Cryogenic vacuum valve with actuation times down to 50 ms.

We have conceived, built, and operated a cryogenic vacuum valve with opening and closing times as short as 50 ms that can be used in strong magnetic fields and across a broad range of duty cycles. It is used to seal a cryogenic Penning trap at liquid-helium temperature for long-term storage of highly charged ions in a vacuum better than 10-15 hPa from a room-temperature ion beamline at vacuum conditions around 10-9 hPa. It will significantly improve any experiment where a volume at the most extreme vacuum conditions must be temporarily connected to a less demanding vacuum during repeated experimental cycles. We describe the design of this valve and show measurements that characterize its main features.

Generalized propensity score approach to causal inference with spatial interference.

Many spatial phenomena exhibit interference, where exposures at one location may affect the response at other locations. Because interference violates the stable unit treatment value assumption, standard methods for causal inference do not apply. We propose a new causal framework to recover direct and spill-over effects in the presence of spatial interference, taking into account that exposures at nearby locations are more influential than exposures at locations further apart. Under the no unmeasured confounding assumption, we show that a generalized propensity score is sufficient to remove all measured confounding. To reduce dimensionality issues, we propose a Bayesian spline-based regression model accounting for a sufficient set of variables for the generalized propensity score. A simulation study demonstrates the accuracy and coverage properties. We apply the method to estimate the causal effect of wildland fires on air pollution in the Western United States over 2005-2018.

A Uniform Description of Perioperative Brain MRI Findings in Infants with Severe Congenital Heart Disease: Results of a European Collaboration.

BACKGROUND AND PURPOSE: A uniform description of brain MR imaging findings in infants with severe congenital heart disease to assess risk factors, predict outcome, and compare centers is lacking. Our objective was to uniformly describe the spectrum of perioperative brain MR imaging findings in infants with congenital heart disease. MATERIALS AND METHODS: Prospective observational studies were performed at 3 European centers between 2009 and 2019. Brain MR imaging was performed preoperatively and/or postoperatively in infants with transposition of the great arteries, single-ventricle physiology, or left ventricular outflow tract obstruction undergoing cardiac surgery within the first 6 weeks of life. Brain injury was assessed on T1, T2, DWI, SWI, and MRV. A subsample of images was assessed jointly to reach a consensus. RESULTS: A total of 348 MR imaging scans (180 preoperatively, 168 postoperatively, 146 pre- and postoperatively) were obtained in 202 infants. Preoperative, new postoperative, and cumulative postoperative white matter injury was identified in 25%, 30%, and 36%; arterial ischemic stroke, in 6%, 10%, and 14%; hypoxic-ischemic watershed injury in 2%, 1%, and 1%; intraparenchymal cerebral hemorrhage, in 0%, 4%, and 5%; cerebellar hemorrhage, in 6%, 2%, and 6%; intraventricular hemorrhage, in 14%, 6%, and 13%; subdural hemorrhage, in 29%, 17%, and 29%; and cerebral sinovenous thrombosis, in 0%, 10%, and 10%, respectively. CONCLUSIONS: A broad spectrum of perioperative brain MR imaging findings was found in infants with severe congenital heart disease. We propose an MR imaging protocol including T1-, T2-, diffusion-, and susceptibility-weighted imaging, and MRV to identify ischemic, hemorrhagic, and thrombotic lesions observed in this patient group.

Basophils control T-cell responses and limit disease activity in experimental murine colitis.

Basophils have been recognized as important inducers of T helper type 2 (Th2) responses. Using the colitis model of adoptive transfer of CD4(+) CD62L(+) T cells into lymphopenic hosts, we have analyzed how basophils regulate T-cell responses and modulate disease activity. Transferred T cells rapidly proliferate, produce large amounts of interleukin (IL)-3, and expand the number of basophils in an IL-3-dependent manner. Depletion of basophils with two different antibodies substantially upregulated Th1 cytokines in transferred T cells at day 8. Increased Th1 cytokine expression persisted until the end of the experiment when basophil-depleted mice showed exacerbation of colitis with more severe loss of weight, histological damage, colonic leukocyte infiltration, and expression of pro-inflammatory cytokines. In vitro, we show that basophil-derived IL-4 and IL-6 downregulates expression of interferon-γ, IL-2, and tumor necrosis factor in T cells. These data show a beneficial role of basophils in a T-cell driven model of autoimmunity.

Bayesian geostatistical modelling with informative sampling locations.

We consider geostatistical models that allow the locations at which data are collected to be informative about the outcomes. A Bayesian approach is proposed, which models the locations using a log Gaussian Cox process, while modelling the outcomes conditionally on the locations as Gaussian with a Gaussian process spatial random effect and adjustment for the location intensity process. We prove posterior propriety under an improper prior on the parameter controlling the degree of informative sampling, demonstrating that the data are informative. In addition, we show that the density of the locations and mean function of the outcome process can be estimated consistently under mild assumptions. The methods show significant evidence of informative sampling when applied to ozone data over Eastern U.S.A.

A novel statistical model for mandibular helical axis analysis.

The purpose of this study was to establish a new statistical method for the analysis of noisy mandibular helical axis parameters, especially the position vector of the finite helical axis (FHA). The subjects were children with anterior cross-bite who had received orthodontic treatment. Maximum mouth-opening was measured by means of an opto-electronic motion analysis system. These movements were compared with similar movement in the same group after treatment of their anterior cross-bite. Each curve of FHA position vectors was modelled as a spline function with random coefficients. To determine the optimal number of knots, two criteria were used: deviance information criteria (DIC) and mean squared prediction error (MSE). We were interested in estimating a typical curve for a population. Self-modelling regression (SEMOR) was extended to three dimensions to model groups of three-dimensional curves. Each curve was modelled as a spline function using nine knots. Population average curves were created using SEMOR. This study provided detailed information about jaw movement for comparing cross-bite to normal occlusion by calculating the population mean curves of the position vector of the FHA. Our results suggested that the two population mean curves for the position vector of the FHA were significantly different in the closing phase. The combination of a spline function with random coefficients and SEMOR extended to three dimensions can be used not only for FHA analysis but also for the analysis of other jaw movements.

Effects of Toll-like receptor 4 on Porphyromonas gingivalis-induced bone loss in mice.

BACKGROUND AND OBJECTIVE: Toll-like receptor 4 (TLR-4)/myeloid differentiation protein-2 complex ligation by lipopolysaccharide induces production of pro-inflammatory cytokines and co-stimulatory molecules on antigen presenting cells. The aim of this study was to determine the role of the TLR-4 in bone loss-resistant C57BL mice and in bone loss-susceptible BALB/c mice after infection with Porphyromonas gingivalis. MATERIAL AND METHODS: The BALB/c and C57BL/10 mice, either normal or TLR-4 deficient, were infected or sham-infected orally four times, at 4 day intervals, with 10(9) colony forming units of P. gingivalis. At 47 days, defleshed jaws were stained and photographed in a standardized position. We measured the surface area of the root trunk to assess the alveolar bone loss. RESULTS: Porphyromonas gingivalis-infected wild-type BALB/c mice lost 13.8% more bone than P. gingivalis-infected wild-type C57BL/10 mice. In contrast, P. gingivalis-infected TLR-4-deficient C57BL/10 mice lost 12.7% more bone than P. gingivalis-infected TLR-4-deficient BALB/c mice. Porphyromonas gingivalis-infected wild-type C57BL/6 and TLR-2 knockout C57BL/6 mice had similar bone levels to sham-infected control mice. CONCLUSION: Toll-like receptor 4 is protective for C57BL/10 but detrimental to BALB/c mice, since its absence allowed C57BL/10 but not BALB/c mice to lose alveolar bone. Toll-like receptor 2 does not contribute to this protection in genetically similar C57BL/6 mice.

Characterisation of recombinant immunoreactive antigens of the scab mite Sarcoptes scabiei.

Sarcoptic mange (or scabies) is an important skin disease which can affect a variety of species including humans, cattle, goats, sheep, horses, pigs, rabbits, and dogs. Approximately 300 million people are affected worldwide and in lifestock animals the infestation may lead to substantial economic losses caused by depression in growth and feed conversion rates. Diagnosis of Sarcoptes infestation is difficult and only a few serological tests have been developed using whole mite antigen for diagnosis of mange in animals. Here we describe the isolation and characterisation of cDNAs of several immunoreactive clones and their recombinant expression in Escherichia coli. Three of the proteins contain repetitive sequences which suggests that they might be involved in immune evasion. The application of these antigens in serodiagnosis and the suitability for diagnosis is discussed.

Analysis of the relationship between socioeconomic factors and stomach cancer incidence in Slovenia.

An unequal population distribution of well-known major risk factors explains much of the variation in the incidence of stomach cancer worldwide. The aim of this study was to determine whether geographical variation of the stomach cancer incidence rate between Slovenia's municipalities during years 1995-2001 could partially be explained by variations in the socioeconomic status as an indirect stomach cancer risk factor. A composite measure of each region's socioeconomic status, labelled as deprivation index, was created from basic socioeconomic characteristics of each municipality using factor analysis. Municipalities' standardized incidence ratios for all stomach cancers and non-cardia stomach cancer were calculated. A fully Bayesian spatial model with a conditionally autoregressive prior was applied using Markov chain Monte Carlo techniques and WinBUGS software. Spatially smoothed maps of stomach cancer incidence rates by 192 Slovenian municipalities show a clear west-to-east gradient. This pattern resembles the geographical variation of socioeconomic indices, but these indices are not significant predictors of stomach cancer incidence. Geographical variation of stomach cancer incidence in Slovenia could be partially explained by the heterogeneous socioeconomic characteristics of its municipalities. It is possible that the socioeconomic status indices used in our study were not enough powerful predictors of stomach cancer risk. Some further methodological research is needed to explain why this association was not statistically evident with the current modeling approach.

Ene-diamine versus imine-amine isomeric preferences.

Cyanide-catalyzed aldimine coupling was employed to synthesize compounds with 1,2-ene-diamine and alpha-imine-amine structural motifs: 1,2,N,N'-tetraphenyletheylene-1,2-diamine (13) and (+/-)-2,3-di-(2-hydroxyphenyl)-1,2-dihydroquinoxaline (17), respectively. Single-crystal X-ray diffraction provided solid-state structures and density functional theory calculations were used to probe isomeric preferences within this and the related hydroxy-ketone/ene-diol system. The ene-diamine and imine-amine core structures were calculated (B3LYP/6-311++G(d,p)) to be essentially identical in energy (DeltaG = 0.2 kcal/mol in favor of the imine-amine, within the error of the calculation). However, additional effects-such as pi conjugation-in 13 render an ene-diamine structure that is slightly more stable than the imine-amine tautomer (14) (DeltaG = 0.2-0.7 kcal/mol, within the error of the calculation). In contrast, the intramolecular hydrogen bonding present in 17 significantly favors the imine-amine isomer over the ene-diamine tautomer (18) (DeltaG = 7.2-8.9 kcal/mol). For both 13 and 17, the optimized calculated structures (B3LYP/6-31+G(d')) are identical to those observed by single-crystal X-ray diffraction.

The OH-initiated oxidation of 1,3-butadiene in the presence of O2 and NO: a photolytic route to study isomeric selective reactivity.

We report the study of the isomeric selective OH-initiated oxidation of 1,3-butadiene in the presence of O2 and NO using the LP/LIF technique. The photolysis of monodeuterated 1-iodo-3-buten-2-ol provides only one of the possible OD-butadiene adducts, the minor addition channel product, simplifying the oxidation mechanism. We find, based on analysis of OD time-dependent traces that prompt rearrangement of initial beta-hydroxyalkyl radicals to alpha-hydroxyalkyl radicals occurs in agreement with RRKM/ME theoretical predictions. We report a rate constant of (3.3+/-1.0) x 10(-11) cm3 molecules(-1) s(-1) for deuterium abstraction from the alpha-hydroxyalkyl radical at 298 +/-2 K. Our approach demonstrates the feasibility of isomeric selective kinetic studies of the OH-initiated oxidation of unsaturated hydrocarbons.

Cyanide-catalyzed cyclizations via aldimine coupling.

Aldimine coupling (AIC) is the nitrogen analogue of the benzoin condensation and has been applied to dialdimines, providing the first examples of cyclizations effected by cyanide-catalyzed AIC. Sodium cyanide promoted the facile, intramolecular cyclization of several dialdimines in N,N-dimethylformamide, methanol, or methylene chloride/water (phase-transfer conditions) yielding a variety of six-membered heterocycles. Under aerobic conditions, an oxidative cyclization occurs to provide the diimine heterocycle. Oligomerization was observed with rigid dialdimines for which cyclization was precluded.

The nuclear dot protein sp100, characterization of domains necessary for dimerization, subcellular localization, and modification by small ubiquitin-like modifiers.

The Sp100 and promyelocytic leukemia proteins (PML) are constituents of nuclear domains, known as nuclear dots (NDs) or PML bodies, and are both covalently modified by the small ubiquitin-related protein SUMO-1. NDs play a role in autoimmunity, virus infections, and in the etiology of acute promyelocytic leukemia. To date, little is known about the function of the Sp100 protein. Here we analyzed Sp100 domains that determine its subcellular localization, dimerization, and SUMOylation. A functional nuclear localization signal and an ND-targeting region that coincides with an Sp100 homodimerization domain were mapped. Sequences similar to the Sp100 homodimerization/ND-targeting region occur in several other proteins and constitute a novel protein motif, termed HSR domain. The lysine residue of the Sp100 protein, to which SUMO-1 is covalently linked, was mapped within and may therefore modulate the previously described HP1 protein-binding site. A consensus sequence for SUMOylation of proteins in general is suggested. SUMOylation strictly depended on a functional nuclear localization signal but was not necessary for nuclear import or ND targeting. A three-dimensional structure of Sp100, which supports the mapping data and provides additional information on Sp100 structure/function relationships, was generated by computer modeling. Taken together, our studies indicate the existence of well defined Sp100 domains with functions in ND targeting, nuclear import, nuclear SUMOylation, and protein-protein interaction.

Detailed characterization of the binding site of the lipoprotein lipase-specific monoclonal antibody 5D2.

Monoclonal antibody (MAb) 5D2 recognizes lipoprotein lipases (LPL) from different species but not related lipases. This MAb is a unique reagent, used world-wide, because it differentiates between monomeric inactive and dimeric active LPL, inhibits human LPL enzyme activity, and binds to C-terminal LPL sequences involved in interactions with lipoproteins, lipoprotein receptors, and heparin. In this study we have analyzed the fine specificity of the MAb epitope recognition in order to better understand its functional properties and species-specific LPL immune reactivity. In peptide scan assays, MAb 5D2 reacted with all, except two, 13 amino acid-long peptides located between positions 380 and 410. Peptides from the amino terminal end of this region reacted more strongly than those from the carboxyl terminal end. Furthermore, only a peptide from the amino terminal end competed effectively with the binding of MAb 5D2 to native LPL bound to microtiter plates or nitrocellulose. A systematic peptide mutagenesis study indicated that 8 amino acids of the reactive region, mainly located in the amino terminal end, are critical for binding and probably directly interact with MAb 5D2. The experimentally determined antigenicities of species-specific LPL peptides and of the corresponding denatured full-length LPL proteins on immunoblots were consistent with these findings. According to a proposed 3D-model for LPL, only the amino terminal end of the antigenic region is easily surface-accessible. These data combined with 3D-modelling of monoclonal antibody (MAb)-lipoprotein lipase (LPL) protein interaction provide new insight into the known biological effects of MAb 5D2 on LPL and the antigenic determinants that are recognized.

A highly amplified mouse gene is homologous to the human interferon-responsive Sp100 gene encoding an autoantigen associated with nuclear dots.

In human cells, three proteins are currently known to colocalize in di screte nuclear domains (designated nuclear dots): Sp100, a transcription-activating protein autoantigenic primarily in patients with primary biliary cirrhosis; PML, a tumor suppressor protein involved in development of acute promyelocytic leukemia; and NDP52, a protein of unknown function. Here we report sequence similarities between the Sp100 protein and a putative protein encoded by a highly amplified mouse gene which is visible as an inherited homogeneously staining region (HSR) on chromosome 1 of some mouse populations. By in situ hybridization, the Sp100 gene was mapped to locus 2q37, the syntenic region of the HSR on mouse chromosome 1. Unlike the highly amplified mouse gene, Sp100 was found to be a single-copy gene and showed no restriction fragment length polymorphisms. Sequence similarities in the promoter regions and similar exon-intron organizations of the two genes were revealed. As for Sp100, steady-state levels of the mRNAs of the HSR-encoded genes could be greatly increased by interferon (IFN) treatment. As in human cells, IFN treatment led to an enlargement in both size and number of nuclear dots in mouse cells as visualized by immunofluorescence staining with autoimmune sera from patients with primary biliary cirrhosis. These data indicate that a gene located in the inherited HSR of mice, designated mSp100, is homologous to the human Sp100 gene, has a similar gene organization, and responds similarly to IFN treatment.

The occurrence of trophoblastic disease in Western Samoa.

In order to study the occurrence of hydatidiform mole and choriocarcinoma in the island of Western Samoa in the South Pacific, a delivery based study was carried out. All deliveries, both livebirths and stillbirths at the main referral centre (National Hospital), all livebirths at the district hospitals/health centres and all live home deliveries 1980-87 were included. Thirty-two hydatidiform mole cases were recorded on pathological and clinical grounds. No case of choriocarcinoma was encountered. The incidence rate of hydatidiform mole was estimated to be 0.90 per 1000 deliveries, the estimated frequency rate being 1:1109 deliveries. The mean age of cases was 31 years, ranging from 19 to 48. It is suggested that the incidence of trophoblastic disease is not significant in Western Samoa in terms of geographical variations. The importance of methodology in estimating the incidence was also discussed.

Non-invasive treatment of vascular and muscle contraction headache: a comparative longitudinal clinical study.

The purpose of this investigation was to evaluate the long-term course of non-invasively treated chronic headache. A total of 1015 adult patients with primary diagnosis of vascular/migraine or muscle contraction headache participated in the study investigating symptom frequency and severity over a 36 month period after receiving treatment. Treatment consisted of either: relaxation training (stepwise relaxation/hypnosis/autogenic training/cognitive behavior therapy); biofeedback (thermal/photoplethysmograph/EMG); micro-electrical therapy (TENS/Neurotransmitter Modulation) or multimodal treatment (combination of any of the above two treatments). Seven hundred and ninety-three patients returned sufficient data to be included in the analysis. Patients were randomly assigned to treatment groups and received either short term intervention (15 or less treatments) or long term intervention (greater than 15 treatments). Results indicate that all treatment conditions significantly reduced frequency and intensity of cephalalgia. Repeated measure analysis of variance indicated that grouping variables of Biofeedback treatment, symptoms being evidenced less than 2 years and receiving over 15 treatment sessions best predicted successful intervention.

Production and characterization of monoclonal antibodies against secretory proteinase of Candida albicans CBS 2730.

We describe the production and characterization of three murine monoclonal antibodies (M1-M3) which are directed against different epitopes of the secretory aspartic proteinase of Candida albicans CBS 2730. All antibodies belonged to the IgM class, and they recognized denatured enzyme. Only antibody M1 was capable to react with the active proteinase. Differential reactivity was also observed with a large fragment of the proteinase of C. albicans. All antibodies recognized the corresponding proteinase of C. tropicalis 293 both in the active, and in the denatured state. Denatured porcine pepsin was also recognized by all three antibodies. However, active pepsin was recognized only by antibodies M1 and M2. The antibodies did not inhibit enzymatic activity, and they were not suited for immunofluorescence detection of proteinase on fungal cells. However, employing Western blot analysis, proteinase antigen was detected by antibody M 1 in the serum of a patient suffering from candidal pneumonia. The circulating proteinase antigen was found to be bound to patient's IgM. Implications for the use of monoclonal antibodies in the serodiagnosis of candidosis, and first experiences with other monoclonal anti-proteinase antibodies are discussed.