Leveraging big data of immune checkpoint blockade response identifies novel potential targets.

BACKGROUND: The development of immune checkpoint blockade (ICB) has changed the way we treat various cancers. While ICB produces durable survival benefits in a number of malignancies, a large proportion of treated patients do not derive clinical benefit. Recent clinical profiling studies have shed light on molecular features and mechanisms that modulate response to ICB. Nevertheless, none of these identified molecular features were investigated in large enough cohorts to be of clinical value. MATERIALS AND METHODS: Literature review was carried out to identify relevant studies including clinical dataset of patients treated with ICB [anti-programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1), anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) or the combination] and available sequencing data. Tumor mutational burden (TMB) and 37 previously reported gene expression (GE) signatures were computed with respect to the original publication. Biomarker association with ICB response (IR) and survival (progression-free survival/overall survival) was investigated separately within each study and combined together for meta-analysis. RESULTS: We carried out a comparative meta-analysis of genomic and transcriptomic biomarkers of IRs in over 3600 patients across 12 tumor types and implemented an open-source web application (predictIO.ca) for exploration. TMB and 21/37 gene signatures were predictive of IRs across tumor types. We next developed a de novo GE signature (PredictIO) from our pan-cancer analysis and demonstrated its superior predictive value over other biomarkers. To identify novel targets, we computed the T-cell dysfunction score for each gene within PredictIO and their ability to predict dual PD-1/CTLA-4 blockade in mice. Two genes, F2RL1 (encoding protease-activated receptor-2) and RBFOX2 (encoding RNA-binding motif protein 9), were concurrently associated with worse ICB clinical outcomes, T-cell dysfunction in ICB-naive patients and resistance to dual PD-1/CTLA-4 blockade in preclinical models. CONCLUSION: Our study highlights the potential of large-scale meta-analyses in identifying novel biomarkers and potential therapeutic targets for cancer immunotherapy.

Herpetiform pemphigus with characteristic transmission electron microscopic findings of various-sized ballooning vacuoles in keratinocytes without acantholysis.

We report a unique case of a Japanese woman with herpetiform pemphigus (HP) who had IgG autoantibodies reactive with nondesmosomal sites of keratinocytes and presented characteristic transmission electron microscopic (TEM) findings of various-sized vacuoles in keratinocytes without acantholysis. The patient presented with pruritic annular oedematous erythemas with small blisters lining the margins on the trunk and extremities. Histopathological examinations showed intraepidermal blisters with prominent infiltrations of eosinophils. Direct and indirect immunofluorescence tests revealed the presence of in vivo bound and circulating IgG autoantibodies to the keratinocyte cell surfaces. However, enzyme-linked immunosorbent assays for desmoglein (Dsg) 1, Dsg3 and desmocollins 1-3 showed negative results. Immunoblotting using the full-length human Dsg1 recombinant protein showed a positive band. TEM examination showed various-sized vacuoles squashing the nuclei in many keratinocytes, resulting in rupture of the cells. Immunoelectron microscopic examination revealed IgG deposition over the entire keratinocyte cell surfaces, which spared the desmosomes. IgG antibodies were also present on the inside walls of the vacuoles around the nuclei of keratinocytes and on the cell surfaces of infiltrating eosinophils. This patient also had marked eosinophilia and high levels of thymus and activation-regulated chemokine and interleukin-5 in the serum. These results indicated a novel autoantigen on the nondesmosomal keratinocyte cell surfaces and the pathogenesis of bullous spongiotic change with inflammation in HP.

Delayed lupus nephritis in the course of systemic lupus erythematosus is associated with a poorer treatment response: a multicentre, retrospective cohort study in Japan.

OBJECTIVE: The objective of this study was to investigate possible differences in treatment responses between two categories for the onset of lupus nephritis. METHODS: We performed a multicentre, retrospective cohort study of class III-V lupus nephritis patients diagnosed between 1997 and 2014. The renal responses to initial induction therapy were compared between patients who developed lupus nephritis within one year from diagnosis of systemic lupus erythematosus (early (E-) LN) and the remainder (delayed (D-) LN) using the Kaplan-Meier method. We determined the predictors of renal response as well as renal flares and long-term renal outcomes using multivariate Cox regression analyses. RESULTS: A total of 107 E-LN and 70 D-LN patients were followed up for a median of 10.2 years. Log-rank tests showed a lower cumulative incidence of complete response in D-LN compared with E-LN patients. Multivariate analysis identified D-LN (hazard ratio (HR) 0.48, 95% confidence interval (CI) 0.33-0.70), nephrotic syndrome at baseline, and a chronicity index greater than 2 as negative predictors of complete response. D-LN patients were more likely to experience renal flares. D-LN (HR 2.54, 95% CI 1.10-5.83) and decreased renal function were significant predictors of chronic kidney disease at baseline. CONCLUSION: D-LN was a predictor of poorer treatment outcomes, in addition to renal histology and severity of nephritis at lupus nephritis onset.

Double-core ionization photoelectron spectroscopy of C6H6: Breakdown of the "intuitive" ortho-meta-para binding energy ordering of K-1K-1 states.

Single-site Double-Core Hole (ss-DCH or K-2) and two-site Double-Core Hole (ts-DCH or K-1K-1) photoelectron spectra including satellite lines were experimentally recorded for the aromatic C6H6 molecule using the synchrotron radiation and multielectron coincidence technique. Density functional theory and post-Hartree-Fock simulations providing binding energies and relative intensities allow us to clearly assign the main K-2 line and its satellites. K-1K-1 states' positions and assignments are further identified using a core-equivalent model. We predict that, contrary to what has been observed in the C2H2n series of molecules, the K-1K-1 energy-level ordering in C6H6 does not reflect the core-hole distances between the two holes.

Isoforms of Group 1 Allergens from a Tropical/Subtropical Para Grass (Urochloa mutica) Display Different Levels of IgE Reactivity and Cross-reactivity.

Summary: Group 1 grass pollen allergens, or beta-expansins, are the most important major allergens from tropical/subtropical grasses. This study aimed to investigate the sequence similarity, and immunoreactivity of group 1 allergens from Para grass (Urochloa mutica). Three isoforms (Uro m 1.01, Uro m 1.02, and Uro m 1.03) were cloned from cDNA of Para grass pollen. The acidic-neutral isoforms rUro m 1.01 and rUro m 1.02 could effectively inhibited beta-expansins in pollen extract of Bermuda and Johnson grasses, suggesting that these isoforms could be major cross-reacting allergens among these grasses. In contrast, the basic isoform rUro m 1.03 had limited IgE reactivity. Thus, group 1 allergens both acidic-neutral and basic isoforms could have markedly different IgE reactivity.

Characterization of patients with systemic lupus erythematosus who meet the diagnostic criteria for TAFRO syndrome.

Purpose TAFRO syndrome is a novel disorder manifesting as fever, anasarca, thrombocytopenia, renal insufficiency and organomegaly, and its etiology has not been clarified. The aim of this study was to elucidate similarities and differences between systemic lupus erythematosus (SLE) and TAFRO syndrome. Methods We examined 46 consecutive patients diagnosed with SLE and determined whether they meet the proposed diagnostic criteria for TAFRO syndrome (2015 version). Results Of the 46 patients with SLE, four (8.7%) also met the TAFRO syndrome criteria (TAFRO-like group). All patients in the TAFRO-like group were males, and their mean age was significantly higher than that of the non-TAFRO group (67.5 ± 8.7 vs. 39.3 ± 18.1 years, p = 0.004). C-reactive protein and γ-glutamyl transpeptidase levels were significantly higher, and frequencies of anti-dsDNA and anti-Sm antibodies were significantly lower in the TAFRO-like than non-TAFRO group. Elder cases (onset age ≥ 50 years) met significantly more categories of the diagnostic criteria for TAFRO syndrome than did those with younger cases. Conclusions Several patients with SLE, especially elder cases, showed features similar to those of TAFRO syndrome. Although exclusion of SLE is needed in the diagnostic criteria for TAFRO syndrome, TAFRO syndrome-like SLE should be considered.

Relationship between bidet toilet use and haemorrhoids and urogenital infections: a 3-year follow-up web survey.

Given the growing use of electric bidet toilets in Japan and other countries, we assessed the relationship between bidet toilet use and haemorrhoids or urogenital infections. Data were collected using a web-based longitudinal survey. In total, 10 305 subjects randomly selected from panels of a Japanese website research company for the baseline survey in 2013 were asked about their frequency of bidet toilet use and receipt of a doctor's diagnosis or subjective symptom of haemorrhoids and urogenital infections. One- and three-year follow-up surveys were performed in 2014 and 2016, respectively, and information on newly diagnosed/experienced outcomes occurring during the follow-up period were collected. Cumulative incidence of haemorrhoids and urogenital infections was not significantly increased by habitual use of a bidet toilet. In men, more habitual users reported subjective symptoms of irritated skin around the anus, which were newly experienced during follow-up than non-habitual users (adjusted risk ratio 1.36 (95% confidence interval 1.06-1.75)). Further studies are needed to confirm this relationship. Several of the outcomes were significantly more prevalent in habitual users, but these results were probably explained by reverse causation.

Collective bulk carrier delocalization driven by electrostatic surface charge accumulation.

In the classic transistor, the number of electric charge carriers--and thus the electrical conductivity--is precisely controlled by external voltage, providing electrical switching capability. This simple but powerful feature is essential for information processing technology, and also provides a platform for fundamental physics research. As the number of charges essentially determines the electronic phase of a condensed-matter system, transistor operation enables reversible and isothermal changes in the system's state, as successfully demonstrated in electric-field-induced ferromagnetism and superconductivity. However, this effect of the electric field is limited to a channel thickness of nanometres or less, owing to the presence of Thomas-Fermi screening. Here we show that this conventional picture does not apply to a class of materials characterized by inherent collective interactions between electrons and the crystal lattice. We prepared metal-insulator-semiconductor field-effect transistors based on vanadium dioxide--a strongly correlated material with a thermally driven, first-order metal-insulator transition well above room temperature--and found that electrostatic charging at a surface drives all the previously localized charge carriers in the bulk material into motion, leading to the emergence of a three-dimensional metallic ground state. This non-local switching of the electronic state is achieved by applying a voltage of only about one volt. In a voltage-sweep measurement, the first-order nature of the metal-insulator transition provides a non-volatile memory effect, which is operable at room temperature. Our results demonstrate a conceptually new field-effect device, extending the concept of electric-field control to macroscopic phase control.

Changes in the expression of α-tocopherol-related genes in liver and mammary gland biopsy specimens of peripartum dairy cows.

Blood α-tocopherol (α-Toc) concentrations decline gradually throughout the prepartum period, reaching the nadir after calving in dairy cows. The 6 α-Toc-related molecules [α-Toc transfer protein (TTPA); afamin; scavenger receptor class B, Type I; ATP-binding cassette transporter A1; tocopherol-associated protein (SEC14L2); and cytochrome P450 family 4, subfamily F, polypeptide 2 (CYP4F2)] are expressed in liver and other peripheral tissues. These molecules could regulate α-Toc transport, blood concentrations, and metabolism of α-Toc. Therefore, the aim of this study was to evaluate the changes in the expression of α-Toc-related genes in liver and mammary gland tissues of dairy cows around calving, which have remained elusive until now. In experiment (Exp.) 1, 28 multiparous Holstein cows were used (from -5 to 6 wk relative to parturition) to monitor the changes in dietary α-Toc intake, blood concentrations of α-Toc, and lipoproteins; in Exp. 2, 7 peripartum Holstein cows were used (from -4 to 4 wk relative to parturition) for liver tissue biopsy; and in Exp. 3, 10 peripartum Holstein cows were used (from -8 to 6 wk relative to parturition) to carry out the mammary gland tissue biopsy and milk sampling. In Exp. 1, the serum α-Toc concentrations declined gradually with decreasing amount of α-Toc intake and plasma high-density lipoprotein concentrations toward calving time. However, in the early lactation period after calving, serum α-Toc concentrations remained at a lower concentration despite the recovery of α-Toc intake and plasma high-density lipoprotein concentrations. In Exp. 2, just after calving, the TTPA, SEC14L2, afamin, and albumin mRNA expression levels in the liver were temporarily downregulated, and the hepatic mRNA levels of endoplasmic reticulum stress-induced unfolded protein response markers and acute-phase response marker increased at calving. In Exp. 3, the concentrations of α-Toc in colostrum were greater than those in precolostrum (samples were collected at wk -1 relative to parturition) and mature milk. The expression of TTPA, SEC14L2, and CYP4F2 mRNA in bovine mammary gland tissue was detected. However, TTPA and SEC14L2 mRNA expressions showed the opposite trends: the expression levels of TTPA mRNA peaked whereas SEC14L2 mRNA reached a nadir at calving. These results indicate that the expression of α-Toc-related genes involved in specific α-Toc transfer and metabolism in the liver and mammary gland are altered during calving. Moreover, these changes might be associated with the maintenance of lower serum α-Toc concentrations after calving.

High and pointed type of femoral localized reaction frequently extends to complete and incomplete atypical femoral fracture in patients with autoimmune diseases on long-term glucocorticoids and bisphosphonates.

Once a localized reaction (beaking) was detected, discontinuation of bisphosphonates (BPs) and switching to vitamin D supplementation or teriparatide therapy effectively improved its shape. When the localized reaction was high, of the pointed type, and/or accompanied by prodromal pain, the risks of complete and incomplete atypical femoral fracture increased and consideration of prophylactic fixation for such patients was required. INTRODUCTION: Femoral localized reaction (localized periosteal thickening of the lateral cortex, beaking) is reported to precede atypical femoral fractures (AFFs) and to develop in 8-10% of patients with autoimmune diseases taking BPs and glucocorticoids. The aims of the present study were to retrospectively investigate the shapes of localized reaction to consider how to manage the condition. METHODS: Twenty femora of 12 patients with autoimmune diseases who were on BPs and glucocorticoids exhibited femoral localized reaction. The heights of localized reaction were measured and the shapes classified as pointed, arched, and other. Localized reaction changes were divided into three categories: deterioration, no change, and improvement. A severe form of localized reaction was defined; this was associated with prodromal pain, de novo complete AFF, or incomplete AFF with a fracture line at the localized reaction. RESULTS: The mean height of localized reaction was 2.3 ± 0.8 mm (range, 1.0-3.7 mm) and the pointed type was 35%. Localized reaction was significantly higher (3.3 ± 0.8 vs. 2.1 ± 0.7 mm; p = 0.003) and the pointed type more common (78 vs. 27%; p = 0.035) in those with the severe form of localized reaction. Seven patients with localized reactions discontinued BPs just after localized reaction was detected, but five continued on BPs for 2 years. Localized reaction deterioration was more common in patients who continued than discontinued BPs (100 vs. 29%; p = 0.027). After 2 years, all patients had discontinued BPs and localized reaction did not deteriorate further in any patient. CONCLUSIONS: Once a localized reaction was detected, discontinuation of BPs and switching to vitamin D supplementation or teriparatide therapy effectively improved it. When the localized reaction was high, of the pointed type, and/or accompanied by prodromal pain, the risks of complete and incomplete AFF increased and consideration of prophylactic fixation for such patients was required.

Singlet fission in pancake-bonded systems.

We theoretically investigate the potential of pancake-bonded systems for efficient singlet fission by examining phenalenyl radical dimer and tetramer models. In the dimer model, we propose an efficient way to satisfy the excitation energy level matching required for singlet fission by tuning the diradical character by changing the intermolecular distance. In the tetramer model, electronic couplings required for both singlet fission and charge mobility are found to be maximized simultaneously in the face-to-face configuration, which is usually known to be difficult to achieve due to a trade-off relationship between them in conventional π-conjugated molecules like pentacene. In addition, on the basis of the quasi-degenerate second-order perturbation analysis, we obtain a simplified and more efficient crystal-structure design guideline that pancake-bonded systems cause highly-active singlet fission.

The cumulative incidence of and risk factors for latent beaking in patients with autoimmune diseases taking long-term glucocorticoids and bisphosphonates.

SUMMARY: The incidence of beaking, which has been reported to precede atypical femoral fracture, was high and increased over 2 years in patients with autoimmune diseases who were taking bisphosphonates and glucocorticoids. Regular femoral X-rays are strongly recommended to screen for beaking, and bisphosphonate drug holidays should be considered. INTRODUCTION: Atypical femoral fractures (AFFs) have been recently recognized as complications associated with bisphosphonate (BP) use. AFFs are considered to be stress fractures; localized periosteal thickening of the lateral cortex is often present at the fracture site; this thickening is termed "beaking." Beaking has been reported to precede AFF. The aims of the present study were to evaluate the incidence of latent beaking in patients with autoimmune diseases taking BPs and glucocorticoids and to identify risk factors for beaking. METHODS: A total of 125 patients with autoimmune diseases who were taking BPs and glucocorticoids was included; 116 patients underwent X-rays and analysis of serum and urine bone metabolic markers annually for 2 years. Mean patient age was 54.5 years; there were 105 (90.5%) females and the mean duration of disease was 13.2 years. Focal lateral cortical thickening in femoral X-rays was defined as beaking. RESULTS: Beaking was detected in 15 femora of 10 patients (8.0%) at the time of recruitment. Over the 2-year observation period, the incidence of beaking increased to 21 femora of 12 patients (10.3%), and a complete AFF at the location of beaking occurred in one patient. Beaking was associated with a longer duration of BP treatment (6.1 ± 1.0 years vs. 5.0 ± 2.9 years, p = 0.01). Age 40-60 years, BP therapy ≥4 years, and diabetes mellitus were significantly associated with beaking. CONCLUSIONS: The incidence of beaking was high, and increased over 2 years, in patients with autoimmune diseases who were taking BPs and glucocorticoids. Regular femoral X-rays are strongly recommended to screen for beaking. Long-term BP/glucocorticoid use was a risk factor for beaking in patients with autoimmune diseases; BP drug holidays should be considered.

Characterization of the dextran-binding domain in the glucan-binding protein C of Streptococcus mutans.

AIMS: Streptococcus mutans produces multiple glucan-binding proteins (Gbps), among which GbpC encoded by the gbpC gene is known to be a cell-surface-associated protein involved in dextran-induced aggregation. The purpose of the present study was to characterize the dextran-binding domain of GbpC using bioinformatics analysis and molecular techniques. METHODS AND RESULTS: Bioinformatics analysis specified five possible regions containing molecular binding sites termed GB1 through GB5. Next, truncated recombinant GbpC (rGbpC) encoding each region was produced using a protein expression vector and five deletion mutant strains were generated, termed CDGB1 through CDGB5 respectively. The dextran-binding rates of truncated rGbpC that included the GB1, GB3, GB4 and GB5 regions in the upstream sequences were higher than that of the construct containing GB2 in the downstream region. In addition, the rates of dextran-binding for strains CDGB4 and CD1, which was entire gbpC deletion mutant, were significantly lower than for the other strains, while those of all other deletion mutants were quite similar to that of the parental strain MT8148. Biofilm structures formed by CDGB4 and CD1 were not as pronounced as that of MT8148, while those formed by other strains had greater density as compared to that of CD1. CONCLUSION: Our results suggest that the dextran-binding domain may be located in the GB4 region in the interior of the gbpC gene. SIGNIFICANCE AND IMPACT OF THE STUDY: Bioinformatics analysis is useful for determination of functional domains in many bacterial species.

Single photon simultaneous K-shell ionization and K-shell excitation. I. Theoretical model applied to the interpretation of experimental results on H2O.

We present in detail a theoretical model that provides absolute cross sections for simultaneous core-ionization core-excitation (K(-2)V) and compare its predictions with experimental results obtained on the water molecule after photoionization by synchrotron radiation. Two resonances of different symmetries are assigned in the main K(-2)V peak and comparable contributions from monopolar (direct shake-up) and dipolar (conjugate shake-up) core-valence excitations are identified. The main peak is observed with a much greater width than the total experimental resolution. This broadening is the signature of nuclear dynamics.

Single photon simultaneous K-shell ionization and K-shell excitation. II. Specificities of hollow nitrogen molecular ions.

The formalism developed in the companion Paper I is used here for the interpretation of spectra obtained recently on the nitrogen molecule. Double core-hole ionization K(-2) and core ionization-core excitation K(-2)V processes have been observed by coincidence electron spectroscopy after ionization by synchrotron radiation at different photon energies. Theoretical and experimental cross sections reported on an absolute scale are in satisfactory agreement. The evolution with photon energy of the relative contribution of shake-up and conjugate shake-up processes is discussed. The first main resonance in the K(-2)V spectrum is assigned to a K(-2)π(∗) state mainly populated by the 1s→ lowest unoccupied molecular orbital dipolar excitation, as it is in the K(-1)V NEXAFS (Near-Edge X-ray Absorption Fine Structure) signals. Closer to the K(-2) threshold Rydberg resonances have been also identified, and among them a K(-2)σ(∗) resonance characterized by a large amount of 2s/2p hybridization, and double K(-2)(2σ(∗)/1π/3σ)(-1)1π(∗2) shake-up states. These resonances correspond in NEXAFS spectra to, respectively, the well-known σ(∗) shape resonance and double excitation K(-1)(2σ(∗)/1π/3σ)(-1)1π(∗2) resonances, all being positioned above the threshold.

Effect of molecular orientation angle of imidazolium ring on frictional properties of imidazolium-based ionic liquid.

Ionic liquids have significant potential as lubricants, and it is known that ionic liquids exhibit characteristic behavior at solid-liquid interfaces. Although it is believed that the structure of ionic liquids at the interface contributes to the tribological properties in the region of boundary-mixed lubrication, this contribution has not been clarified because such analysis is difficult. In this research, we clarify the lubrication mechanism of an imidazolium-based ionic liquid by comparing the results of friction tests with interfacial molecular orientation analysis using sum frequency generation spectroscopy. Consequently, we clarify that the tilt angle of the imidazolium ring affects the friction coefficient of the ionic liquid; that is, the larger tilt angle, the lower the friction coefficient.

Association between anti-U1 ribonucleoprotein antibodies and inflammatory mediators in cerebrospinal fluid of patients with neuropsychiatric systemic lupus erythematosus.

OBJECTIVE: We investigated possible associations between neurotoxic inflammatory mediators (IMs) and anti-U1RNP antibodies (Abs) in cerebrospinal fluid (CSF) of neuropsychiatric systemic lupus erythematosus (NPSLE). METHODS: Serum and CSF anti-U1RNP Abs were detected using an RNA-immunoprecipitation assay and CSF anti-U1RNP Ab levels were measured by ELISA. IFN-α, MCP-1 and IL-8 levels in CSF were determined by quantitative multiplex cytokine analysis. IM levels were compared among anti-U1RNP-positive and anti-U1RNP-negative NPSLE as well as other rheumatic disease controls (controls). RESULTS: Anti-U1RNP Abs were detected in serum (58%) and in CSF (18%) of 82 NPSLE patients. CSF MCP-1 levels were higher in NPSLE than in controls. CSF IFN-α level was higher in CSF anti-U1RNP Ab-positive than in -negative patients or controls. When limited to serum anti-U1RNP Ab-positive patients, however, levels of all three IMs in CSF were higher in CSF anti-U1RNP Ab-positive than in -negative patients. Anti-U1RNP Ab levels in CSF correlated with CSF MCP-1, but not IFN-α and IL-8 levels. CONCLUSIONS: CSF anti-U1RNP Ab positivity is associated with increased level of CSF IFN-α. MCP-1 levels correlated with CSF anti-U1RNP Ab levels, whereas the increased CSF MCP-1 was not specific to CSF anti-U1RNP Ab-positive NPSLE.

Cytogenetic validation of DS02R1-estimated dose for atomic bomb survivors in Hiroshima and Nagasaki with FISH.

INTRODUCTION: For Hiroshima and Nagasaki survivors, it has not been possible to calculate individual doses from the cytogenetic data and compare them with the physically estimated doses. This is because the cytogenetic studies used solid Giemsa staining which only provides the percent of cells bearing at least one stable-type aberration (most of the unstable-type aberrations had already disappeared), and a gamma-ray dose plus a 10-times neutron dose was used to integrate the data for both cities. OBJECTIVES: To compare the FISH-derived gamma-ray dose with the DS02R1-derived gamma-ray dose after correcting for a contribution of the neutron dose. It was also an attempt to determine if the frequency of stable-type aberrations had remained unchanged after the exposure. METHODS: Stable exchange-type aberration data was obtained using the 2-color FISH method from 1,868 atomic bomb survivors in Hiroshima and Nagasaki. The collected frequency was first extended to a genome-equivalent frequency. Then, by using known induction rates of exchange-type aberrations in vitro caused by neutrons and gamma-rays, respectively, and the mean relationship between the neutron and gamma-ray doses in the DS02R1 estimates for the survivors, the gamma-ray effect was estimated from the total yield of translocations. RESULTS: It was found that over 95% of individual cytogenetic gamma-ray doses fell within the expected range of plus/minus about 1 Gy from the DS02R1 dose and the mean slope for the linear regression was 0.98, which reassures us of the validity of the DS02R1 study. CONCLUSIONS: The present results demonstrate the validity of the individual DS02R1 doses, and that the frequency of stable-type aberrations in blood lymphocytes did not decay over the years, and thus is useful for retrospective dose evaluations of exposures which took place in the distant past.

Near-edge x-ray absorption fine structures revealed in core ionization photoelectron spectroscopy.

Simultaneous core ionization and core excitation have been observed in the C(2)H(2n) (n=1, 2, 3) molecular series using synchrotron radiation and a magnetic bottle time-of-flight electron spectrometer. Rich satellite patterns corresponding to (K(-2)V) core excited states of the K(-1) molecular ions have been identified by detecting in coincidence the photoelectron with the two Auger electrons resulting from the double core hole relaxation. A theoretical model is proposed providing absolute photoionization cross sections and revealing clear signatures of direct (monopolar) and conjugate (dipolar near-edge x-ray absorption fine structure) shakeup lines of comparable magnitude.

Single photon K(-2) and K(-1)K(-1) double core ionization in C(2)H(2n) (n=1-3), CO, and N(2) as a potential new tool for chemical analysis.

We have observed single photon double K-shell photoionization in the C(2)H(2n) (n=1-3) hydrocarbon sequence and in N(2) and CO, using synchrotron radiation and electron coincidence spectroscopy. Our previous observations of the K(-2) process in these molecules are extended by the observations of a single photon double photoionization with one core hole created at each of the two neighboring atoms in the molecule (K(-1)K(-1) process). In the C(2)H(2n) sequence, the spectroscopy of K(-1)K(-1) states is much more sensitive to the bond length than conventional electron spectroscopy for chemical analysis spectroscopy based on single K-shell ionization. The cross section variation for single photon K(-1)K(-1) double core ionization in the C(2)H(2n) sequence and in the isoelectronic C(2)H(2n), N(2) and CO molecules validates a knock-out mechanism in which a primary ionized 1s photoelectron ejects another 1s electron of the neighbor atom. The specific Auger decay from such states is clearly observed in the CO case.