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This study examines patterns of and explanations for racial/ethnic-education disparities in infant mortality in the United States. Using linked birth and death data (2007-2010), we find that while education-specific infant mortality rates are similar for Mexican Americans and Whites, infants of college-educated African American women experience 3.1 more deaths per 1,000 live births (Rate Ratio = 1.46) than infants of White women with a high school degree or less. The high mortality rates among infants born to African American women of all educational attainment levels are fully accounted for by shorter gestational lengths. Supplementary analyses of data from the National Longitudinal Study of Adolescent to Adult Health show that college-educated African American women exhibit similar socioeconomic, contextual, psychosocial, and health disadvantages as White women with a high school degree or less. Together, these results demonstrate African American-White infant mortality and socioeconomic, health, and contextual disparities within education levels, suggesting the role of life course socioeconomic disadvantage and stress processes in the poorer infant health outcomes of African Americans relative to Whites.

Background: Prior weathering research finds that US-born Black women experience more rapidly deteriorating birthweight outcomes at older ages than US-born White women. Objective: The present study extends this literature by evaluating maternal age–birthweight associations across a variety of racial/ethnic-nativity groups. Methods: Race/ethnicity-nativity stratified average marginal effects of maternal age on low and very low birthweight are estimated using data from 2014 through 2018 US cohort natality files. Results: Older maternal ages at birth are associated with higher probabilities of low and very low birthweight for most racial/ethnic-nativity groups. Consistent with the weathering hypothesis, birth at older maternal ages (e.g., 30‒34 or 40+) is more predictive of low and very low birthweight for US-born Black, American Indian/Alaskan Native, and US-born Mexican American women than for US-born Whites. In contrast, some foreign-born populations exhibit relatively weak relationships between maternal age and low birthweight, suggesting the role of healthy immigrant selection. Contribution: Some disadvantaged racial/ethnic-nativity groups ‒ US-born Black, American Indian/Alaskan Native, and US-born Mexican American women ‒ exhibit more rapid increases in the risk of low birthweight at older maternal ages than US-born White women. These patterns are consistent with the weathering hypothesis. Future research may benefit from using linked family data and sibling modeling approaches to estimate causal models of weathering.

Recent qualitative research argues that Asian Americans’ educational attainments are not predicated on their parents’ education, diverging from status attainment theory. Using data from two nationa...

Background Temozolomide (TMZ) is the standard of care chemotherapy for newly diagnosed glioblastoma (ndGBM), the most common primary malignant brain tumor in adults. However, 50% of patients do not respond to TMZ due to expression of O6-methylguanine-DNA methyltransferase (MGMT), the enzyme involved in repair of TMZ-induced damage. Tumor Treating Fields (TTFields) are alternating electric fields that display anti-mitotic effects on cancerous cells, and have been shown to induce a state of BRCAness in various cancer types. Concurrent treatment with TMZ and TTFields demonstrated a major advance in treatment of patients with ndGBM, and was approved by the FDA in 2014. Recently, the addition of lomustine (CCNU) to TMZ demonstrated clinical benefit in ndGBM patients, with improved overall and progression free survival. The aim of the current study was to examine in GBM cells the effect of TTFields in conjunction with TMZ and CCNU. Materials and Methods U-87 MG, LN229, U118 and LN18 human GBM cell lines were tested for their MGMT expression levels, and treated with TTFields (200 kHz, of 0.83 V/cm RMS) for 72 h using the inovitro system. Efficacy of concomitant application of TTFields with TMZ and/or CCNU was tested by measuring cell count, colony formation, and apoptosis levels. Results U-87 MG and LN229 displayed no expression of MGMT, while U118 and LN18 expressed low and high levels of MGMT, respectively. Application of TMZ and TTFields resulted in increased cytotoxicity compared with each treatment alone, with an additive interaction seen in all examined cell lines. The cytotoxic effect resulting from co-application of CCNU with TTFields suggested a synergistic interaction between the two modalities for U-87 MG, LN229, and U118, an additivity for LN18. Concurrent TTFields/TMZ/CCNU was more efficacious than TTFields or TMZ/CCNU separately in all cell lines. Conclusions Application of TTFields with TMZ was additive, irrespective of MGMT expression levels, while TTFields with CCNU was additive when MGMT was plentiful, but displayed tendency to synergism when MGMT was absent or limited. These outcomes are in line with the BRCAness state induced by TTFields, as in the absence of MGMT, DNA damage induced by CCNU requires the BRCA pathway for repair. Application of TTFields together with TMZ and CCNU demonstrated increased efficacy, suggesting potential benefit of such therapy for ndGBM treatment.

A growing line of research underscores that sociodemographic factors may contribute to disparities in the impact of COVID-19. Further, stages of disease theory suggests that disparities may grow as the pandemic unfolds and more advantaged areas are better able to apply growing knowledge and mitigation strategies. In this paper, we focus on the role of county-level household overcrowding on disparities in COVID-19 mortality in U.S. counties. We examine this relationship across three theoretically important periods of the pandemic from April–October 2020, that mark both separate stages of community knowledge and national mortality levels. We find evidence that the percentage of overcrowded households is a stronger predictor of COVID-19 mortality during later periods of the pandemic. Moreover, despite a relationship between overcrowding and poverty at the county-level, overcrowding plays an independent role in predicting COVID-19 mortality. Our findings underscore that areas disadvantaged by overcrowding may be more vulnerable to the effects of COVID-19 and that this vulnerability may lead to changing disparities over time., Highlights • County-level overcrowding is positively associated with COVID-19 mortality rates. • The overcrowding-mortality relationship is strongest during June and July. • Overcrowding and poverty additively shape county-level COVID-19 mortality. • Social disparities in mortality may change with new knowledge and disease spread. • Policies must consider how social disadvantages shape COVID-19 mortality over time.

Background: Recent studies of US adult mortality demonstrate a growing disadvantage among southern states. Few studies have examined long-term trends and geographic patterns in US early life (ages 1 to 24) mortality, ages at which key risk factors and causes of death are quite different than among adults. Objective: This article examines trends and variations in early life mortality rates across US states and census divisions. We assess whether those variations have changed over a 50-year time period and which causes of death contribute to contemporary geographic disparities. Methods: We calculate all-cause and cause-specific death rates using death certificate data from the Multiple Cause of Death files, combining public-use files from 1965‒2004 and restricted data with state geographic identifiers from 2005‒2014. State population (denominator) data come from US decennial censuses or intercensal estimates. Results: Results demonstrate a persistent mortality disadvantage for young people (ages 1 to 24) living in southern states over the last 50 years, particularly those located in the East South Central and West South Central divisions. Motor vehicle accidents and homicide by firearm account for most of the contemporary southern disadvantage in US early life mortality. Contribution: Our results illustrate that US children and youth living in the southern United States have long suffered from higher levels of mortality than children and youth living in other parts of the country. Our findings also suggest the contemporary southern disadvantage in US early life mortality could potentially be reduced with state-level policies designed to prevent deaths involving motor vehicles and firearms.

The Hispanic Paradox in birth outcomes is well documented for the US as a whole, but little work has considered geographic variation underlying the national pattern. This inquiry is important given the rapid growth of the Hispanic population and its geographic dispersion. Using birth records data from 2014 through 2016, we document state variation in birthweight differentials between US-born white women and the three Hispanic populations with the largest numbers of births: US-born Mexican women, foreign-born Mexican women, and foreign-born Central and South American women. Our analyses reveal substantial geographic variation in Hispanic immigrant-white low birthweight disparities. For example, Hispanic immigrants in Southeastern states and in some states from other regions have reduced risk of low birthweight relative to whites, consistent with a "Hispanic Paradox." A significant portion of Hispanic immigrants' birthweight advantage in these states is explained by lower rates of smoking relative to whites. However, Hispanic immigrants have higher rates of low birthweight in California and several other Western states. The different state patterns are largely driven by geographic variation in smoking among whites, rather than geographic differences in Hispanic immigrants' birthweights. In contrast, US-born Mexicans generally have similar or slightly higher odds of low birthweight than whites across the US. Overall, we show that the Hispanic Paradox in birthweight varies quite dramatically by state, driven by geographic variation in low birthweight among whites associated with white smoking disparities across states.

Although much literature examines racial/ethnic variation in college attendance, comparable research on the prestige of colleges attended is quite limited. Of particular interest are the colleges attended by Asian and Hispanic Americans, two populations with varied education outcomes across ethnicity and nativity. The analysis draws on a diverse sample from the National Longitudinal Study of Adolescent to Adult Health to estimate OLS and Heckman selection models of prestige of the bachelor's institution attended among current college enrollees (Wave III) and graduates (Wave IV). Across all model specifications Chinese Americans tend to enroll and graduate from more prestigious colleges than Whites and most other racial/ethnic-nativity groups in the analysis. In contrast, economic disadvantage accounts for Mexican Americans' enrollment at less prestigious colleges than Whites. These findings suggest the important role of college prestige in stratification, especially for specific Asian American populations.

Stratification research in the status attainment tradition contends that adolescent educational expectations are a central determinant of educational attainment. Little research, however, has assessed the robustness of the powerful expectations-attainment associations revealed in cross-sectional models. Using data from the National Longitudinal Study of Adolescent to Adult Health to estimate OLS, school fixed effects, and sibling fixed effects models, this study examines the association between adolescent expectations and educational attainment. The analysis reveals that adolescent expectations may play a much smaller role in predicting educational attainment than revealed in cross-sectional models. Point estimates of the association between adolescent expectations and educational attainment from sibling fixed effects models are over 50 percent lower than OLS estimates, suggesting that family-level characteristics confound this relationship. Results from these analyses demonstrate that respondents’ educational expectations likely exert less influence on educational attainment than status attainment research would suggest.

Utilizing data from the National Longitudinal Study of Adolescent to Adult Health (Add Health), the current study examines which maternal age at birth provides offspring with optimal opportunities for higher educational attainment. The results show that maternal age has a curvilinear relationship with offspring's educational attainment, i.e., the offspring of younger and older mothers are distinctly disadvantaged. Maternal ages 31 through 40 are associated with the highest offspring educational attainment, suggesting that women who give birth in their 30s have more favorable characteristics than younger or older mothers. The analysis demonstrates that-with the exception of early teenage childbearing-the association between maternal age and offspring's educational attainment likely reflects selection patterns in fertility timing, rather than direct within-family effects of maternal age on offspring's educational attainment. Thus, the results provide insufficient evidence to conclude that delaying childbearing beyond age 18 directly benefits or harms offspring's educational attainment.

β-Adrenergic receptors (βAR) and D(2)-like dopamine receptors (which include D(2)-, D(3)- and D(4)-dopamine receptors) activate G(s) and G(i), the stimulatory and inhibitory heterotrimeric G proteins, respectively, which in turn regulate the activity of adenylyl cyclase (AC). β(2)-Adrenergic receptors (β(2)AR) and D(4)-dopamine receptors (D(4)DR) co-immunoprecipitated when co-expressed in HEK 293 cells, suggesting the existence of a signaling complex containing both receptors. In order to determine if these receptors are closely associated with each other, and with other components involved in G protein-mediated signal transduction, β(2)AR, D(4)DR, G protein subunits (Gα(i1) and the Gβ(1)γ(2) heterodimer) and AC were tagged so that bioluminescence resonance energy transfer (BRET) could be used to monitor their interactions. All of the tagged proteins retained biological function. For the first time, FlAsH-labeled proteins were used in BRET experiments as fluorescent acceptors for the energy transferred from Renilla luciferase-tagged donor proteins. Our experiments revealed that β(2)AR, D(4)DR, G proteins and AC were closely associated in a functional signaling complex in cellulo. Furthermore, BRET experiments indicated that although activation of G(i) caused a conformational change within the heterotrimeric protein, it did not cause the Gβγ heterodimer to dissociate from the Gα(i1) subunit. Evidence for the presence of a signaling complex in vivo was obtained by purifying βAR from detergent extracts of mouse brain with alprenolol-Sepharose and showing that the precipitate also contained both D(2)-like dopamine receptors and AC.

Binding of tetanus toxin to rat brain membranes was of lower affinity and capacity when binding was determined in 150 mM NaCl, 50 mM Tris-HCl (pH 7.4) than in 25 mM Tris-acetate (pH 6.0). Binding under both conditions was reduced by treating the membranes with neuraminidase. Pronase treatment, however, reduced toxin binding only in the Tris-saline buffer (pH 7.4). In addition, the concentration of gangliosides required to inhibit toxin binding was 100-fold higher in Tris-saline compared to Tris-acetate buffer. The toxin receptors in the membranes were analyzed by ligand blotting techniques. Membrane components were dissolved in sodium dodecyl sulfate, separated by polyacrylamide gel electrophoresis, and transferred to nitrocellulose sheets, which were overlaid with 125I-labeled toxin. Tetanus toxin bound only to material that migrated in the region of the dye front and was extracted with lipid solvents. Gangliosides isolated from the lipid extracts or other sources were separated by TLC on silica gel and the chromatograms were overlaid with labeled tetanus toxin. The toxin bound to areas where the major rat brain gangliosides migrated. When equimolar amounts of different purified gangliosides were applied to the chromatogram, binding of the toxin was in the order GD1b approximately equal to GT1b approximately equal to GQ1b greater than GD2 greater than GD3 much greater than GD1a approximately equal to GM1. Thus, the toxin appears to have the highest affinity for gangliosides with a disialyl group linked to the inner galactosyl residue. When binding of tetanus toxin to transfers and chromatograms was determined in the Tris-saline buffer (pH 7.4), the toxin bound to the same components but the extent of binding was markedly reduced compared with the low-salt and -pH conditions. Our results indicate that the interaction of tetanus toxin with rat brain membranes and gangliosides is greatly reduced under more physiological conditions of salt and pH and raise the possibility that other membrane components such as sialoglycoproteins may be receptors for the toxin under these conditions.

Down-regulation is a classic response of most G protein-coupled receptors to prolonged agonist stimulation. We recently showed that when expressed in baby hamster kidney cells, the human β1-but not the β2-adrenergic receptor (AR) is totally resistant to agonist-mediated down-regulation, whereas both have similar rates of basal degradation (Liang, W., Austin, S., Hoang, Q., and Fishman, P. H. (2003) J. Biol. Chem. 278, 39773–39781). To identify the underlying mechanism(s) for this resistance, we investigated the role of proteasomes, lysosomes, and ubiquitination in the degradation of β1AR expressed in baby hamster kidney and human embryonic kidney 293 cells. Both lysosomal and proteasomal inhibitors reduced β1AR degradation in agonist-stimulated cells but were less effective on basal degradation. To determine whether β1AR trafficked to lysosomes we used confocal fluorescence microscopy. We observed some colocalization of β1AR and lysosomal markers in agonist-treated cells but much less than that of β2AR even in cells co-transfected with arrestin-2, which increases β1AR internalization. Ubiquitination of β2AR readily occurred in agonist-stimulated cells, whereas ubiquitination of β1AR was not detectable even under conditions optimal for that of β2AR. Moreover, in cells expressing βAR chimeras in which the C termini have been switched, the chimeric β1AR with β2AR C-tail underwent ubiquitination and down-regulation, but the chimeric β2AR with β1AR C-tail did not. Our results demonstrate for the first time that β1AR and β2AR differ in the ability to be ubiquitinated. Because ubiquitin serves as a signal for sorting membrane receptors to lysosomes, the lack of agonist-mediated ubiquitination of β1AR may prevent its extensive trafficking to lysosomes and, thus, account for its resistance to down-regulation.

Prolonged agonist stimulation results in down-regulation of most G protein-coupled receptors. When we exposed baby hamster kidney cells stably expressing the human beta1-adrenergic receptor (beta 1AR) to agonist over a 24-h period, we instead observed an increase of approximately 30% in both beta 1AR binding activity and immune-detected receptors. In contrast, beta 2AR expressed in these cells exhibited a decrease of > or =50%. We determined that the basal turnover rates of the two subtypes were similar (t(1/2) approximately 7 h) and that agonist stimulation increased beta 2AR but not beta 1AR turnover. Blocking receptor trafficking to lysosomes with bafilomycin A1 had no effect on basal turnover of either subtype but blocked agonist-stimulated beta 2AR turnover. As beta 1AR mRNA levels increased in agonist-stimulated cells, beta 1AR up-regulation appeared to result from increased synthesis with no change in degradation. To explore the basis for the subtype differences, we expressed chimeras in which the C termini had been exchanged. Each chimera responded to persistent agonist stimulation based on the source of its C-tail; beta 1AR with a beta 2AR C-tail underwent down-regulation, and beta 2AR with a beta 1AR C-tail underwent up-regulation. The C-tails had a corresponding effect on agonist-stimulated receptor phosphorylation and internalization with the order being beta 2AR > beta 1AR with beta 2AR C-tail > beta 2AR with a beta 1AR C-tail > beta 1AR. As internalization may be a prerequisite for down-regulation, we addressed this possibility by co-expressing each subtype with arrestin-2. Although beta 1AR internalization was increased to that of beta 2AR, down-regulation still did not occur. Instead, beta 1AR accumulated inside the cells. We conclude that in unstimulated cells, both subtypes appear to be turned over by the same mechanism. Upon agonist stimulation, both subtypes are internalized, and beta 2AR but not beta 1AR undergoes lysosomal degradation, the fate of each subtype being regulated by determinants in its C-tail.

Prolonged agonist exposure often induces downregulation of G protein-coupled receptors (GPCRs). Although downregulation of the prototypical beta(2)-adrenergic receptor (beta(2)AR) has been extensively studied, the underlying mechanisms have yet to be resolved. As even less is known about the beta(1)-subtype, we investigated the downregulation of human beta(1)AR stably expressed in Chinese hamster fibroblasts in response to the agonist isoproterenol or the cell-permeable, chlorophenylthio-cAMP (CPT-cAMP). While either effector mediated decreases in both beta(1)AR binding activity and steady-state beta(1)AR mRNA levels, there were significant differences in their actions. Whereas agonist-mediated downregulation of beta(1)AR followed first-order kinetics, that induced by CPT-cAMP was delayed for several hours and approximately 50% of the former. Furthermore, agonist but not CPT-cAMP induced beta(1)AR internalization, and inhibiting internalization also suppressed agonist-mediated downregulation. The latter, however, was more sensitive than the former to agonist concentration (EC(50) of 0.3 vs 48 nM). Thus, at < or =1 nM agonist, downregulation occurred without internalization and with a pattern similar to that mediated by CPT-cAMP. The amounts of beta(1)AR downregulated or internalized were proportional to initial receptor levels but reached saturation at approximately 2 and 3 pmol/mg of protein, respectively. The fate of beta(1)AR protein during downregulation was determined by immunoblotting with anti-C-terminal antibodies. In agonist-treated cells, beta(1)AR protein disappeared with time and without any immunoreactive degradation products. Agonist-mediated downregulation of the human beta(1)AR appears to be a complex process that consists of both agonist- and cAMP-specific components. The former involves both receptor internalization and degradation whereas the latter involves a reduction in receptor mRNA.

We investigated the regulation of β2-adrenergic receptors (β2AR) by protein kinase C (PKC) in rat C6 glioma cells at the levels of receptor activity, protein expression and gene expression. Cells exposed to 4β-phorbol-12-myristate-13-acetate (PMA), a potent activator of PKC, exhibited a time- and concentration-dependent decrease in β2AR binding activity. Maximum down-regulation was ∼50% by 24 h and western blot analysis revealed a parallel decrease in β2AR protein. In addition, PMA treatment resulted in an acute desensitization of β2AR-stimulated cyclic AMP response prior to any reduction in receptor levels. PMA exposure also affected steady-state β2AR mRNA levels in a time-dependent, biphasic manner. During the first 4 h, levels decreased by ∼60% and then slowly recovered to ∼75% of control by 24 h. As the reduction in receptor mRNA was not due to a decrease in its stability, we examined β2AR gene transcription by nuclear run-on assays. Transcriptional activity in nuclei from C6 cells treated with PMA for 2 h was reduced by 70% compared to controls. Thus PKC can regulate β2AR at least two levels: the first being an acute desensitization of receptor function, and the second being a more prolonged repression of receptor gene transcription that in turn results in decreased receptor expression.

In the current study, we investigated the mechanism by which protein kinase C (PKC) regulates the expression of beta1-adrenergic receptor (beta1AR) mRNA in rat C6 glioma cells. Exposure of the cells to 4beta-phorbol-12-myristate-13-acetate (PMA), an activator PKC, resulted in a down-regulation of both beta1AR binding sites and mRNA levels in a time- and concentration-dependent manner. This effect was not observed with phorbol esters that do not activate PKC and was blocked by bisindolylmaleimide, a specific PKC inhibitor. Activation of PKC did not reduce the half-life of beta1AR mRNA but significantly decreased the activity of the beta1AR promoter, as determined by reporter analysis. A putative response element, with partial homology to a consensus cAMP response element, was identified by mutation analysis of the promoter at positions -343 to -336, relative to the translational start site. Mutation of this putative regulatory element, referred to as a beta1AR-PKC response element, completely blocked the PKC-mediated down-regulation of beta1AR promoter activity. Gel mobility shift analysis detected two specific bands when C6 cell extracts were incubated with a labeled DNA probe containing the beta1AR-PKC response element sequence. Formation of one of these bands was inhibited by an oligonucleotide probe containing a consensus CRE and disrupted by an antibody for cAMP response element binding protein. Based on these studies, we propose that the PKC-induced down-regulation of beta1AR gene transcription in C6 cells is mediated in part by a cAMP response element binding protein-dependent mechanism acting on a novel response element.

The mechanism by which cholera toxin (CT) is internalized from the plasma membrane before its intracellular reduction and subsequent activation of adenylyl cyclase is not well understood. Ganglioside GM1, the receptor for CT, is predominantly clustered in detergent-insoluble glycolipid rafts and in caveolae, noncoated, cholesterol-rich invaginations on the plasma membrane. In this study, we used filipin, a sterol-binding agent that disrupts caveolae and caveolae-like structures, to explore their role in the internalization and activation of CT in CaCo-2 human intestinal epithelial cells. When toxin internalization was quantified, only 33% of surface-bound toxin was internalized by filipin-treated cells within 1 h compared with 79% in untreated cells. However, CT activation as determined by its reduction to form the A1 peptide and CT activity as measured by cyclic AMP accumulation were inhibited in filipin-treated cells. Another sterol-binding agent, 2-hydroxy-β-cyclodextrin, gave comparable results. The cationic amphiphilic drug chlorpromazine, an inhibitor of clathrin-dependent, receptor-mediated endocytosis, however, affected neither CT internalization, activation, nor activity in contrast to its inhibitory effects on diphtheria toxin cytotoxicity. As filipin did not inhibit the latter, the two drugs appeared to distinguish between caveolae- and coated pit–mediated processes. In addition to its effects in CaCo-2 cells that express low levels of caveolin, filipin also inhibited CT activity in human epidermoid carcinoma A431 and Jurkat T lymphoma cells that are, respectively, rich in or lack caveolin. Thus, filipin inhibition correlated more closely with alterations in the biochemical characteristics of CT-bound membranes due to the interactions of filipin with cholesterol rather than with the expressed levels of caveolin and caveolar structure. Our results indicated that the internalization and activation of CT was dependent on and mediated through cholesterol- and glycolipid-rich microdomains at the plasma membrane rather than through a specific morphological structure and that these glycolipid microdomains have the necessary components required to mediate endocytosis.

CGP 12177A originally was developed as a hydrophilic antagonist to detect cell surface β1- and β2-adrenergic receptors, and sub-sequently was found to be a partial agonist for the atypical or β3-adrenergic receptor. Using hamster cells stably expressing either the human β1-, human β2- or rat β1-adrenergic receptor, we found that CGP 12177A behaved as an agonist for β1-adrenergic receptors. Whereas at low concentrations, CGP 12177A behaved as an antagonist and inhibited isoproterenol stimulation of adenylyl cyclase activity, at higher concentrations, it stimulated a response even in the absence of isoproterenol. The agonistic properties of CGP 12177A were positively correlated with the level of β1-adrenergic receptor expression. Thus, at low receptor densities, CGP 12177A behaved as a weak, partial agonist whereas as high receptor densities, the drug was a full agonist. At similar high densities of the β2-adrenergic receptor, CGP 12177A acted only as a partial agonist. Competition binding studies t...

This is the history of discoveries of several enzyme tumor markers in the awardees laboratory. The first, β-glucuronidase, was originally related to the physiological actions of estrogens and androgens. Perfection of histo-chemical techniques based on new substrates demonstrated the dual localization of β-glucuronidase in endoplasmic reticulum and lysosomes. Tumor tissues, in general, are enriched with β-glucuronidase. Next, acid phosphatase of the prostate gland possesses the distinctive property of undergoing inhibition by L-tartrate. This organ-specific inhibitor was incorporated into the Fishman-Lerner method for measuring serum acid phosphatase of prostatic origin. This significantly increased the specificity of the measurement of serum acid phosphatase for prostatic cancer. Finally, the discovery of the Regan Isoenzyme, placental alkaline phosphatase (PLAP) in a patient with disseminated lung cancer provided a tumor marker useful in the management of gonadal tumors, in particular. Closely related to PLAP is germ cell alkaline phosphatase which is eutopically expressed in seminoma. Finally, radioimmunolocalization and radioimmunotherapy of PLAP in these tumors have been achieved by others.

During lower hybrid current drive on tokamaks, suprathermal electrons are generated that emit hard x‐ray bremsstrahlung. A pinhole camera has been installed on the PBX‐M tokamak that records 128×128 pixel images of the hard x‐ray plasma bremsstrahlung emitted in the 30–200 keV photon energy range. The camera has a temporal resolution of 3 ms and a spatial resolution of 3–4 cm in the plasma. The detector is a 230‐mm‐diam hard x‐ray image intensifier. This instrument has identified hollow radiation profiles on PBX‐M, indicating off‐axis current drive. A detailed account of the construction of the hard x‐ray camera, its operation, and its performance is given.

コレラや旅行者下痢症の原因物質であるコレラ毒素 (CT) とI型非耐熱性腸管毒素 (LT-I) は構造的にも機能的にも類似している。どちらも、特異的細胞表面受容体に結合するホモペンタメリックBサブユニットと、標的細胞でアデニリルシクラーゼを持続的に活性化するモノメリックAサブユニットをもっている。ヒト腸管細胞において、サイクリックAMPの上昇は毒素の病態生理学的作用をもたらす。両毒素とも膜の外側に向いているAサブユニットと結合し、さらに特徴的な遅滞期の間にホロ毒素は細胞内に取り込まれ、A1ペプチドを放出させる細胞間プロセシングを受けるのである。後者は、刺激Gタンパクのαサブユニット (GSα) を修飾するADP-リボシルトランスフェラーゼで、アデニルシクラーゼを活性化状態にしておく。ゴルジ装置の崩壊物質であるブレフェルジンA細胞を曝すると、A1ペプチドの放出が阻止され、したがってアデニリルシクラーゼの活性が阻害される。このことから、インタクトのゴルジ装置が毒素のプロセシングと活性化のために必要であることが示唆される。ガングリオシドGM1は、コレラ毒素の唯一天然の機能的受容体であり、かつLT-1の機能的受容体としても役目を果たしうることが確認されてきた。ヒトを含むいくつかの種の腸管細胞はさらに、毒素結合に必要なポリラクトサミニルグリカン決定基を有するガラクトタンパク質として同定されているLT-1に対するレセプターをもっている。矛盾することに、両毒素は、GM1欠損細胞の表面上に産生されてきたGM1オリゴ糖を含むネオガングリオタンパク質に結合できるが、アデニリルシクラーゼを活性化することはできない。活性化はクロロキニン存在下で起こりうるが、遅延したラグ相下では起こらない。このことから、毒素は、ネオガングリオタンパク質に結合するとすれば、別々の細胞内経路に入り、それから天然のレセプターに結合することが示唆される。さらに、GM1-オリゴ糖や様々な脂質から合成された一連のネオガングリオ脂質によって毒素作用における受容体構造の影響が示される。GM1-欠損細胞によって取り込まれると、毒素結合は維持されるが多様な毒素活性がもたらされる。一連のネオ糖脂質に関しては、後者はオリゴ糖と脂質部分の間の距離に逆相関している。

High poloidal beta discharges in PBX-M routinely enter the H mode regime: typically, a quiescent phase followed by an MHD-active phase characterize the H mode period. An analysis of the energy transport during these phases is conducted using the experimental data and the code TRANSP; effective thermal diffusivities are computed. The quiescent H phase is characterized by a decrease of the thermal ion energy transport and a flattening of the associated effective diffusivity profile. Enhanced fast ion losses are observed during the MHD-active phase; particles in the lower end of the fast-ion energy spectrum with a large perpendicular velocity component are predominantly affected. Folding these losses into the analysis permits to reproduce the measured stored energy and time evolution of the neutron production rate during the MHD-active phase. During the MHD-active phase, the ion thermal diffusivity maintained a profile (magnitude and shape) similar to that obtained at the end of the quiescent H phase, suggesting, within the uncertainty of this analysis, that the MHD activity does not affect the thermal plasma energy transport. The observed stored energy (beta) saturation results from the enhanced losses in the fast-ion population. An analysis without inclusion of enhanced fast ion losses fails to reproduce the experimental measurements. Throughout the H mode period the electron effective diffusivity remains lower than the ion effective diffusivity. An error analysis is presented