Indirect induction of radiation lymphomas in mice. Evidence for a novel, transmissible leukemogen.

The transmission of a lymphomagenic agent(s) from the bone marrow of irradiated mice to thymic target cells has been demonstrated by: (a) the induction of T cell lymphomas in nonirradiated thymic grafts implanted in irradiated, Thy-l-congenic mice, (b) the induction of T cell lymphomas of host origin in mice infused with bone marrow from irradiated, Thy-l-congenic donors. The latter procedure also yields an appreciable number of pre-B cell lymphomas of uncertain origin. The results confirm Kaplan's theory that radiation induces thymic lymphomas in mice by an indirect mechanism. However, the previously described radiation leukemia virus is clearly not involved in the majority of transferred lymphomas. We propose that the mediating agent in radiation lymphomagenesis is a novel, transmissible agent induced in the bone marrow, but exerting its transforming activity on cells in the thymus. The nature and mode of action of the agent are under investigation

Ubiquitin charging of human class III ubiquitin-conjugating enzymes triggers their nuclear import

Ubiquitin is a small polypeptide that is conjugated to proteins and commonly serves as a degradation signal. The attachment of ubiquitin (Ub) to a substrate proceeds through a multi-enzyme cascade involving an activating enzyme (E1), a conjugating enzyme (E2), and a protein ligase (E3). We previously demonstrated that a murine E2, UbcM2, is imported into nuclei by the transport receptor importin-11. We now show that the import mechanism for UbcM2 and two other human class III E2s (UbcH6 and UBE2E2) uniquely requires the covalent attachment of Ub to the active site cysteine of these enzymes. This coupling of E2 activation and transport arises from the selective interaction of importin-11 with the Ub-loaded forms of these enzymes. Together, these findings reveal that Ub charging can function as a nuclear import trigger, and identify a novel link between E2 regulation and karyopherin-mediated transport

Antibiotic prophylaxis is associated with subsequent resistant infections in children with an initial extended-spectrum-cephalosporin-resistant Enterobacteriaceae infection

ABSTRACT The objective of this study was to assess the association between previous antibiotic use, particularly long-term prophylaxis, and the occurrence of subsequent resistant infections in children with index infections due to extended-spectrum-cephalosporin-resistant Enterobacteriaceae . We also investigated the concordance of the index and subsequent isolates. Extended-spectrum-cephalosporin-resistant Escherichia coli and Klebsiella spp. isolated from normally sterile sites of patients aged &lt;22 years were collected along with associated clinical data from four freestanding pediatric centers. Subsequent isolates were categorized as concordant if the species, resistance determinants, and fumC-fimH ( E. coli ) or tonB ( Klebsiella pneumoniae ) type were identical to those of the index isolate. In total, 323 patients had 396 resistant isolates; 45 (14%) patients had ≥1 subsequent resistant infection, totaling 73 subsequent resistant isolates. The median time between the index and first subsequent infections was 123 (interquartile range, 43 to 225) days. In multivariable Cox proportional hazards analyses, patients were 2.07 times as likely to have a subsequent resistant infection (95% confidence interval, 1.11 to 3.87) if they received prophylaxis in the 30 days prior to the index infection. In 26 (58%) patients, all subsequent isolates were concordant with their index isolate, and 7 (16%) additional patients had at least 1 concordant subsequent isolate. In 12 of 17 (71%) patients with E. coli sequence type 131 (ST131)-associated type 40-30, all subsequent isolates were concordant. Subsequent extended-spectrum-cephalosporin-resistant infections are relatively frequent and are most commonly due to bacterial strains concordant with the index isolate. Further study is needed to assess the role prophylaxis plays in these resistant infections. </jats:p

Stellar 36,38^{36,38}Ar(n,γ)37,39(n,\gamma)^{37,39}Ar reactions and their effect on light neutron-rich nuclide synthesis

The $^{36}$Ar$(n,\gamma)^{37}$Ar ($t_{1/2}$ = 35 d) and $^{38}$Ar$(n,\gamma)^{39}$Ar (269 y) reactions were studied for the first time with a quasi-Maxwellian ($kT \sim 47$ keV) neutron flux for Maxwellian Average Cross Section (MACS) measurements at stellar energies. Gas samples were irradiated at the high-intensity Soreq applied research accelerator facility-liquid-lithium target neutron source and the $^{37}$Ar/$^{36}$Ar and $^{39}$Ar/$^{38}$Ar ratios in the activated samples were determined by accelerator mass spectrometry at the ATLAS facility (Argonne National Laboratory). The $^{37}$Ar activity was also measured by low-level counting at the University of Bern. Experimental MACS of $^{36}$Ar and $^{38}$Ar, corrected to the standard 30 keV thermal energy, are 1.9(3) mb and 1.3(2) mb, respectively, differing from the theoretical and evaluated values published to date by up to an order of magnitude. The neutron capture cross sections of $^{36,38}$Ar are relevant to the stellar nucleosynthesis of light neutron-rich nuclides; the two experimental values are shown to affect the calculated mass fraction of nuclides in the region A=36-48 during the weak $s$-process. The new production cross sections have implications also for the use of $^{37}$Ar and $^{39}$Ar as environmental tracers in the atmosphere and hydrosphere.Comment: 18 pages + Supp. Mat. (13 pages) Accepted for publication in Phys. Rev. Let

Meeting Report: Mode(s) of Action of Asbestos and Related Mineral Fibers

Background: Although asbestos in general is well known to cause a range of neoplastic and non-neoplastic human health effects, not all asbestos fiber types have the same disease-causing potential, and the mode of action (MOA) of specific types of asbestos and related fibers for various health outcomes are not well understood

Utilization of ACP CPT codes among high-need Medicare beneficiaries in 2017: A brief report

IMPORTANCE: Medicare beneficiaries with high medical needs can benefit from Advance Care Planning (ACP). Medicare reimburses clinical providers for ACP discussions, but it is unknown whether high-need beneficiaries are receiving this service. OBJECTIVE: To compare rates of billed ACP discussions among a cohort of high-need Medicare beneficiaries with the non-high-needs Medicare population. DESIGN: Retrospective analysis of Medicare Fee-for-Service (FFS) claims in 2017 comparing high-need beneficiaries (seriously ill, frail, ESRD, and disabled) with non-high need beneficiaries. SETTING: Nationally representative FFS Medicare 20% sample. PARTICIPANTS: Medicare beneficiaries were assigned to one of the following classifications: seriously ill (65+), frail (65+), seriously ill and frail (65+); non-high need (65+); end stage renal disease (ESRD) or disabled ( \u3c 65). All participants had data available for years 2016-2017. EXPOSURE: Receipt of a billed ACP discussion, CPT codes 99497 or 99498. MAIN OUTCOME AND MEASURE: Rates of billed ACP visits were compared between high-need patients and non-high-need patients. Rates were adjusted for the 65+ population for sex, age, race/ethnicity, Charlson comorbidity index, Medicare/Medicaid dual eligibility status, and Hospital Referral Region. RESULTS: Among the 65+ groups, those most likely to have a billed ACP discussion included seriously ill and frail (5.2%), seriously ill (4.2%), and frail (3.3%). Rates remained consistent after adjusting (4.5%, 4.0%, 3.1%, respectively). Each subgroup differed significantly (p \u3c .05) from non-high need beneficiaries (2.3%) in both unadjusted and adjusted analyses. Among the \u3c 65 high need groups, the rates were 2.7% for ESRD and 1.3% for the disabled (the latter p \u3c .05 compared with non-high needs). CONCLUSIONS AND RELEVANCE: While rates of billed ACP discussions varied among patient groups with high medical needs, overall they were relatively low, even among a cohort of patients for whom ACP may be especially relevant

Functional Amyloid Formation within Mammalian Tissue

Amyloid is a generally insoluble, fibrous cross-β sheet protein aggregate. The process of amyloidogenesis is associated with a variety of neurodegenerative diseases including Alzheimer, Parkinson, and Huntington disease. We report the discovery of an unprecedented functional mammalian amyloid structure generated by the protein Pmel17. This discovery demonstrates that amyloid is a fundamental nonpathological protein fold utilized by organisms from bacteria to humans. We have found that Pmel17 amyloid templates and accelerates the covalent polymerization of reactive small molecules into melanin—a critically important biopolymer that protects against a broad range of cytotoxic insults including UV and oxidative damage. Pmel17 amyloid also appears to play a role in mitigating the toxicity associated with melanin formation by sequestering and minimizing diffusion of highly reactive, toxic melanin precursors out of the melanosome. Intracellular Pmel17 amyloidogenesis is carefully orchestrated by the secretory pathway, utilizing membrane sequestration and proteolytic steps to protect the cell from amyloid and amyloidogenic intermediates that can be toxic. While functional and pathological amyloid share similar structural features, critical differences in packaging and kinetics of assembly enable the usage of Pmel17 amyloid for normal function. The discovery of native Pmel17 amyloid in mammals provides key insight into the molecular basis of both melanin formation and amyloid pathology, and demonstrates that native amyloid (amyloidin) may be an ancient, evolutionarily conserved protein quaternary structure underpinning diverse pathways contributing to normal cell and tissue physiology

Can obsessions drive you mad? Longitudinal evidence that obsessive-compulsive symptoms worsen the outcome of early psychotic experiences

Although there is substantial comorbidity between psychotic disorder and obsessive-compulsive disorder (OCD), little is known about how these clinical phenotypes, and their subclinical extended phenotypes, covary and impact on each other over time. This study examined cross-sectional and longitudinal associations between both (extended) phenotypes in the general population.status: publishe