Core Surface Flow Changes Associated With the 2017 Pacific Geomagnetic Jerk.

A geomagnetic jerk was seen in Swarm satellite data in 2017 over the Pacific region. We invert time series of spatial gradient secular variation data between 2014 and 2020, reduced to a grid of points at satellite altitude, for spatially- and temporally-regularized core surface flow. Pacific region flow acceleration was almost constant before and after the jerk, with a sharp change, especially in the azimuthal component, at the jerk epoch, despite the temporal regularization. Azimuthal acceleration is oppositely signed either side of 160°W, where it effectively vanishes, and also reverses sign at the jerk epoch. Acceleration features drift westward at about 900 km year-1. Unlike previous studies, the evidence presented here for low latitude waves does not depend on imposing flow equatorial symmetry, quasi- or tangential geostrophy, or band-pass filtering, and has no reliance on stochastic models or numerical simulations.

Secreted products of Fasciola hepatica inhibit the induction of T cell responses that mediate allergy.

There is evidence from epidemiology studies of a negative association between infection with helminth parasites and the development of allergy and asthma. Here, we demonstrate that the excretory/secretory products of the helminth Fasciola hepatica (FHES) protected mice against ovalbumin (OVA)-induced allergic asthma when administered at time of allergen sensitization. FHES reduced the accumulation of mucus, eosinophils and lymphocytes into the airways of allergen-challenged mice. Furthermore, FHES treatment suppressed Th2 responses in the airways. Interestingly, systemic administration of FHES at allergen challenge had no effect on airway inflammation, demonstrating that alum-induced Th2 response is set following initial allergen sensitization. Our findings highlight the immunomodulatory potential of molecules secreted by F. hepatica.

Gain of function mutations in p53.

We report that the expression of murine or human mutant p53 proteins in cells with no endogenous p53 proteins confers new or additional phenotypes upon these cells. Mutant p53 proteins expressed in cell lines lacking p53 resulted in either enhanced tumorigenic potential in nude mice ((10)3 cells) or enhanced plating efficiency in agar cell culture (human SAOS-2 cells). Also, mutant human p53 alleles, unlike the wild-type p53 protein, could also enhance the expression of a test gene regulated by the multi-drug resistance enhancer-promoter element. These data demonstrate a gain of function associated with p53 mutations in addition to the loss of function shown previously to be associated with mutations in this tumour suppressor gene.

The admixed brushtail possum genome reveals invasion history in New Zealand and novel imprinted genes.

Combining genome assembly with population and functional genomics can provide valuable insights to development and evolution, as well as tools for species management. Here, we present a chromosome-level genome assembly of the common brushtail possum (Trichosurus vulpecula), a model marsupial threatened in parts of their native range in Australia, but also a major introduced pest in New Zealand. Functional genomics reveals post-natal activation of chemosensory and metabolic genes, reflecting unique adaptations to altricial birth and delayed weaning, a hallmark of marsupial development. Nuclear and mitochondrial analyses trace New Zealand possums to distinct Australian subspecies, which have subsequently hybridised. This admixture allowed phasing of parental alleles genome-wide, ultimately revealing at least four genes with imprinted, parent-specific expression not yet detected in other species (MLH1, EPM2AIP1, UBP1 and GPX7). We find that reprogramming of possum germline imprints, and the wider epigenome, is similar to eutherian mammals except onset occurs after birth. Together, this work is useful for genetic-based control and conservation of possums, and contributes to understanding of the evolution of novel mammalian epigenetic traits.

Scalable, Green Fabrication of Single-Crystal Noble Metal Films and Nanostructures for Low-Loss Nanotechnology Applications.

The confinement of spatially extended electromagnetic waves to nanometer-scale metal structures can be harnessed for application in information processing, energy harvesting, sensing, and catalysis. Metal nanostructures enable negative refractive index, subwavelength resolution imaging, and patterning through engineered metamaterials and promise technologies that will operate in the quantum plasmonics regime. However, the controlled fabrication of high-definition single-crystal subwavelength metal nanostructures has remained a significant hurdle due to the tendency for polycrystalline metal growth using conventional physical vapor deposition methods and the challenges associated with placing solution-grown nanocrystals in desired orientations and locations on a surface to manufacture functional devices. Here, we introduce a scalable and green wet chemical approach to monocrystalline noble metal thin films and nanostructures. The method enables the fabrication of ultrasmooth, epitaxial, single-crystal films of controllable thickness that are ideal for the subtractive manufacture of nanostructures through ion beam milling and additive crystalline nanostructure via lithographic patterning for large-area, single-crystal metasurfaces and high aspect ratio nanowires. Our single-crystal nanostructures demonstrate improved feature quality, pattern transfer yield, reduced optical and resistive losses, and tailored local fields to yield greater optical response and improved stability compared to those of polycrystalline structures-supporting greater local field enhancements and enabling practical advances at the nanoscale.

The mdm-2 oncogene can overcome wild-type p53 suppression of transformed cell growth.

Expression of a p53-associated protein, Mdm-2 (murine double minute-2), can inhibit p53-mediated transactivation. In this study, overexpression of the Mdm-2 protein was found to result in the immortalization of primary rat embryo fibroblasts (REFs) and, in conjunction with an activated ras gene, in the transformation of REFs. The effect of wild-type p53 on the transforming properties of mdm-2 was determined by transfecting REFs with ras, mdm-2, and normal p53 genes. Transfection with ras plus mdm-2 plus wild-type p53 resulted in a 50% reduction in the number of transformed foci (relative to the level for ras plus mdm-2); however, more than half (9 of 17) of the cell lines derived from these foci expressed low levels of a murine p53 protein with the characteristics of a wild-type p53. These results are in contrast to previous studies which demonstrated that even minimal levels of wild-type p53 are not tolerated in cells transformed by ras plus myc, E1A, or mutant p53. The mdm-2 oncogene can overcome the previously demonstrated growth-suppressive properties of p53.

Immunological evidence for the association of p53 with a heat shock protein, hsc70, in p53-plus-ras-transformed cell lines.

A rabbit antiserum was prepared against the C-terminal peptide of 21 amino acids from the human heat shock protein hsp70. These antibodies were shown to be specific for this highly inducible heat shock protein (72 kilodaltons [kDa] in rat cells), and for a moderately inducible, constitutively expressed heat shock protein, hsc70 (74 kDa). In six independently derived rat cell lines transformed by a murine cDNA-genomic hybrid clone of p53 plus an activated Ha-ras gene, elevated levels of p53 were detected by immunoprecipitation by using murine-specific anti-p53 monoclonal antibodies. In all cases, the hsc70, but not the hsp70, protein was coimmunoprecipitated with the murine p53 protein. Similarly, antiserum to heat shock protein coimmunoprecipitated p53. Western blot (immunoblot) analysis demonstrated that the hsc70 and p53 proteins did not share detectable antigenic epitopes. The results provide clear immunological evidence for the specific association of a single heat shock protein, hsc70, with p53 in p53-plus-ras-transformed cell lines. A p53 cDNA clone, p11-4, failed to produce clonable cell lines from foci of primary rat cells transfected with p11-4 plus Ha-ras. A mutant p53 cDNA clone derived from p11-4, SVKH215, yielded a 2- to 35-fold increase in the number of foci produced after transfection of rat cells with SVKH215 plus Ha-ras. When cloned, 87.5% of these foci produced transformed cell lines. SVKH215 encodes a mutant p53 protein that binds preferentially to the heat shock proteins of 70 kDa compared with binding by the parental p11-4 p53 gene product. These data suggest that the p53-hsc70 protein complex could have functional significance in these transformed cells.

Activating mutations for transformation by p53 produce a gene product that forms an hsc70-p53 complex with an altered half-life.

The 11-4 p53 cDNA clone failed to transform primary rat fibroblasts when cotransfected with the ras oncogene. Two linker insertion mutations at amino acid 158 or 215 (of 390 amino acids) activated this p53 cDNA for transformation with ras. These mutant cDNAs produced a p53 protein that lacked an epitope, recognized by monoclonal antibody PAb246 (localized at amino acids 88 to 110 in the protein) and preferentially bound to a heat shock protein, hsc70. In rat cells transformed by a genomic p53 clone plus ras, two populations of p53 proteins were detected, PAb246+ and PAb246-, which did or did not bind to this monoclonal antibody, respectively. The PAb246- p53 preferentially associated with hsc70, and this protein had a half-life 4- to 20-fold longer than free p53 (PAb246+). These data suggest a possible functional role for hsc70 in the transformation process. cDNAs for p53 derived from methylcholanthrene-transformed cells transform rat cells in cooperation with the ras oncogene and produce a protein that bound with the heat shock proteins. Recombinant clones produced between a Meth A cDNA and 11-4 were tested for the ability to transform rat cells. A single amino acid substitution at residue 132 was sufficient to activate the 11-4 p53 cDNA for transformation. These studies have identified a region between amino acids 132 and 215 in the p53 protein which, when mutated, can activate the p53 cDNA. These results also call into question what the correct p53 wild-type sequence is and whether a wild-type p53 gene can transform cells in culture.

A functionally inactive p53 Li-Fraumeni syndrome mutant.

Germline mutations in the tumor-suppressor p53 have been recently identified in Li-Fraumeni syndrome patients. We analysed the function of one of these mutations, an arg-to-trp substitution at amino acid 245 in the murine p53 gene. This p53LFS mutant could not, unlike wild-type p53, suppress foci formation of rat embryo-fibroblasts. Like other p53 mutants it cooperated with activated ras to transform rat embryo fibroblasts. Overexpression of p53LFS thus resulted in a phenotype similar to other mutant p53s. The p53LFS protein was also transcriptionally inactive in contrast to previous studies using a p53LFS/GAL4 fusion protein. To better understand the functional domain disrupted in p53LFS, we developed a dimerization assay and showed that p53LFS still dimerized. In addition, p53LFS retained its ability to bind SV40 large T antigen and not hsc70, both characteristics of wild-type p53. Using immunofluorescence, we localized p53LFS to the nucleus. From these results we conclude that p53LFS represents an unusual p53 mutant in that it retains many characteristics of wild-type p53, however activities critical for growth suppression are lost.

A critical role for the TLR signaling adapter Mal in alveolar macrophage-mediated protection against Bordetella pertussis.

Bordetella pertussis causes whooping cough, an infectious disease of the respiratory tract that is re-emerging despite high vaccine coverage. Here we examined the role of Toll-like receptor (TLR) adapter protein Mal in the control of B. pertussis infection in the lungs. We found that B. pertussis bacterial load in the lungs of Mal-defective (Mal(-/-)) mice exceeded that of wild-type (WT) mice by up to 100-fold and bacteria disseminated to the liver in Mal(-/-) mice and 50% of these mice died from the infection. Macrophages from Mal(-/-) mice were defective in an early burst of pro-inflammatory cytokine production and in their ability to kill or constrain intracellular growth of B. pertussis. Importantly, the B. pertussis bacterial load in the lungs inversely correlated with the number of alveolar macrophages. Despite the maintenance and expansion of other cell populations, alveolar macrophages were completely depleted from the lungs of infected Mal(-/-) mice, but not from infected WT mice. Our findings define for the first time a role for a microbial pattern-recognition pathway in the survival of alveolar macrophages and uncover a mechanism of macrophage-mediated immunity to B. pertussis in which Mal controls intracellular survival and dissemination of bacteria from the lungs.

Course of tricuspid atresia in the Fontan era.

Tricuspid atresia is an uncommon form of congenital heart disease and long-term survival was rare before the Fontan era. It was thought that the long-term survival of patients with tricuspid atresia would be improved by the introduction of the Fontan procedure and its subsequent modifications. This study reviews the clinical course of 84 patients with tricuspid atresia identified in the first year of life in the Fontan era. Prior palliative operations, their results and their ultimate application for the Fontan procedure were considered. Eleven patients died before surgical intervention and 5 did not undergo catheterization or echocardiographic confirmation before death. Five children underwent the Fontan procedure without prior palliation and 1 child does not require palliation at the present time. Sixty-seven patients (80%) had surgical procedures before evaluation for the suitability of a Fontan operation. Thirty-four patients had a second surgical palliation and 9 patients had a third palliation. The surgical mortalities for the first, second and third palliative surgery were 17.9, 17.6 and 0%, respectively. Thirty-two patients (38%) underwent the Fontan procedure and 2 deaths occurred (6%). An estimate of the probability of surviving for 1 year was 64% (95% confidence limits 54 to 74%) and that of 8 years was 55% (95% confidence limits 44 to 66%).

Inhibition of human monocyte function by prophylactic doses of chloroquine.

The effect of prophylactic doses of chloroquine on the phagocytic function of human monocytes was studied in young healthy male volunteers. They received placebo, 300, or 600 mg of chloroquine base/week for six weeks. In each subject, the phagocytic function was tested before and at the end of the chloroquine intake period. In the 600-mg chloroquine group, it was also tested six weeks after receiving the last dose. Chloroquine at both doses inhibited the phagocytosis of IgG-coated sheep red blood cells and of zymosan particles. The effect was more pronounced with the 600 mg dose of chloroquine. The phagocytic activity returned to normal values six weeks after the end of treatment.

Immunodiagnosis of human fascioliasis by enzyme-linked immunosorbent assay using excretory-secretory products.

In sera from patients with fascioliasis the enzyme-linked immunosorbent assay (ELISA) was used to detect antibody using excretory-secretory products (ES) from Fasciola hepatica adult worms. The specificity of ES-ELISA (with OD values greater than 0.38) allowed the differentiation among fascioliasis, schistosomiasis, clonorchiasis, and other human parasite infections.

Detection of specific anti-giardia serum antibody by an immunofluorescence test in children with clinical giardiasis.

In 50 of 100 children with clinical giardiasis studied, the presence of Giardia lamblia was proven by stool and/or duodenal aspirate examination; the presence of the parasite was not demonstrated in the rest. Serum antibodies to G. lamblia were investigated in all children by an indirect immunofluorescent test (IIF) with G. lamblia trophozoites as antigen. It was found that all the children with positive duodenal aspirate had positive serology (titers greater than or equal to 1/32). The best correlation between parasitological and serological procedures were in the 1-5-year-old age group, and there was an age dependent increase of the antibody titer. Most of the parasitologically negative children were serologically negative. Our results support the use of IIF as a useful diagnostic procedure in the diagnosis of giardiasis in children.

Longitudinal study of giardiasis in three day care centres of Havana City.

The prevalence, incidence and reinfection of giardiasis were studied in 365 children attending three day care centres (DCCs) in Havana City. Three stool samples were obtained from each child every 6 months during an 18-month period. We identified three distinct groups of children according to their patterns of infection. In the largest group (51%) children were never found infected. In the second group, they were found infected once or twice during the study period, and in the third and the smallest group (9%) they were found infected in most or all the study periods. This last group seems to be children 'predisposed' to Giardia lamblia infection. The prevalence of giardiasis (20%) remained almost constant throughout the study period. The incidence declined from 16 to 11%, and reinfection increased from 36 to 49%. All the children had normal nutritional status and the only clinical manifestation that correlated strongly with the frequency of cross-sectional surveys positive to Giardia was the number of diarrhoeal episodes recorded during the last 6 months of the study period. Further studies will be necessary to ascertain the causes that determine the 'predisposition' to giardiasis in children.

Evaluation of the immune response in symptomatic and asymptomatic human giardiasis.

To better understand the common association of Giardia lamblia infection and allergic reactivity, total and specific IgE values were evaluated and different manifestations of symptomatic and asymptomatic infected human hosts were analyzed. The humoral, cellular, and nonspecific immune responses were evaluated in Cuban adults. Increased total serum IgE levels were significantly higher (p < 0.01) in Giardia patients than in negative controls; cure of giardiasis was characterized by a decrease in IgE levels and some patients regained normal IgE values. The skin test was positive in 91% (103/123) of chronic patients and only in 23% (20/123) of negative controls (p < 0.05). A positive test was seen in patients with antecedents of recent giardiasis (< 4 months). Specific IgE was higher in patients than in control sera, and in the former it decreased with sera dilution. During the follow-up period of cured patients, the proportion of IgE decreased and the opposite occurred in noncured patients. The cellular response evaluated by LIF was positive in 92% (11/12) of carriers and significantly higher (p < 0.05) than in symptomatic patients 8% (1/12); the same occurred with IgG and IgA antibody response; titers mainly of IgA were higher in asymptomatic carriers than in patients; all carriers were negative to the skin test. These results indicate the presence of total and specific IgE responses in humans infected with Giardia, but the response in symptomatic cases (patients) is different from that in asymptomatic cases (carriers).(ABSTRACT TRUNCATED AT 250 WORDS)

Kinetics of antibody-based antigen detection in serum and faeces of sheep experimentally infected with Fasciola hepatica.

The monoclonal antibody ES78 was used in a sandwich immunosorbent assay (Sandwich ELISA) for the detection of antigens in sera and faeces in the course of Fasciola hepatica infection in 10 experimentally infected sheep. All infected sheep had circulating antigens in the first week post-infection (WPI). Antigenemia was detectable until WPI 3 in four infected sheep, WPI 4 in five infected sheep and in only one sheep by WPI 5. The detection of coproantigens (Fa(g)) was possible in five infected sheep at WPI-4, in four sheep at WPI-5 and in one sheep only at WPI-6. This technique was compared to an indirect ELISA for the detection of antibodies using excretory secretory antigens of F. hepatica. A significant correlation was found between Fa(g) and egg output and also with adult worm numbers. Our method demonstrated that the diagnosis of active fasciolosis in sheep is possible during all periods of infection.

Kinetics of antibody-based antigen detection in serum and faeces of sheep experimentally infected with Fasciola hepatica.

The monoclonal antibody ES78 was used in a sandwich immunosorbent assay (Sandwich ELISA) for the detection of antigens in sera and faeces in the course of Fasciola hepatica infection in 10 experimentally infected sheep. All infected sheep had circulating antigens in the first week post-infection (WPI). Antigenemia was detectable until WPI 3 in four infected sheep, WPI 4 in five infected sheep and in only one sheep by WPI 5. The detection of coproantigens (Fag) was possible in five infected sheep at WPI-4, in four sheep at WPI-5 and in one sheep only at WPI-6. This technique was compared to an indirect ELISA for the detection of antibodies using excretory secretory antigens of F. hepatica. A significant correlation was found between Fag and egg output and also with adult worm numbers. Our method demonstrated that the diagnosis of active fasciolosis in sheep is possible during all periods of infection.

Identification of Dirofilaria immitis-infected dogs with a coagglutination assay.

The presence of Dirofilaria immitis excretory-secretory (ES) products was detected in the urine of infected dogs using a coagglutination assay. Urine samples from 30 naturally infected dogs were positive. Seventeen of them were microfilaremic, whereas 13 had become amicrofilaremic after receiving 2 courses of diethylcarbamazine. Urine samples from 20 dogs infected with other parasites, Dipetalonema reconditum (7), Toxocara canis (5), and Ancylostoma caninum (8), and urine samples from 20 healthy dogs were negative. The assay detected 200 ng/ml or more of ES products. This assay is simple, easy to perform with minimum training, and requires no equipment. Therefore it should be useful to detect canine filariasis under field conditions.

Partial characterization of the epitope on excretory-secretory products of Fasciola hepatica recognized by monoclonal antibody ES78.

This report contains a partial characterization of the epitope recognized by monoclonal antibody (MAb) ES78 produced against excretory-secretory (ES) antigens of Fasciola hepatica. ES78 is currently used for the detection of ES antigens in serum and stool samples of cattle and humans with fasciolosis, using a highly sensitive and specific sandwich enzyme-linked immunosorbent assay (ELISA). The epitope was characterized by periodate oxidation, alkaline borohydride reduction, trichloroacetic acid precipitation, beta-mercaptoethanol treatment, and enzymatic proteolysis. These results, together with those of the 2-site ELISA, lectin immunoassays, and beta-galactosidase digestion, showed that MAb ES78 reacts with a partly protein/partly carbohydrate antigenic determinant that is found on several ES molecules of adult specimens of F. hepatica and contains at least 1 disulfide bond and beta-galactose probably as galactose-beta(1-3)-N-acetylgalactosamine disaccharide.