Search for magnetic monopoles produced via the Schwinger mechanism.

Electrically charged particles can be created by the decay of strong enough electric fields, a phenomenon known as the Schwinger mechanism1. By electromagnetic duality, a sufficiently strong magnetic field would similarly produce magnetic monopoles, if they exist2. Magnetic monopoles are hypothetical fundamental particles that are predicted by several theories beyond the standard model3-7 but have never been experimentally detected. Searching for the existence of magnetic monopoles via the Schwinger mechanism has not yet been attempted, but it is advantageous, owing to the possibility of calculating its rate through semi-classical techniques without perturbation theory, as well as that the production of the magnetic monopoles should be enhanced by their finite size8,9 and strong coupling to photons2,10. Here we present a search for magnetic monopole production by the Schwinger mechanism in Pb-Pb heavy ion collisions at the Large Hadron Collider, producing the strongest known magnetic fields in the current Universe11. It was conducted by the MoEDAL experiment, whose trapping detectors were exposed to 0.235 per nanobarn, or approximately 1.8 × 109, of Pb-Pb collisions with 5.02-teraelectronvolt center-of-mass energy per collision in November 2018. A superconducting quantum interference device (SQUID) magnetometer scanned the trapping detectors of MoEDAL for the presence of magnetic charge, which would induce a persistent current in the SQUID. Magnetic monopoles with integer Dirac charges of 1, 2 and 3 and masses up to 75 gigaelectronvolts per speed of light squared were excluded by the analysis at the 95% confidence level. This provides a lower mass limit for finite-size magnetic monopoles from a collider search and greatly extends previous mass bounds.

Sustaining attention in affective contexts during adolescence: age-related differences and association with elevated symptoms of depression and anxiety.

Sustained attention, a key cognitive skill that improves during childhood and adolescence, tends to be worse in some emotional and behavioural disorders. Sustained attention is typically studied in non-affective task contexts; here, we used a novel task to index performance in affective versus neutral contexts across adolescence (N = 465; ages 11-18). We asked whether: (i) performance would be worse in negative versus neutral task contexts; (ii) performance would improve with age; (iii) affective interference would be greater in younger adolescents; (iv) adolescents at risk for depression and higher in anxiety would show overall worse performance; and (v) would show differential performance in negative contexts. Results indicated that participants performed more poorly in negative contexts and showed age-related performance improvements. Those at risk of depression performed more poorly than those at lower risk. However, there was no difference between groups as a result of affective context. For anxiety there was no difference in performance as a function of severity. However, those with higher anxiety showed less variance in their reaction times to negative stimuli than those with lower anxiety. One interpretation is that moderate levels of emotional arousal associated with anxiety make individuals less susceptible to the distracting effects of negative stimuli.

First Search for Dyons with the Full MoEDAL Trapping Detector in 13 TeV pp Collisions.

The MoEDAL trapping detector consists of approximately 800 kg of aluminum volumes. It was exposed during run 2 of the LHC program to 6.46 fb^{-1} of 13 TeV proton-proton collisions at the LHCb interaction point. Evidence for dyons (particles with electric and magnetic charge) captured in the trapping detector was sought by passing the aluminum volumes comprising the detector through a superconducting quantum interference device (SQUID) magnetometer. The presence of a trapped dyon would be signaled by a persistent current induced in the SQUID magnetometer. On the basis of a Drell-Yan production model, we exclude dyons with a magnetic charge ranging up to five Dirac charges (5g_{D}) and an electric charge up to 200 times the fundamental electric charge for mass limits in the range 870-3120 GeV and also monopoles with magnetic charge up to and including 5g_{D} with mass limits in the range 870-2040 GeV.

Magnetic Monopole Search with the Full MoEDAL Trapping Detector in 13 TeV pp Collisions Interpreted in Photon-Fusion and Drell-Yan Production.

MoEDAL is designed to identify new physics in the form of stable or pseudostable highly ionizing particles produced in high-energy Large Hadron Collider (LHC) collisions. Here we update our previous search for magnetic monopoles in Run 2 using the full trapping detector with almost four times more material and almost twice more integrated luminosity. For the first time at the LHC, the data were interpreted in terms of photon-fusion monopole direct production in addition to the Drell-Yan-like mechanism. The MoEDAL trapping detector, consisting of 794 kg of aluminum samples installed in the forward and lateral regions, was exposed to 4.0 fb^{-1} of 13 TeV proton-proton collisions at the LHCb interaction point and analyzed by searching for induced persistent currents after passage through a superconducting magnetometer. Magnetic charges equal to or above the Dirac charge are excluded in all samples. Monopole spins 0, ½, and 1 are considered and both velocity-independent and-dependent couplings are assumed. This search provides the best current laboratory constraints for monopoles with magnetic charges ranging from two to five times the Dirac charge.

Machine learning techniques for detecting topological avatars of new physics.

The search for highly ionizing particles in nuclear track detectors (NTDs) traditionally requires experts to manually search through samples in order to identify regions of interest that could be a hint of physics beyond the standard model of particle physics. The advent of automated image acquisition and modern data science, including machine learning-based processing of data presents an opportunity to accelerate the process of searching for anomalies in NTDs that could be a hint of a new physics avatar. The potential for modern data science applied to this topic in the context of the MoEDAL experiment at the large Hadron collider at the European Centre for Nuclear Research, CERN, is discussed. This article is part of a discussion meeting issue 'Topological avatars of new physics'.

First Evidence for cos2ß>0 and Resolution of the Cabibbo-Kobayashi-Maskawa Quark-Mixing Unitarity Triangle Ambiguity.

We present first evidence that the cosine of the CP-violating weak phase 2ß is positive, and hence exclude trigonometric multifold solutions of the Cabibbo-Kobayashi-Maskawa (CKM) Unitarity Triangle using a time-dependent Dalitz plot analysis of B^{0}→D^{(*)}h^{0} with D→K_{S}^{0}π^{+}π^{-} decays, where h^{0}∈{π^{0},η,ω} denotes a light unflavored and neutral hadron. The measurement is performed combining the final data sets of the BABAR and Belle experiments collected at the ϒ(4S) resonance at the asymmetric-energy B factories PEP-II at SLAC and KEKB at KEK, respectively. The data samples contain (471±3)×10^{6}BB[over ¯] pairs recorded by the BABAR detector and (772±11)×10^{6}BB[over ¯] pairs recorded by the Belle detector. The results of the measurement are sin2ß=0.80±0.14(stat)±0.06(syst)±0.03(model) and cos2ß=0.91±0.22(stat)±0.09(syst)±0.07(model). The result for the direct measurement of the angle ß of the CKM Unitarity Triangle is ß=[22.5±4.4(stat)±1.2(syst)±0.6(model)]°. The measurement assumes no direct CP violation in B^{0}→D^{(*)}h^{0} decays. The quoted model uncertainties are due to the composition of the D^{0}→K_{S}^{0}π^{+}π^{-} decay amplitude model, which is newly established by performing a Dalitz plot amplitude analysis using a high-statistics e^{+}e^{-}→cc[over ¯] data sample. CP violation is observed in B^{0}→D^{(*)}h^{0} decays at the level of 5.1 standard deviations. The significance for cos2ß>0 is 3.7 standard deviations. The trigonometric multifold solution π/2-ß=(68.1±0.7)° is excluded at the level of 7.3 standard deviations. The measurement resolves an ambiguity in the determination of the apex of the CKM Unitarity Triangle.

Genetic diagnosis of developmental disorders in the DDD study: a scalable analysis of genome-wide research data.

BACKGROUND: Human genome sequencing has transformed our understanding of genomic variation and its relevance to health and disease, and is now starting to enter clinical practice for the diagnosis of rare diseases. The question of whether and how some categories of genomic findings should be shared with individual research participants is currently a topic of international debate, and development of robust analytical workflows to identify and communicate clinically relevant variants is paramount. METHODS: The Deciphering Developmental Disorders (DDD) study has developed a UK-wide patient recruitment network involving over 180 clinicians across all 24 regional genetics services, and has performed genome-wide microarray and whole exome sequencing on children with undiagnosed developmental disorders and their parents. After data analysis, pertinent genomic variants were returned to individual research participants via their local clinical genetics team. FINDINGS: Around 80,000 genomic variants were identified from exome sequencing and microarray analysis in each individual, of which on average 400 were rare and predicted to be protein altering. By focusing only on de novo and segregating variants in known developmental disorder genes, we achieved a diagnostic yield of 27% among 1133 previously investigated yet undiagnosed children with developmental disorders, whilst minimising incidental findings. In families with developmentally normal parents, whole exome sequencing of the child and both parents resulted in a 10-fold reduction in the number of potential causal variants that needed clinical evaluation compared to sequencing only the child. Most diagnostic variants identified in known genes were novel and not present in current databases of known disease variation. INTERPRETATION: Implementation of a robust translational genomics workflow is achievable within a large-scale rare disease research study to allow feedback of potentially diagnostic findings to clinicians and research participants. Systematic recording of relevant clinical data, curation of a gene-phenotype knowledge base, and development of clinical decision support software are needed in addition to automated exclusion of almost all variants, which is crucial for scalable prioritisation and review of possible diagnostic variants. However, the resource requirements of development and maintenance of a clinical reporting system within a research setting are substantial. FUNDING: Health Innovation Challenge Fund, a parallel funding partnership between the Wellcome Trust and the UK Department of Health.

DECIPHER: database for the interpretation of phenotype-linked plausibly pathogenic sequence and copy-number variation.

The DECIPHER database (https://decipher.sanger.ac.uk/) is an accessible online repository of genetic variation with associated phenotypes that facilitates the identification and interpretation of pathogenic genetic variation in patients with rare disorders. Contributing to DECIPHER is an international consortium of >200 academic clinical centres of genetic medicine and ≥1600 clinical geneticists and diagnostic laboratory scientists. Information integrated from a variety of bioinformatics resources, coupled with visualization tools, provides a comprehensive set of tools to identify other patients with similar genotype-phenotype characteristics and highlights potentially pathogenic genes. In a significant development, we have extended DECIPHER from a database of just copy-number variants to allow upload, annotation and analysis of sequence variants such as single nucleotide variants (SNVs) and InDels. Other notable developments in DECIPHER include a purpose-built, customizable and interactive genome browser to aid combined visualization and interpretation of sequence and copy-number variation against informative datasets of pathogenic and population variation. We have also introduced several new features to our deposition and analysis interface. This article provides an update to the DECIPHER database, an earlier instance of which has been described elsewhere [Swaminathan et al. (2012) DECIPHER: web-based, community resource for clinical interpretation of rare variants in developmental disorders. Hum. Mol. Genet., 21, R37-R44].

First Observation of CP Violation in B[over ¯]

We report a measurement of the time-dependent CP asymmetry of B[over ¯]^{0}→D_{CP}^{(*)}h^{0} decays, where the light neutral hadron h^{0} is a π^{0}, η, or ω meson, and the neutral D meson is reconstructed in the CP eigenstates K^{+}K^{-}, K_{S}^{0}π^{0}, or K_{S}^{0}ω. The measurement is performed combining the final data samples collected at the ϒ(4S) resonance by the BABAR and Belle experiments at the asymmetric-energy B factories PEP-II at SLAC and KEKB at KEK, respectively. The data samples contain (471±3)×10^{6} BB[over ¯] pairs recorded by the BABAR detector and (772±11)×10^{6} BB[over ¯] pairs recorded by the Belle detector. We measure the CP asymmetry parameters -η_{f}S=+0.66±0.10(stat)±0.06(syst) and C=-0.02±0.07(stat)±0.03(syst). These results correspond to the first observation of CP violation in B[over ¯]^{0}→D_{CP}^{(*)}h^{0} decays. The hypothesis of no mixing-induced CP violation is excluded in these decays at the level of 5.4 standard deviations.

DECIPHER: web-based, community resource for clinical interpretation of rare variants in developmental disorders.

Patients with developmental disorders often harbour sub-microscopic deletions or duplications that lead to a disruption of normal gene expression or perturbation in the copy number of dosage-sensitive genes. Clinical interpretation for such patients in isolation is hindered by the rarity and novelty of such disorders. The DECIPHER project (https://decipher.sanger.ac.uk) was established in 2004 as an accessible online repository of genomic and associated phenotypic data with the primary goal of aiding the clinical interpretation of rare copy-number variants (CNVs). DECIPHER integrates information from a variety of bioinformatics resources and uses visualization tools to identify potential disease genes within a CNV. A two-tier access system permits clinicians and clinical scientists to maintain confidential linked anonymous records of phenotypes and CNVs for their patients that, with informed consent, can subsequently be shared with the wider clinical genetics and research communities. Advances in next-generation sequencing technologies are making it practical and affordable to sequence the whole exome/genome of patients who display features suggestive of a genetic disorder. This approach enables the identification of smaller intragenic mutations including single-nucleotide variants that are not accessible even with high-resolution genomic array analysis. This article briefly summarizes the current status and achievements of the DECIPHER project and looks ahead to the opportunities and challenges of jointly analysing structural and sequence variation in the human genome.

Expanded statistical analysis of squats on the Great Britain (GB) mainline network.

Squat defects are one of the most common rail surface defects. Significant research effort has gone into understand squat defects over the last 10 years which has brought about important developments in the understanding of their initiation mechanism; however, further work is still required to fully understand squat and the best methods to control them. This study considers records of squat defects over a period 9 years, considering 2600 km of track across 8 different routes on the GB mainline network. The analysis separately reviews squats on: plainline, crossings, joints and welds. Results include an overview of the main factors influencing the development of each type of squats, practical methods to immediately reduce and manage squat defects and recommends focus areas for further research to understand squat defects. Results suggest that squats on plainline, crossings, joints and welds, all correlate with different influencing factors; headcheck defects appear to significantly influence the probability of squats and how other factors influence squat development. There is a strong connection between total head wear rate (combined material removal due to traffic and grinding) and squats; 90 % of all squats appear on rail with a headwear rate of <0.2 mm/year. Overall larger section rail (60 kg/m vs 56 kg/m) and harder material (260 Brinell vs 220 Brinell) is significantly less susceptible to squat damage. Track curvature has an influence of squat development, especially in rail with no headcheck cracking, where the tightest curves are significantly more likely to sustain squat damage. The probability of squat at vertical discontinuities, i.e. joints and crossings are significantly more likely as train speed increases. Whilst squats on joints are 1000 time more likely than squats on welds.

DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources.

Many patients suffering from developmental disorders harbor submicroscopic deletions or duplications that, by affecting the copy number of dosage-sensitive genes or disrupting normal gene expression, lead to disease. However, many aberrations are novel or extremely rare, making clinical interpretation problematic and genotype-phenotype correlations uncertain. Identification of patients sharing a genomic rearrangement and having phenotypic features in common leads to greater certainty in the pathogenic nature of the rearrangement and enables new syndromes to be defined. To facilitate the analysis of these rare events, we have developed an interactive web-based database called DECIPHER (Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources) which incorporates a suite of tools designed to aid the interpretation of submicroscopic chromosomal imbalance, inversions, and translocations. DECIPHER catalogs common copy-number changes in normal populations and thus, by exclusion, enables changes that are novel and potentially pathogenic to be identified. DECIPHER enhances genetic counseling by retrieving relevant information from a variety of bioinformatics resources. Known and predicted genes within an aberration are listed in the DECIPHER patient report, and genes of recognized clinical importance are highlighted and prioritized. DECIPHER enables clinical scientists worldwide to maintain records of phenotype and chromosome rearrangement for their patients and, with informed consent, share this information with the wider clinical research community through display in the genome browser Ensembl. By sharing cases worldwide, clusters of rare cases having phenotype and structural rearrangement in common can be identified, leading to the delineation of new syndromes and furthering understanding of gene function.

Modifiable reporting unit problems and time series of long-term human activity.

This paper responds to a resurgence of interest in constructing long-term time proxies of human activity, especially but not limited to models of population change over the Pleistocene and/or Holocene. While very much agreeing with the need for this increased attention, we emphasize three important issues that can all be thought of as modifiable reporting unit problems: the impact of (i) archaeological periodization, (ii) uneven event durations and (iii) geographical nucleation-dispersal phenomena. Drawing inspiration from real-world examples from prehistoric Britain, Greece and Japan, we explore their consequences and possible mitigation via a reproducible set of tactical simulations. This article is part of the theme issue 'Cross-disciplinary approaches to prehistoric demography'.

The Management Standards Indicator Tool and the estimation of risk.

BACKGROUND: The Health & Safety Executive's (HSE) Indicator Tool offers a measure of exposure to psychosocial work conditions that may be linked to stress-related outcomes. The HSE recommends that Indicator Tool data should be used as a basis for discussions concerned with the identification of psychosocial work conditions that might warrant prioritization for intervention. However, operational constraints may render discussions difficult to convene and, when they do take place, the absence of information on harms associated with exposures can make it difficult to identify intervention priorities. AIMS: To examine (i) the utility of the Indicator Tool for the identification of a manageable number of psychosocial work conditions as intervention candidates and (ii) whether administration of a measure of stress-related outcomes alongside the Indicator Tool can facilitate the identification of intervention priorities. METHODS: One thousand and thirty-eight employees in the London region of the Her Majesty's Prison Service completed the Indicator Tool and a measure of psychological well-being. Odds ratios were calculated to estimate the risk of impairment to well-being associated with exposure to psychosocial work conditions. RESULTS: The Indicator Tool identified 34 psychosocial work conditions as warranting improvement. Intervention priority was given to those working conditions that were both reported to be poor by ≥50% of respondents and associated with risk of impairment to well-being. This method allowed for the identification of four areas. CONCLUSIONS: Augmentation of the Indicator Tool with a measure of stress-related outcomes and the calculation of simple risk estimation statistics can assist the prioritization of intervention candidates.

One-step site-directed mutagenesis of the Kex2 protease oxyanion hole.

BACKGROUND: Members of the subtilisin family of serine proteases usually have a conserved asparagine residue that stabilizes the oxyanion transition state of peptide-bond hydrolysis. Yeast Kex2 protease is a member of the subtilisin family that differs from the degradative subtilisin proteases in its high substrate specificity, it processes pro-alpha-factor, the precursor of the alpha-factor mating pheromone of yeast, and also removes the pro-peptide from its own precursor by an intramolecular cleavage reaction. Curiously, the mammalian protease PC2, a Kex2 homolog that is likely to be required for pro-insulin processing, has an aspartate in place of asparagine at the 'oxyanion hole'. RESULTS: We have tested the effect of making substitutions of the conserved oxyanion-hole asparagine (Asn 314) of the Kex2 protease. To do this, we have developed a rapid method of site-directed mutagenesis, involving homologous recombination of a polymerase chain reaction product in yeast. Using this method, we have substituted alanine or aspartate for Asn 314 in a form of Kex2 engineered for secretion. Transformants expressing the two mutant enzymes could be identified by failure either to produce mature alpha-factor or to mate. The Ala 314 enzyme was unstable but the Asp 314 enzyme accumulated to a high level, so that it could be purified and its activity towards various substrates tested in vitro. We found that, with three peptides that are good substrates of wild-type Kex2, the k(cal) of the Asp 314 enzyme was reduced approximately 4500-fold and its K(M) approximately 4-fold, relative to the wild-type enzyme. For the peptide substrate corresponding to the cleavage site of pro-alpha-factor, however, k(cat) of the Asp 314 enzyme was reduced only 125-fold, while the K(m) was increased 3-fold. Despite its reduced catalytic activity, however, processing of the mutant enzyme in vivo - by the intramolecular cleavage that removes its amino-terminal pro-domain - occurs at an unchanged rate. CONCLUSIONS: The effects of the Asn 314-Asp substitution reveal contributions to the reaction specificity of the Kex2 protease of substrate residues amino-terminal to the pair of basic residues at the cleavage site. Aspartate at the oxyanion hole appears to confer k(caf) discrimination between substrates by raising the energy barrier for productive substrate binding: this may have implications for pro-insulin processing by the PC2 protease, which has an aspartate at the equivalent position. The rate of intramolecular cleavage of pro-Kex2 may be limited by a step other than catalysis, presumably protein folding.

Cvt18/Gsa12 is required for cytoplasm-to-vacuole transport, pexophagy, and autophagy in Saccharomyces cerevisiae and Pichia pastoris.

Eukaryotic cells have the ability to degrade proteins and organelles by selective and nonselective modes of micro- and macroautophagy. In addition, there exist both constitutive and regulated forms of autophagy. For example, pexophagy is a selective process for the regulated degradation of peroxisomes by autophagy. Our studies have shown that the differing pathways of autophagy have many molecular events in common. In this article, we have identified a new member in the family of autophagy genes. GSA12 in Pichia pastoris and its Saccharomyces cerevisiae counterpart, CVT18, encode a soluble protein with two WD40 domains. We have shown that these proteins are required for pexophagy and autophagy in P. pastoris and the Cvt pathway, autophagy, and pexophagy in S. cerevisiae. In P. pastoris, Gsa12 appears to be required for an early event in pexophagy. That is, the involution of the vacuole or extension of vacuole arms to engulf the peroxisomes does not occur in the gsa12 mutant. Consistent with its role in vacuole engulfment, we have found that this cytosolic protein is also localized to the vacuole surface. Similarly, Cvt18 displays a subcellular localization that distinguishes it from the characterized proteins required for cytoplasm-to-vacuole delivery pathways.

The Body Mass Index of Adolescents Attending Seventh-Day Adventist Schools in Australia: 2001-2012.

BACKGROUND: We examined the body mass index (BMI) of students attending Seventh-day Adventist (Adventist) schools in Australia in 2001 and 2012. METHODS: A total of 3069 students attending Adventist schools in Australia responded to a health and lifestyle survey in 2001 (N = 1335) and 2012 (N = 1734). The survey captured self-reported height and weight, demographics (age, sex, year level, religion), and select health behaviors. RESULTS: Compared with national norms, lower rates of overweight and obesity were observed in the study cohort, but higher rates of underweight. There was no change in the mean BMI of the students attending Adventist schools in Australia from 2001 to 2012. Regression analyses indicated that a lower BMI was associated with age, sex, more regularly eating breakfast, consuming less soft drink, and having a regular exercise program. The students reported a high consumption of fruits, vegetables, and whole grains compared with Australian national norms, and 29% claimed to be vegetarian. CONCLUSIONS: Students attending Adventist schools appear to have a lower prevalence of overweight and obesity than the secular population, but a higher prevalence of underweight. The mechanisms through which Adventist schools may influence student's BMI warrants further investigation.

Hypoglycemic effects of peroxovanadium compounds in Sprague-Dawley and diabetic BB rats.

Highly purified peroxovanadium (pV) compounds, each containing an oxo ligand, one or two peroxo anions, and an ancillary ligand in the inner coordination sphere of vanadium, were shown to decrease plasma glucose markedly in both normal Sprague-Dawley and insulin-deprived diabetic BB rats. Maximal decreases in plasma glucose were at 60-100 min after intravenous, intraperitoneal, or subcutaneous administration. Synergism between these compounds and insulin was observed. Whereas parenterally administered orthovanadate or vanadyl sulfate did not induce hypoglycemia before inducing acute mortality, pV compounds effected hypoglycemia at doses much lower than those inducing acute mortality. When administered subcutaneously over a period of 3 days to insulin-deprived diabetic BB rats, pV compounds, but not vanadate, caused a significant decrease in plasma glucose concentrations and prevented the appearance of ketosis in these animals. Thus, pV compounds are the first agents other than insulin that acutely and markedly reduce plasma glucose in hypoinsulinemic diabetic BB rats.

Intracellular signal transduction: The role of endosomes.

Polypeptide hormones, growth factors, and other biologically significant molecules are specifically internalized by target cells. Exposure of cells to these ligands results in the formation of ligand-receptor complexes on the cell surface and subsequent internalization of these complexes into the endosomal apparatus (endosomes, or ENs). The study of ENs has identified several important functions for this unique cellular organelle. These include the dissociation of ligand from receptor and receptor recycling to the cell surface and the degradation of some internalized ligands, as well as the delivery of others to lysosomes. More recently, it has become apparent that ENs fulfill another critical role, that of signal transduction. In this article, we review the evidence substantiating this role for ENs and propose three models by which ENs participate in cell signaling.

A role for tyrosine phosphorylation in both activation and inhibition of the insulin receptor tyrosine kinase in vivo.

Upon insulin binding, a conformational change in the insulin receptor (IR) leads to IR beta-subunit autophosphorylation, an increase in IR beta-subunit exogenous tyrosine kinase activity, and the rapid endocytosis of the ligand-receptor complex into endosomes. Previous work has shown that upon internalization, rat hepatic endosomal IRs manifest increased autophosphorylating and exogenous tyrosine kinase activity compared to IRs located at the plasma membrane. As this period of enhanced activity is associated with reduced endosomal IR beta-subunit phosphotyrosine content, it has been proposed that partial dephosphorylation of the internalized IR beta-subunit by an endosomally located phosphotyrosine phosphatase(s) [PTPase(s)] mediates this effect. To test whether endosomal PTPase activity was required for internalization-dependent augmentation of IR tyrosine kinase activity, the present study used the peroxovanadium PTPase inhibitor, bisperoxo(1,10-phenanthroline)oxovanadate anion [bpV(phen)], to block IR dephosphorylation within this subcellular compartment. Rats were pretreated with bpV(phen) before receiving insulin (1.5 micrograms/100 g BW). bpV(phen) inhibited the dephosphorylation of 32P-labeled hepatic endosomal IR by approximately 97% at 15 min post-bpV(phen) injection and prevented a decrease in IR beta-subunit phosphotyrosine content after IR internalization. Fifteen-minute bpV(phen) pretreatment produced a significant reduction (75%; P < 0.001) in maximal insulin-stimulated endosomal IR exogenous kinase activity and decreased IR autophosphorylating activity by 4.3-fold in this subcellular fraction. In conclusion, these findings suggest that an hepatic endosomal PTPase(s) regulates internalization-dependent increases in IR exogenous tyrosine kinase activity.