence of IgA1 protease and autotransporter beta-barrel domains. MspA was cloned, and a recombinant protein of the expected size was expressed and after being affinity purified was used to raise rabbit polyclonal monospecific antiserum. Immunoblot studies showed that ca. 125- and 95-kDa fragments of MspA are secreted in meningococcal strain MC58, which are absent from the isogenic mutant. Secretion of MspA was shown to be modified in an AspA isogenic mutant. A strain survey showed that MspA is expressed by all ST-32 and ST-41/44 (lineage 3) strains, but none of the ST-8 (A4) strains examined. Sera from patients convalescing from meningococcal disease were shown to contain MspA-specific antibodies. In bactericidal assays, anti-MspA serum was shown to kill the homologous strain (MC58) and another ST-32 strain. Escherichia coli-expressing recombinant MspA was shown to adhere to both human bronchial epithelial cells and brain microvascular endothelial cells.

Kinetic origin of the chelate effect. Base hydrolysis, H-exchange reactivity, and structures of syn,anti-[Co(cyclen)(NH3)2]3+ and syn,anti-[Co(cyclen)(diamine)]3+ ions (diamine = H2N(CH2)2NH2, H2N(CH2)3NH2).

The synthesis of syn,anti-[Co(cyclen)en](ClO4)3 (1(ClO4)3) and syn,anti-[Co(cyclen)tn](ClO4)3 (2(ClO4)3) is reported, as are single-crystal X-ray structures for syn,anti-[Co(cyclen)(NH3)2](ClO4)3 (3(ClO4)3). 3(ClO4)3: orthorhombic, Pnma, a = 17.805(4) A, b = 12.123(3) A, c = 9.493(2) A, alpha = beta = gamma = 90 degrees, Z = 4, R1 = 0.030. 1(ClO4)3: monoclinic, P2(1)/n, a = 8.892(2) A, b = 15.285(3) A, c = 15.466(3) A, alpha = 90 degrees, beta = 91.05(3) degrees, gamma = 90 degrees, Z = 4, R1 = 0.0657. 2Br3: orthorhombic, Pca2(1) a = 14.170(4) A, b = 10.623(3) A, c = 12.362(4) A, alpha = beta = gamma = 90 degrees, Z = 4, R1 = 0.0289. Rate constants for H/D exchange (D2O, I = 1.0 M, NaClO4, 25 degrees C) of the syn and anti NH protons (rate law: kobs = ko + kH[OD-]) and the apical NH, and the NH3 and NH2 protons (rate law: kobs = kH[OD-]) in the 1, 2, and 3 cations are reported. Deprotonation constants (K = [Co(cyclen-H)(diamine)2+]/[Co(cyclen)(diamine)3+][OH-]) were determined for 1 (5.5 +/- 0.5 M-1) and 2 (28 +/- 3 M-1). In alkaline solution 1, 2, and 3 hydrolyze to [Co(cyclen)(OH)2]+ via [Co(cyclen)(amine)OH)]2+ monodentates. Hydrolysis of 3 is two step: kobs(1) = kOH(1)[OH-], kobs(2) = ko + kOH(2)[OH-] (kOH(1) = (2.2 +/- 0.4) x 10(4) M-1 s-1, ko = (5.1 +/- 1.2) x 10(-4) s-1, kOH(2) = 1.0 +/- 0.1 M-1 s-1). Hydrolysis of 2 is biphasic: kobs(1) = k1K[OH-]/(1 + K[OH-] (k1 = 5.0 +/- 0.2 s-1, K = 28 M-1), kobs(2) = k2K2[OH-]/(1 + K2[OH-]) (k2 = 3.5 +/- 1.2 s-1, K2 = 1.2 +/- 0.8 M-1). Hydrolysis of 1 is monophasic: kobs = k1k2KK2[OH-]2/(1 + K[OH-1])(k-1 + k2K2[OH-]) (k1 = 0.035 +/- 0.004 s-1, k-1 = 2.9 +/- 0.6 s-1, K = 5.5 M-1, k2K2 = 4.0 M-1 s-1). The much slower rate of chelate ring-opening in 1, compared to loss of NH3 from 3, is rationalized in terms of a reduced ability of the former system to allow the bond angle expansion required to produce the SN1CB trigonal bipyramidal intermediate.

Frequency-derived distributed optical-fiber sensing technique: theory and characterization.

Frequency-derived distributed optical-fiber sensing is a method for remote measurement of the spatial distribution of linear birefringence in an optical fiber, allowing a corresponding measurement of those external measurands that influence this birefringence. The method employs a pump-probe scheme, which, by use of the optical Kerr effect, generates an optical modulation of the probe beam, with a modulation frequency whose temporal variation maps the spatial distribution of birefringence. We provide a complete theoretical analysis of this method by using Jones calculus and graphic representation on the Poincaré sphere. The relevant characterization of the technique and some experimental results are also presented; these show good agreement with the theory.

Power measurement of noise-initiated Brillouin scattering in optical fibers for sensing applications.

We discuss the measurement of noise-initiated Brillouin scattered power in optical fibers and its application to distributed sensing systems. In particular, we consider the use of Brillouin scattering in the nonlinear regime, demonstrating a novel processing technique that compensates for the nonlinear growth of the scattered signals. The signal-to-noise ratio performance of this technique is evaluated, highlighting the importance of the noise contributed by the random statistics of the scattered field and yielding the conditions for optimum system operation.

Interferometric optical time-domain reflectometry for distributed optical-fiber sensing.

The technique of optical time-domain reflectometry is analyzed to determine the effect of an optical phase modulation on light backscattered in an optical fiber. It is shown that the spatial distribution along the fiber of an external phase modulation can be measured with a spatial resolution close to that of optical time-domain reflectometry. A distributed interferometric sensor arrangement that employs this technique is investigated experimentally, and a satisfactory interrogation of more than 1000 resolution intervals is demonstrated.

Temperature and strain dependence of the power level and frequency of spontaneous Brillouin scattering in optical fibers.

The strain dependence of the optical power of Brillouin scattering in optical fibers has been measured for the first time to our knowledge. Together with measurements of the dependence of Brillouin power on temperature and the variation of Brillouin frequency with temperature and strain, we demonstrate, for what we believe to be the first time, the feasibility of a simultaneous temperature and strain sensor based on spontaneous Brillouin scattering.

Single-shot distributed optical-fiber temperature sensing by the frequency-derived technique.

We present, for the first time to our knowledge, a distributed optical-fiber temperature sensor, based on a pulsed laser, that provides distributed temperature measurement by use of a single pulse propagating in an optical fiber. The system uses the frequency-derived technique based on the optical Kerr effect. The performance of the system is investigated for the temperature range 33-150 degrees C. A linear relationship between the temperature and the derived frequency is obtained. The best temperature resolution was determined to be +/-1.2 degrees C. The best measured spatial resolution was 0.56 m.

Developing gossypol derivatives with enhanced antitumor activity.

Preclinical and clinical studies have pointed to the antitumor potential of the naturally occurring polyphenolic binaphthyl dialdehyde, gossypol, as well as its purified (-,+) enantiomers. To explore further the antitumor properties of this multifunctional agent, we synthesized several reactive derivatives including the (-,+) enantiomers of gossypolone and four different gossypol Schiff's bases (AR1, AR2, AR3, AR4). The biological activities of these new agents were screened by measuring their in vitro antiproliferative activity against malignant (MCF-7, MCF-7/adr) or immortalized (HBL-100) human breast epithelial cell lines. Racemic gossypolone showed relatively uniform antiproliferative activity against all of the breast epithelial cell lines with 3- to 5-fold less activity than (--)-gossypol against MCF-7 and MCF-7/adr cells. Of interest, the relative antitumor potency of purified gossypolone enantiomers was reverse that of gossypol enantiomers, since (+)-gossypolone showed up to 3-fold greater inhibition of MCF-7 culture growth than (--)-gossypolone. Of the Schiff's base derivatives only AR3 with its isopropyl amine substituent demonstrated cytotoxic activity comparable to that of (--)-gossypol; derivatives with ethyl, propyl, or butyl amine substituents (AR1, AR2, AR4) had little growth inhibitory activity at culture concentrations up to 25 microM. AR3 activity was greatest against HBL-100 and MCF-7 cells [MCF-7 IC50 values: AR3 = 0.9 microM, (--)-gossypol = 2.3 microM]; unlike (--)-gossypol, however, AR3 showed substantially reduced activity against the multidrug-resistant subline, MCF-7/adr. These structure-activity comparisons suggest that isolation of (-,+)-enantiomers of AR3 and additional chemical modifications including the synthesis of an isopropyl amine Schiff's base of gossypolone will likely yield a newer generation of gossypol analogues with enhanced anticancer potential.

Simultaneous strain and temperature sensing with photogenerated in-fiber gratings.

A new technique for simultaneous strain and temperature sensing is demonstrated. The approach employs two different types of photogenerated fiber grating, namely, a fiber Bragg grating and a fiber polarization-rocking filter. The method relies on the different dependencies of the fiber refractive index and birefringence on strain and temperature. Both of these measurands can be determined from the effect that they have on the resonant wavelength of each grating. The information is provided in the frequency domain, avoiding the problem of limited unambiguous signal range associated with the use of competing optical fiber interferometers.