An extremely energetic cosmic ray observed by a surface detector array.

Cosmic rays are energetic charged particles from extraterrestrial sources, with the highest-energy events thought to come from extragalactic sources. Their arrival is infrequent, so detection requires instruments with large collecting areas. In this work, we report the detection of an extremely energetic particle recorded by the surface detector array of the Telescope Array experiment. We calculate the particle's energy as [Formula: see text] (~40 joules). Its arrival direction points back to a void in the large-scale structure of the Universe. Possible explanations include a large deflection by the foreground magnetic field, an unidentified source in the local extragalactic neighborhood, or an incomplete knowledge of particle physics.

The pCONUS2 and pCONUS2 HPC Neck Bridging Devices : Results from an International Multicenter Retrospective Study.

INTRODUCTION: Bifurcation aneurysms represent an ongoing endovascular challenge with a variety of techniques and devices designed to address them. We present our multicenter series of the pCONUS2 and pCONUS2 HPC devices when treating bifurcation aneurysms. METHODS: We performed a retrospective review of our prospectively maintained databases at 3 tertiary neurointerventional centers to identify all patients who underwent coil embolization with the pCONUS2 or pCONUS2 HPC device between February 2015 and August 2021. We recorded baseline demographics, aneurysm data, complications, immediate and delayed angiographic results. RESULTS: We identified 55 patients with 56 aneurysms, median age 63 years (range 42-78 years), 67.3% female (n = 37). The commonest aneurysm location was the MCA bifurcation (n = 40, 71.4%). Average dome height was 8.9 ± 4.2 mm (range 3.2-21.5 mm), average neck width 6.4 ± 2.5 mm (range 2.6-14 mm), and average aspect ratio 1.3 ± 0.6 (range 0.5-3.3). The pCONUS2 was used in 64.3% and the pCONUS2 HPC in 35.7%. The procedural technical success rate was 98.2%. Intraoperative complications occurred in 5 cases (8.9%), 4 of which were related to the coils with partial thrombus formation on the pCONUS2 HPC seen in 1 case that was resolved with heparin. In relation to the procedure and treatment of the aneurysm the overall permanent morbidity was 1.8% (n = 1/55) and mortality 0%. Delayed angiographic follow-up (48 aneurysms) at median 12 months postprocedure (range 3-36 months) demonstrated adequate occlusion of 83.4% of aneurysms. CONCLUSION: The pCONUS2 and pCONUS2 HPC devices carry a high technical success rate, low complication and retreatment rate, and good rates of adequate occlusion. Larger prospective confirmatory studies are required.

Surpass flow diverter in the treatment of intracranial aneurysms: a prospective multicenter study.

BACKGROUND AND PURPOSE: Incomplete occlusion and recanalization of large and wide-neck brain aneurysms treated by endovascular therapy remains a challenge. We present preliminary clinical and angiographic results of an experimentally optimized Surpass flow diverter for treatment of intracranial aneurysms in a prospective, multicenter, nonrandomized, single-arm study. MATERIALS AND METHODS: At 24 centers, 165 patients with 190 intracranial aneurysms of the anterior and posterior circulations were enrolled. The primary efficacy end point was the percentage of intracranial aneurysms with 100% occlusion on 6-month DSA. The primary safety end point was neurologic death and any stroke through a minimum follow-up of 6 months. RESULTS: Successful flow-diverter delivery was achieved in 161 patients with 186 aneurysms (98%); the mean number of devices used per aneurysm was 1.05. Clinical follow-up (median, 6 months) of 150 patients (93.2%), showed that the primary safety end point occurred in 18 subjects. Permanent neurologic morbidity and mortality were 6% and 2.7%, respectively. Morbidity occurred in 4% and 7.4% of patients treated for aneurysms of the anterior and posterior circulation, respectively. Neurologic death during follow-up was observed in 1.6% and 7.4% of patients with treated intracranial aneurysms of the anterior and posterior circulation, respectively. Ischemic stroke at ≤30 days, SAH at ≤7 days, and intraparenchymal hemorrhage at ≤7 days were encountered in 3.7%, 2.5%, and 2.5% of subjects, respectively. No disabling ischemic strokes at >30 days or SAH at >7 days occurred. New or worsening cranial nerve deficit was observed in 2.7%. Follow-up angiography available in 158 (86.8%) intracranial aneurysms showed 100% occlusion in 75%. CONCLUSIONS: Clinical outcomes of the Surpass flow diverter in the treatment of intracranial aneurysms show a safety profile that is comparable with that of stent-assisted coil embolization. Angiographic results showed a high rate of intracranial aneurysm occlusion.

Spatial dynamics of the invasive defoliator amber-marked birch leafminer across the Anchorage landscape.

The amber-marked birch leafminer (Profenusa thomsoni [Konow]) (Hymenoptera: Tenthredinidae) has caused severe infestations of birch species in Anchorage, AK, since 2002. Its spatial distribution has been monitored since 2006 and summarized using interpolated surfaces based on simple kriging. Results indicate that this insect pest is unevenly distributed, occurring in multineighborhood sized patches that migrate from year to year. Patches showing heavy infestation one year are followed by light infestations the following year. In this study, we developed methods of assessing and describing spatial distributions of P. thomsoni as they vary from year to year, and speculate on potential causes of these trends in landscape patterns.

The role of the pipeline embolization device for the treatment of dissecting intracranial aneurysms.

Intracranial dissecting aneurysms constitute rare lesions with complex management and elevated morbidity and mortality. Results of 23 patients harboring such lesions treated with the PED are reported. Standard dual antiplatelet therapy was instituted. Neurologic and angiographic assessments were obtained at 3, 6, and 12 months. Clinical presentation included SAH (52%), symptoms of mass effect (22%), ischemia (4%), and incidental finding (22%). The posterior circulation was affected in 91% of cases. Total occlusion was demonstrated in 69.5% of patients, with an increment to 87.5% considering only patients with at least 3 months of follow-up. Small aneurysms demonstrated higher rates of total occlusion (6/7) compared with large (5/7) and giant (5/9) ones. Good clinical outcome was achieved in 74% of patients. Reconstructive endovascular treatment of intracranial dissecting aneurysms with the PED provided good clinical and angiographic results with acceptable risks, representing an attractive therapeutic option for this complex disease, especially when parent vessel preservation is mandatory.

Indications of proton-dominated cosmic-ray composition above 1.6 EeV.

We report studies of ultrahigh-energy cosmic-ray composition via analysis of depth of air shower maximum (X(max)), for air shower events collected by the High-Resolution Fly's Eye (HiRes) observatory. The HiRes data are consistent with a constant elongation rate d/d[log(E)] of 47.9+/-6.0(stat)+/-3.2(syst) g/cm2/decade for energies between 1.6 and 63 EeV, and are consistent with a predominantly protonic composition of cosmic rays when interpreted via the QGSJET01 and QGSJET-II high-energy hadronic interaction models. These measurements constrain models in which the galactic-to-extragalactic transition is the cause of the energy spectrum ankle at 4x10(18) eV.

First Report of Armillaria sinapina, a Cause of Armillaria Root Disease, Associated with a Variety of Forest Tree Hosts on Sites with Diverse Climates in Alaska.

In August of 2007, a preliminary survey was conducted in Alaska to evaluate potential impacts of climate change on forest trees. Armillaria sinapina, a root-disease pathogen, was isolated from conifer and hardwood hosts on climatically diverse sites spanning 675 km from the Kenai Peninsula to the Arctic Circle. Seven isolates (NKAK1, NKAK2, NKAK5, NKAK6, NKAK9F, NKAK13, and NKAK15) were identified as A. sinapina by using intergenic spacer-1 nucleotide sequences (GenBank Accession Nos. EU665175-EU665181) and somatic pairings. Of particular note is that one isolate (NKAK9F) was obtained from a declining Salix sp. (willow) growing in a flood plain near the Arctic Circle (66°32.316'N, 150°47.717'W). This isolate was collected from mycelial bark fans that were intercalated within multiple bark layers, a sign of disease. All other isolates were derived from rhizomorphs attached to and/or embedded within roots and root collars, but most host trees showed no clear indication of disease. Two isolates were collected from dead trees within a small mortality center (62°08.703'N, 150°04.593'W) that included an isolate from Picea glauca (white spruce; NKAK13) and another isolate from Betula sp. (birch; NKAK15). Additional isolates came from a beetle-killed P. glauca (NKAK1) 120 km northwest of Anchorage (61°48.079'N, 148°16.983'W) and a suppressed (overtopped by other trees in the stand) Tsuga mertensiana (mountain hemlock; NKAK2) 58 km southeast of Anchorage (60°50.679'N, 149°03.742'W). The two remaining isolates originated from the Kenai Peninsula (approximately 60°29.629'N, 149°45.465'W) and were derived from a root-diseased Populus tremuloides (trembling aspen; NKAK5) and a suppressed P. glauca (NKAK6). Although A. mellea sensu lato was previously reported on willow in interior Alaska (1) and A. sinapina was previously reported from sites under coastal influence (4), this represents the first confirmed report of A. sinapina on P. glauca, T. mertensiana, Populus tremuloides, Salix sp., and Betula sp. in Alaska. Unfortunately, pathogenicity of A. sinapina cannot be readily verified under experimental conditions because environmental variables, host-tree status (e.g., species, population, age, and vigor), and inoculum potential are difficult to recreate. Armillaria sinapina is typically regarded as a weak pathogen of diverse hosts (3). However, A. sinapina is predicted to cause more disease on hosts predisposed by climate stress, and climate change is well-documented in Alaska (2). Because A. sinapina occurs on diverse hosts under different climates across a wide geographic range in Alaska, Armillaria root disease could become more prevalent on trees stressed by climate change. References: (1) T. E. Hinds and T. H. Laurent. Plant Dis. Rep. 62:972, 1978. (2) J. J. McCarthy et al., eds. Climate Change 2001: Impacts, Adaptation and Vulnerability. Cambridge University Press, Cambridge, 2001. (3) D. J. Morrison et al. Can. J. Plant Pathol. 7:242, 1985. (4) C. G. Shaw, III and E. M. Loopstra. Phytopathology 78:9714, 1988.

Three autosomal chromosome translocations associated with repeated early embryonic loss (REEL) in the domestic horse (Equus caballus).

Repeated early embryonic loss (REEL) represents a considerable economic loss to the horse industry. Mares that experience REEL may be overlooked as potential carriers of a chromosome abnormality. Here we report three different autosomal translocations in Thoroughbred mares presented for chromosome analysis because of REEL. The karyotypes were 64,XX,t(1;21), 64,XX,t(16;22), and 64,XX,t(4;13), respectively. In order to confirm the chromosomes involved in the translocations, to map the breakpoints, and to determine if the translocations were reciprocal, genes surrounding the breakpoints were identified using existing maps and from the newly assembled horse genome sequence. Bacterial artificial chromosomes containing the genes of interest were identified and mapped to the translocation chromosomes by fluorescence in situ hybridization (FISH). FISH confirmed that the t(16;22) and t(4;13) translocations were reciprocal, while the t(1;21) was not. The breakpoints on horse chromosomes 1 and 16 appear to be the same or near breakpoints previously identified in translocations. These breakpoints are at the fusion boundary of human chromosomes 10 and 15 on horse chromosome 1 and at human chromosome 3p and 3q on horse chromosome 16. These sites may represent ancient breakpoints reused during equid evolution. Overall, chromosome abnormalities may have a greater influence on mare fertility than previously known. Thus, it is important to karyotype subfertile mares exhibiting REEL.

The Relative Influence of Diseases and Other Small-Scale Disturbances on Fuel Loading in the Black Hills.

Disturbances that kill trees in forests often co-occur in time and/or space. This process results in changes in the fuel loading for wildfire. Determining specific causes of changing fuel loads can be complex. Path analysis was used to estimate the relative importance and the strength of interaction of each of nine small-scale disturbances affecting forest stands in the Black Hills. Different disturbances were partitioned according to their indirect and direct effects on fuel loads. Fire and wind had the greatest indirect effects; stem rots had the smallest. Root rots had the largest direct effects. Root rots, strong wind, stem rots, suppression, human disturbances, and tree cutting all caused fuel loads to increase. Treeless meadows, stem cankers, fire, ice/snow damage, failed regeneration, and shallow soil were associated with decreasing fuel loads. Grazing, lightning, bark beetles, and competition had null impacts. Disease control has two aims: reducing fire hazard and enhancing restoration. Understanding the biology and ecology of the agents that create dead wood is as fundamental to restoration ecology as it is to forest pathology. Management and control both begin by first determining the cause.

Measuring positive, negative, and null impacts of forest disturbances: a case study using dwarf mistletoe on Douglas fir.

Not all disease activity causes an impact. Not all impacts are negative. The aim of this study was to examine a method that could conceptually specify when impacts occur and that could quantify both negative and positive disease impacts. For this study, dwarf mistletoe ( Arceuthobium douglasi) of Douglas fir ( Pseudotsuga menziesii) in southwestern Oregon was used as a case study. The method uses six variables for forest growth, mortality, and stand structure, and six categorical disease severity scores. The impact model displays stands as points in multidimensional scaling space, where relative position is determined by values of the six stand variables. Positions in this two-dimensional space change when stand characteristics change. Differences associated with disease severity could be traced as trajectories, and impact was quantified using the length and direction of these trajectories. This multivariate impact assessment method was contrasted to impact assessments based on single variables. Methods based on multiple variables offer a useful way of characterizing impact on multiple objectives. The model indicates that dwarf mistletoe has positive, negative, and neutral impacts and that these could be illustrated and quantified using this method.

Topography of the neurotensin (NT)(8-9) binding site of human NT receptor-1 probed with NT(8-13) analogs.

A series of neurotensin (NT)(8-13) analogs featuring substitution of the Arg8 and/or Arg9 residues with non-natural cationic amino acids was synthesized and evaluated for binding to the human NT receptor-1 (hNTR-1). The modifications were designed to probe specific steric and electrostatic requirements in the N-terminal cationic region of NT(8-13) for receptor binding as a general evaluation of the feasibility of incorporating minor structural changes into a peptide at a crucial polar receptor binding site. Many of the non-natural amino acids are more or less isosteric to Arg but more lipophilic as a result of addition of alkyl groups or through removal or replacement of NH character with methylene or methyl substituents, whereas others vary the distance between the cation and the alpha-amino acid carbon. Substitution of Arg8 with N(G)-alkylated Arg derivatives or homolysine (Hlys) maintained the subnanomolar affinity of NT(8-13) to the hNTR-1. Position 8 incorporation of Hlys produced the most favorable primary amine side-chain substitution to date. Moderate losses in affinity observed with position 9 substitutions were attributed to adverse steric effects. Doubly substituted [Hlys8, DAB9]NT(8-13), in which DAB is 2,4-diaminobutyric acid, was also prepared and tested as the shorter side-chain of DAB is known to be favored in position 9 of NT(8-13). This analog maintained 60% of NT(8-13) binding affinity making it the most favored des-guanidinium-containing analog known. These results demonstrate that adequate receptor binding affinity can be maintained over a structural range of Arg analogs, thus providing a range of peptides expected to exhibit altered pharmacokinetic properties. From the standpoint of the hNTR-1 cationic binding sites, these results help to map out the structural stringency inherent in the formation of a tight binding complex with NT(8-13) and related analogs.

Multivalency effects in protein--carbohydrate interaction: the binding of the Shiga-like toxin 1 binding subunit to multivalent C-linked glycopeptides.

A series of monovalent and bivalent glycopeptides displaying a C-linked analogue of the Pk trisaccharide, the in vivo ligand for the pentavalent Shiga-like toxin binding subunit (SLT-1B), were prepared and evaluated as ligands for SLT-1B by isothermal titration microcalorimetry and competitive enzyme-linked immunosorbent assay (ELISA). Although none of the monovalent ligands showed any enhancement in affinity compared to O-methyl glycoside, two bivalent ligands show significant enhancements in affinity in assays. This observation represents the first calorimetric observation of an enhancement in affinity for this system. In contrast, only one of the two ligands shows an enhancement in the competitive ELISA. Together, these data signal a difference in the means by which the two ligands achieve affinity, apparently triggered by a change in the nature of the linker domain. These results provide a rationalization for apparently contradictory reports from the recent literature and again emphasize the importance of investigating complex binding phenomena by multiple techniques.

[Ultrasound-guided biopsy of non-palpable breast lesions: correlation with the results of fine-needle aspiration biopsy]. / Ultraschallgesteuerte Schneidbiopsien nicht palpabler Mammaläsionen: Korrelation mit den Ergebnissen der ultraschallgesteuerten Feinnadelpunktion.

PURPOSE: The purpose of this study was the clinical evaluation of ultrasound-guided biopsy in comparison with ultrasound-guided fine-needle aspiration biopsy of identical, non-palpable breast lesions. MATERIALS AND METHODS: From August 1997 until July 1998, 73 ultrasound-guided biopsies were performed in 66 patients with non-palpable lesions of the breast. In 18 patients (age 33-77 years) with 20 non-palpable lesions, fine-needle aspiration biopsy (20-G needle) and biopsy (18-G biopsy needle) were performed on a single occasion. This was the patient selection of our retrospective study. RESULTS: One malignant neoplasm was found among the 20 biopsied lesions, while the remaining 19 lesions were of a benign nature. In 20% of the cases, the material obtained by fine-needle biopsy was not sufficient for a cytologic diagnosis, while biopsy allowed a diagnosis in 19/20 cases. No complications were observed. CONCLUSIONS: Ultrasound-guided biopsy using an 18-G needle is a suitable method for the evaluation of non-palpable lesions that are only visible on ultrasound. It represents an attractive alternative to fine-needle aspiration in the absence of experienced cytologic diagnosticians.

Design rationale, synthesis, and characterization of non-natural analogs of the cationic amino acids arginine and lysine.

A series of non-natural isosteric analogs of the cationic, ion-pairing, natural amino acids arginine and lysine have been synthesized, characterized with regard to relevant physical parameters, and protected for routine inclusion in Merrifield solid-phase synthesis. The design of these molecules is based on the concept of steric inhibition of solvation, in that judicious placement of alkyl groups can destabilize aqueous ion solvation and favor ion-pairing [see Beeson & Dix (1993) J. Am. Chem. Soc. 115, 10275]. When the residues are substituted for the natural amino acids in biologically active peptides, enhanced ion-pairing of the peptides to their receptors to increase the peptides' biological activities can result. The increased lipophilicity of the non-natural residues can also improve pharmacokinetic parameters and agonist/antagonist behaviors of peptides. While the synthesis of the L-series is described, the D-isomers were also prepared using identical chemistry.

Proteolytic activity in intact sheets of polarized epithelial cells as determined by a cell-permeable fluorogenic substrate.

The purpose of the present investigation was to develop a system for continuous evaluation of extralysosomal proteolytic activity and its regulation in polarized epithelial cells. Filter inserts containing a tight monolayer of primary cultured pig thyrocytes were placed in a thermostated aluminium block. The cell-permeable, fluorogenic calpain and proteasome substrate succinyl-Leu-Leu-Val-Tyr-7-amino-4-methylcoumarin was added to the apical buffer and fluorescence changes were continuously measured via the fibre optics of a luminometer held at a fixed distance from the cell layer. Basal proteolytic activity was reduced by 60-70% by the proteasome inhibitor lactacystin. Proteolysis was increased within a few minutes after application of Ca(2+)-mobilizing agents (ionomycin, 4-bromo-A23187, thapsigargin and maitotoxin). Forskolin and staurosporine also enhanced the proteolytic activity. We conclude that Ca(2+)mobilization, and possibly also changes of protein kinase activity, rapidly increase non-lysosomal proteolysis in the intact thyroid epithelium.

Synthesis of neurotensin(9-13) analogues exhibiting enhanced human neurotensin receptor binding affinities.

Recent evidence is consistent with neurotensin (NT)(8-13) adopting a Type I beta-turn conformation while binding the NT receptor, which would place the cationic side-chains of Arg(8) and Arg(9) in close proximity. This was the basis for the design, synthesis and analysis of truncated NT(9-13) analogues 1-5 with dicationic position 9 side-chains to emulate the functions of the 8 and 9 side-chains of NT(8-13).

Synthesis and human neurotensin receptor binding activities of neurotensin(8-13) analogues containing position 8 alpha-azido-N-alkylated derivatives of ornithine, lysine, and homolysine.

A series of neurotensin(8-13) (NT) analogues were synthesized through intermediates in which the N-terminal Arg(8) was replaced by various omega-bromo-2(S)-azido residues spanning 3-5 methylene units in side-chain length. Subsequent nucleophilic substitution of the omega-bromo groups with ammonia, methylamine, dimethylamine, or trimethylamine provided peptides containing N-terminal 2(S)-azido residues containing primary through quaternary N-alkylated side chains corresponding in length to ornithine, Lys, and homolysine. The synthetic procedure appears applicable for incorporation of a wide variety of amine-containing nonnatural amino acids into peptides. The particular modifications were intended to enhance physiochemical properties of NT(8-13) responsible for human NT 1 receptor (hNTR) binding, overall lipophilicity, and stability that may influence the potency of the peptides in vivo. When the peptides were tested for hNTR binding, the affinities in each series followed the order primary > secondary > tertiary > quaternary amine with the homolysine side-chain length being favored. All analogues possess binding affinities between acetyl-NT(8-13) and NT(8-13) indicating that the sterically less bulky alpha-azido may be inherently preferable to the acetyl group for N-terminal protection. This study extends the strategy of modifying amine-containing drugs through alkylations to peptide modification. The set of alkylated side chains also offers a new method of steric selection between receptor subtypes and could be used to modify the properties and biological effects of any peptide that contains cationic residues.

Preparation and receptor binding affinities of cyclic C-terminal neurotensin (8-13) and (9-13) analogues.

Cyclic analogues of neurotensin (NT) C-terminal fragments NT(8-13) and NT(9-13) were produced via intramolecular nucleophilic substitution of the Tyr(11) phenoxide anion on a 6-bromohexanoyl side chain substituted at position 8 or 9 and tested for NT receptor binding affinity.