Striosomes Mediate Value-Based Learning Vulnerable in Age and a Huntington's Disease Model.

Learning valence-based responses to favorable and unfavorable options requires judgments of the relative value of the options, a process necessary for species survival. We found, using engineered mice, that circuit connectivity and function of the striosome compartment of the striatum are critical for this type of learning. Calcium imaging during valence-based learning exhibited a selective correlation between learning and striosomal but not matrix signals. This striosomal activity encoded discrimination learning and was correlated with task engagement, which, in turn, could be regulated by chemogenetic excitation and inhibition. Striosomal function during discrimination learning was disturbed with aging and severely so in a mouse model of Huntington's disease. Anatomical and functional connectivity of parvalbumin-positive, putative fast-spiking interneurons (FSIs) to striatal projection neurons was enhanced in striosomes compared with matrix in mice that learned. Computational modeling of these findings suggests that FSIs can modulate the striosomal signal-to-noise ratio, crucial for discrimination and learning.

Heterogeneous Single-Atom Zinc on Nitrogen-Doped Carbon Catalyzed Electrochemical Allylation of Imines.

Organometallic reagents are effective for carbon-carbon bond formation; however, consumption of stoichiometric amounts of metals is problematic. We developed electrochemical allylation reactions of imines catalyzed by nitrogen-doped carbon-supported single-atom zinc, which were fixed on a cathode to afford a range of homoallylic amines efficiently. The system could suppress generation of metallic waste, and the catalyst electrode showed advantages over bulk zinc in terms of activity and robustness. An electrochemical flow reaction was also successfully performed to produce the homoallylic amine continuously with minimum amounts of waste.

Exome-based genome-wide screening of rare variants associated with the risk of polycystic ovary syndrome.

Purpose: Genetic factors associated with the risk of polycystic ovary syndrome (PCOS) remain largely unknown. Here, we conducted an optimal sequence kernel association test (SKAT-O), an exome-based rare variant association study, to clarify whether rare variants in specific genes contribute to the development of PCOS. Methods: SKAT-O was performed using exome data of 44 Japanese patients with PCOS and 301 control women. We analyzed frequencies of rare probably damaging variants in the genome. Results: Rare variants of GSTO2 were more commonly identified in the patient group than in the control group (6/44 vs. 1/301; Bonferroni-corrected p-value, 0.028), while the frequencies of variants in other genes were comparable between the two groups. The identified GSTO2 variants were predicted to affect the function, structure, stability, hydrophobicity, and/or the formation of intrinsically disordered regions of the protein. GSTO2 encodes a glutathione transferase that mediates the oxidative stress response and arsenic metabolism. Previously, common variants in GSTO2 and its paralog GSTO1 were associated with the risk of PCOS. Conclusions: The results indicate that there are no genes whose rare variants account for a large fraction of the etiology of PCOS, although rare damaging variants in GSTO2 may constitute a risk factor in some cases.

Massive digital gene expression analysis reveals different predictive profiles for immune checkpoint inhibitor therapy between adenocarcinoma and squamous cell carcinoma of advanced lung cancer.

BACKGROUND: Immune checkpoint inhibitors prolong the survival of non-small cell lung cancer (NSCLC) patients. Although it has been acknowledged that there is some correlation between the efficacy of anti-programmed cell death-1 (PD-1) antibody therapy and immunohistochemical analysis, this technique is not yet considered foolproof for predicting a favorable outcome of PD-1 antibody therapy. We aimed to predict the efficacy of nivolumab based on a comprehensive analysis of RNA expression at the gene level in advanced NSCLC. METHODS: This was a retrospective study on patients with NSCLC who were administered nivolumab at the Kansai Medical University Hospital. To identify genes associated with response to anti-PD-1 antibodies, we grouped patients into responders (complete and partial response) and non-responders (stable and progressive disease) to nivolumab therapy. Significant genes were then identified for these groups using Welch's t-test. RESULTS: Among 42 analyzed cases (20 adenocarcinomas and 22 squamous cell carcinomas), enhanced expression of MAGE-A4, BBC3, and OTOA genes was observed in responders with adenocarcinoma, and enhanced expression of DAB2, HLA-DPB,1 and CDH2 genes was observed in responders with squamous cell carcinoma. CONCLUSIONS: This study predicted the efficacy of nivolumab based on a comprehensive analysis of mRNA expression at the gene level in advanced NSCLC. We also revealed different gene expression patterns as predictors of the effectiveness of anti PD-1 antibody therapy in adenocarcinoma and squamous cell carcinoma.

The role of the shell in core-shell-structured La-doped NaTaO3 photocatalysts.

NaTaO3, a semiconductor with a perovskite structure, has long been known as a highly active photocatalyst for overall water splitting when appropriately doped with La cations. A profound understanding of the surface feature and why and how it may control the water splitting activity is critical because redox reactions take place at the surface. One surface feature characteristic of La-doped NaTaO3 is a La-rich layer (shell) capping La-poor bulk (core). In this study, we investigate the role of the shell in core-shell-structured La-doped NaTaO3 through systematic chemical etching with an aqueous HF solution. We find that the La-rich shell plays a role in electron-hole recombination, electron mobility and water splitting activity. The shallow electron traps populating the La-rich shell trap the photoexcited electrons, decreasing their mobility. The shallowly trapped electrons remain reactive and are readily available on the surface to be extracted by the cocatalysts for the reduction reaction evolving H2. The presently employed chemical etching method also confirms the presence of a La concentration gradient in the core that regulates the steady-state electron population and water splitting activity. Here, we successfully reveal the nanoarchitecture-photoactivity relationship of core-shell-structured La-doped NaTaO3 that thereby allows tuning of the surface features and spatial distribution of dopants to increase the concentration of photoexcited electrons and therefore the water splitting activity. By recognizing the key factors that control the photocatalytic properties of a highly active catalyst, we can then devise proper strategies to design new photocatalyst materials with breakthrough performances.

Microstimulation of primate neocortex targeting striosomes induces negative decision-making.

Here, we combined MRI-guided electrical microstimulation and viral tracing to examine the function of a corticostriatal circuit implicated by previous cortical microstimulation as modulating affective judgment and decision-making. Local microstimulation of a small part of the pregenual anterior cingulate cortex (pACC) was found to increase avoidance decisions in a cost-benefit decision-making task (Ap-Av task) in which differing amounts of "good" and "bad" options were given simultaneously. No effect of such stimulation was found when the monkeys performed a task in which both offers were rewarding, but given in different amounts. We asked whether we could identify the targets of such corticostriatal circuits when the cortical microstimulation sites were explicitly identified as affecting approach or avoidance in the Ap-Av task. We explored the pACC and caudal orbitofrontal cortex (cOFC) to look for such sites. For each cortical region, we found sites at which microstimulation induced increased avoidance behavior. After identifying these sites, we injected viral tracers carrying constructs allowing subsequent track-tracing post-mortem. For each site identified behaviorally as increasing avoidance choices, we found strong fiber projections to the anterior striatum with large parts of these targeting striosomes subsequently identified by serial section immunohistochemistry. With fMRI, we demonstrated that microstimulation in an anesthetized monkey at sites pre-identified as affecting Ap-Av choices induced blood oxygen level dependent activation of the anterior striatum, confirming that the microstimulation method that we applied was effective in activating the striatum. These findings outline circuits leading from pACC/cOFC to striosomes and causally modulating decision-making under emotional conflict.

Comparison of platinum photodeposition processes on two types of titanium dioxide photocatalysts.

The photodeposition method is useful for the preparation of metal-loaded photocatalysts, by which the metal precursors are adsorbed on the photocatalyst surface and reduced by photoexcited electrons to typically form metallic nanoparticles. In the present study, the photodeposition process of Pt nanoparticles was investigated on anatase and rutile TiO2 photocatalysts. It was found that on the anatase surface, only some of the Pt4+ precursors were first adsorbed in an adsorption equilibrium and reduced to form a smaller number of initial metal species; then, they functioned as electron receivers to reduce the remaining precursors on their metallic surfaces and become larger particles. In contrast, the rutile surface can adsorb most of the precursors and quickly reduce them upon photoirradiation to form nanoparticles, giving a larger number of small nanoparticles. As a result, the Pt-loaded rutile photocatalyst exhibited higher activity in hydrogen evolution from an aqueous methanol solution than the Pt-loaded anatase photocatalyst.

Long-term dopamine neurochemical monitoring in primates.

Many debilitating neuropsychiatric and neurodegenerative disorders are characterized by dopamine neurotransmitter dysregulation. Monitoring subsecond dopamine release accurately and for extended, clinically relevant timescales is a critical unmet need. Especially valuable has been the development of electrochemical fast-scan cyclic voltammetry implementing microsized carbon fiber probe implants to record fast millisecond changes in dopamine concentrations. Nevertheless, these well-established methods have only been applied in primates with acutely (few hours) implanted sensors. Neurochemical monitoring for long timescales is necessary to improve diagnostic and therapeutic procedures for a wide range of neurological disorders. Strategies for the chronic use of such sensors have recently been established successfully in rodents, but new infrastructures are needed to enable these strategies in primates. Here we report an integrated neurochemical recording platform for monitoring dopamine release from sensors chronically implanted in deep brain structures of nonhuman primates for over 100 days, together with results for behavior-related and stimulation-induced dopamine release. From these chronically implanted probes, we measured dopamine release from multiple sites in the striatum as induced by behavioral performance and reward-related stimuli, by direct stimulation, and by drug administration. We further developed algorithms to automate detection of dopamine. These algorithms could be used to track the effects of drugs on endogenous dopamine neurotransmission, as well as to evaluate the long-term performance of the chronically implanted sensors. Our chronic measurements demonstrate the feasibility of measuring subsecond dopamine release from deep brain circuits of awake, behaving primates in a longitudinally reproducible manner.

Realization of red shift of absorption spectra using optical near-field effect.

In many applications such as CO2 reduction and water splitting, high-energy photons in the ultraviolet region are required to complete the chemical reactions. However, to realize sustainable development, the photon energies utilized must be lower than the absorption edge of the materials including the metal complex for CO2 reduction, the electrodes for water splitting, because of the huge amount of lower energy than the visible region received from the sun. In the previous works, we had demonstrated that optical near-fields (ONFs) could realize chemical reactions, by utilizing photon energies much lower than the absorption edge because of the spatial non-uniformity of the electric field. In this paper, we demonstrate that an ONF can realize the red shift of the absorption spectra of the metal-complex material for photocatalytic reduction. By attaching the metal complex to ZnO nano-crystalline aggregates with nano-scale protrusions, the absorption spectra by using diffuse reflection of the metal complex can be shifted to a longer wavelength by 10.6 nm. The results of computational studies based on a first-principles computational program including the ONF effect provide proof of the increase in the absorption of the metal complex at lower photon energies. Since the near-field assisted field increase improves the carrier excitation in the metal-complex materials, this effect may be universal and it could applicable to CO2 reduction using the other metal-complex materials, as well as to the other photo excitation process including water splitting.

A Nickel-Diamine/Mesoporous Silica Composite as a Heterogeneous Chiral Catalyst for Asymmetric 1,4-Addition Reactions.

A chiral composite material, derived from the deposition of a chiral nickel-diamine complex via wet impregnation to MCM-41, was shown to be an efficient heterogeneous catalyst for asymmetric 1,4-addition reactions of 1,3-dicarbonyl compounds with nitroalkenes, and of nitromethane with alkylidenemalonates. It was discovered that MCM-41 enhanced the reactivity and improved the stability of the chiral nickel complex that resides within the mesoporous material.

One-Step Plasma Synthesis of Nb2 O5 Nanofibers and their Enhanced Photocatalytic activity.

Fiberform nanostructured niobium (Nb) was fabricated by one step helium (He) plasma irradiation. He ion implantation formed He nano-bubbles on a Nb plate and led to formation of protrusions while migrating in Nb matrix; fiberform nanostructures (FN) were grown when the fluence became high (>1026  m-2 ). The necessary conditions for the formation of Nb FN were revealed to be the surface temperature range of 900-1100 K and the incident ion energy higher than 70 eV. The sample was oxidized at 573-773 K in an air atmosphere, and Pt nanoparticles were photo-deposited on the Nb2 O5 samples. The surface was analyzed by scanning electron microscope, transmission electron microscope, x-ray photoelectron spectroscopy, and ultraviolet-visible spectrophotometry. Photocatalytic activity of the fabricated materials was studied using methylene blue (MB) decolorization process. An enhanced photocatalytic performance was identified on FN Nb2 O5 substrate with Pt deposition.

11-oxygenated C19 steroids as circulating androgens in women with polycystic ovary syndrome.

11-oxygenated C19 steroids (11oxC19s) are newly specified human androgens. Although median serum levels of 11oxC19 were reported to be higher in patients with polycystic ovary syndrome (PCOS) than in unaffected women, inter-individual variations in androgen levels among PCOS patients have poorly been investigated. Here, we quantified four 11oxC19s, i.e., 11-ketotestosterone (11KT), 11ß-hydroxytestosterone (11OHT), 11ß-hydroxyandrostenedione (11OHΔ4A), and 11-ketoandrostenedione (11KΔ4A), in blood samples of 28 PCOS patients and 31 eumenorrheic women using liquid chromatography-tandem mass spectrometry. We referred to our previous data of classic androgens in these individuals. We found that 11OHT levels were higher in the PCOS group than in the eumenorrheic group. Moreover, although the median values of 11KT, 11KΔ4A, and 11OHΔ4A were comparable between the two groups, these steroids were markedly increased in some patients. Of the 28 patients, 8 had high levels of both 11oxC19s and classic androgens, whereas 4 had an increase only in 11oxC19 levels, and 12 had an increase only in classic androgen levels. Intragroup variations in androgen levels were relatively large in the PCOS group. Levels of 11OHT and 11KT were significantly higher in overweight/obese patients than in normal weight patients and correlated with body mass indexes. These results highlight the clinical significance of 11oxC19s as circulating androgens in PCOS patients and indicate that the accumulation of 11oxC19s and/or classic androgens is an essential feature of PCOS. The profiles of circulating androgens appear to vary among patients. In particular, overweight/obesity likely enhances the 11oxC19s accumulation in PCOS, although this notion awaits further validation.

Robust Binding between Carbon Nitride Nanosheets and a Binuclear Ruthenium(II) Complex Enabling Durable, Selective CO2 Reduction under Visible Light in Aqueous Solution.

Carbon nitride nanosheets (NS-C3 N4 ) were found to undergo robust binding with a binuclear ruthenium(II) complex (RuRu') even in basic aqueous solution. A hybrid material consisting of NS-C3 N4 (further modified with nanoparticulate Ag) and RuRu' promoted the photocatalytic reduction of CO2 to formate in aqueous media, in conjunction with high selectivity (approximately 98 %) and a good turnover number (>2000 with respect to the loaded Ru complex). These represent the highest values yet reported for a powder-based photocatalytic system during CO2 reduction under visible light in an aqueous environment. We also assessed the desorption of RuRu' from the Ag/C3 N4 surface, a factor that can contribute to a loss of activity. It was determined that desorption is not induced by salt additives, pH changes, or photoirradiation, which partly explains the high photocatalytic performance of this material.

Neurogenic pulmonary edema following Cryptococcal meningoencephalitis associated with HIV infection.

Neurogenic pulmonary edema (NPE) is a clinical syndrome characterized by the acute onset of pulmonary edema following a significant central nervous system insult. Only a few cases of NPE after Cryptococcal meningitis have been reported. We report a case of NPE following Cryptococcal meningoencephalitis. A 40-year-old man with no medical history was hospitalized for disturbance of consciousness. Blood glucose level was 124 mg/dL. Non-contrast head computed tomography showed no abnormalities. Lumbar puncture revealed a pressure of over 300 mm H2 O and cerebrospinal fluid (CSF) confirmed a white blood cell count of 65/mm(3) . The CSF glucose level was 0 mg/dL. The patient was empirically started on treatment for presumptive bacterial and viral meningitis. Four days after, the patient died in a sudden severe pulmonary edema. Autopsy was performed. We found at autopsy a brain edema with small hemorrhage of the right basal ganglia, severe pulmonary edema and mild cardiomegaly. Histologically, dilated Virchow-Robin spaces, crowded with Cryptococci were observed. In the right basal ganglia, Virchow-Robin spaces were destroyed with hemorrhage and Cryptococci spread to parenchyma of the brain. No inflammatory reaction of the lung was seen. Finally, acute pulmonary edema in this case was diagnosed as NPE following Cryptococcal meningoencephalitis. After autopsy, we found that he was positive for serum antibodies to human immunodeficiency virus.

Impact of Childhood Cancer on Growth.

Along with improvements in cancer treatment over time, the number of childhood cancer survivors has been growing. Survivors are at risk for serious medical complications, and growth impairment is among the most common. There are multiple factors that may cause impaired growth among survivors. In this article, we review the impact of cancer on growth in children and adolescents. We first provide an overview of growth disturbance among childhood cancer patients and survivors due to nonhormonal causes, including a recent understanding of the effect of targeted cancer therapies (eg, tyrosine kinase inhibitors and immune checkpoint inhibitors) on growth. Then we describe the hormonal causes of growth impairment among survivors, focusing on growth hormone deficiency, including the prevalence, risk factors, and treatment. Lastly, we briefly summarize overgrowth and tall stature in childhood cancer. It is critical to assess the linear growth of children and adolescents, especially in cancer survivors who are at risk for growth disturbance, since growth is an important measure of their health.

Developmental and adult striatal patterning of nociceptin ligand marks striosomal population with direct dopamine projections.

Circuit influences on the midbrain dopamine system are crucial to adaptive behavior and cognition. Recent developments in the study of neuropeptide systems have enabled high-resolution investigations of the intersection of neuromodulatory signals with basal ganglia circuitry, identifying the nociceptin/orphanin FQ (N/OFQ) endogenous opioid peptide system as a prospective regulator of striatal dopamine signaling. Using a prepronociceptin-Cre reporter mouse line, we characterized highly selective striosomal patterning of Pnoc mRNA expression in mouse dorsal striatum, reflecting early developmental expression of Pnoc . In the ventral striatum, Pnoc expression was was clustered across the nucleus accumbens core and medial shell, including in adult striatum. We found that Pnoc tdTomato reporter cells largely comprise a population of dopamine receptor D1 ( Drd1 ) expressing medium spiny projection neurons localized in dorsal striosomes, known to be unique among striatal projections neurons for their direct innervation of midbrain dopamine neurons. These findings provide new understanding of the intersection of the N/OFQ system among basal ganglia circuits with particular implications for developmental regulation or wiring of striatal-nigral circuits.

Hypogonadism and neurocognitive outcomes among childhood cancer survivors.

OBJECTIVE: Childhood cancer survivors are at risk for hypogonadism. The impact of hypogonadism on neurocognitive impairment and emotional distress in the non-cancer population has been shown; however, the relationship among the childhood cancer survivor population is unknown. We aimed to evaluate the contribution of hypogonadism to neurocognitive impairment and emotional distress among survivors. DESIGN: Cross-sectional study using retrospective cohort. METHODS: In total, 3628 survivors who completed standard neurocognitive tests (six domains: processing speed, memory, executive function, attention, academics, and global cognition) and self-reported emotional distress were included in our study. Participants were stratified by sex and gonadal status. Outcomes were compared between hypogonadal and eugonadal groups by multivariable analysis, adjusting for established predictors, and mediation analyses to determine the direct/indirect effects of hypogonadism on outcomes. RESULTS: The hypogonadal group exhibited a higher prevalence of neurocognitive impairment across domains, but no difference in emotional distress. Hypogonadal females exhibited higher relative risk (1.7, 95% CI, 1.2-2.5) for impaired visual processing speed, compared to eugonadal females after adjusting for cancer-related variables. In mediation models, hypogonadism had a significant direct (P < .01) and indirect (from P < .01) impact on impairment in visual processing speed among females. Males demonstrated direct (P = .03) and indirect (P = .04) impact of hypogonadism on motor processing speed. CONCLUSION: Processing speed may be the most vulnerable neurocognitive domain associated with hypogonadism in survivors, while other domains were mainly impacted by cancer-related variables. Our findings support the need for further evaluation of the impact of sex hormone replacement therapy on neurocognitive function.

Striosomes Target Nigral Dopamine-Containing Neurons via Direct-D1 and Indirect-D2 Pathways Paralleling Classic Direct-Indirect Basal Ganglia Systems.

The classic output pathways of the basal ganglia are known as the direct-D1 and indirect-D2, or Go/No-Go, pathways. Balance of the activity in these canonical direct-indirect pathways is considered a core requirement for normal movement control, and their imbalance is a major etiologic factor in movement disorders including Parkinsons disease. We present evidence for a conceptually equivalent parallel system of direct-D1 and indirect-D2 pathways that arise from striatal projection neurons (SPNs) of the striosome compartment rather than from the matrix. These striosomal direct (S-D1) and indirect (S-D2) pathways, as a pair, target dopamine-containing neurons of the substantia nigra (SNpc) instead of the motor output nuclei of the basal ganglia. The novel anatomically and functionally distinct indirect-D2 striosomal pathway targets dopaminergic SNpc cells indirectly via a core region of the external pallidum (GPe). We demonstrate that these S-D1 and S-D2 pathways oppositely modulate striatal dopamine release in freely behaving mice under open-field conditions and oppositely modulate locomotor and other movements. These S-D1 and S-D2 pathways further exhibit different, time-dependent responses during performance of a probabilistic decision-making maze task and respond differently to rewarding and aversive stimuli. These contrasts depend on mediolateral and anteroposterior striatal locations of the SPNs as are the classic direct and indirect pathways. The effects of S-D1 and S-D2 stimulation on striatal dopamine release and voluntary locomotion are nearly opposite. The parallelism of the direct-indirect circuit design motifs of the striosomal S-D and S-D2 circuits and canonical matrix M-D1 and M-D2, and their contrasting behavioral effects, call for a major reformulation of the classic direct-indirect pathway model of basal ganglia function. Given that some striosomes receive limbic and association cortical inputs, the S-D1 and S-D2 circuits likely influence motivation for action and behavioral learning, complementing and possibly reorienting the motoric activities of the canonical matrix pathways. At a fundamental level, these findings suggest a unifying framework for aligning two sets of circuits that share the organizational motif of opponent D1 and D2 regulation, but that have different outputs and can even have opposite polarities in their targets and effects, albeit conditioned by striatal topography. Our findings further delineate a potentially therapeutically important set of pathways influencing dopamine, including a D2 receptor-linked S-D2 pathway likely unknowingly targeted by administration of many therapeutic drugs including those for Parkinsons disease. The novel parallel pathway model that we propose here could help to account for the normally integrated modulatory influence of the basal ganglia on motivation for actions as well as the actions themselves.

Parg deficiency confers radio-sensitization through enhanced cell death in mouse ES cells exposed to various forms of ionizing radiation.

Poly(ADP-ribose) glycohydrolase (Parg) is the main enzyme involved in poly(ADP-ribose) degradation. Here, the effects of Parg deficiency on sensitivity to low and high linear-energy-transfer (LET) radiation were investigated in mouse embryonic stem (ES) cells. Mouse Parg(-/-) and poly(ADP-ribose) polymerase-1 deficient (Parp-1(-/-)) ES cells were used and responses to low and high LET radiation were assessed by clonogenic survival and biochemical and biological analysis methods. Parg(-/-) cells were more sensitive to γ-irradiation than Parp-1(-/-) cells. Transient accumulation of poly(ADP-ribose) was enhanced in Parg(-/-) cells. Augmented levels of phosphorylated H2AX (γ-H2AX) from early phase were observed in Parg(-/-) ES cells. The induction level of p53 phophorylation at ser18 was similar in wild-type and Parp-1(-/-) cells and apoptotic cell death process was mainly observed in the both genotypes. These results suggested that the enhanced sensitivity of Parg(-/-) ES cells to γ-irradiation involved defective repair of DNA double strand breaks. The effects of Parg and Parp-1 deficiency on the ES cell response to carbon-ion irradiation (LET13 and 70 keV/µm) and Fe-ion irradiation (200 keV/µm) were also examined. Parg(-/-) cells were more sensitive to LET 70 keV/µm carbon-ion irradiation than Parp-1(-/-) cells. Enhanced apoptotic cell death also accompanied augmented levels of γ-H2AX in a biphasic manner peaked at 1 and 24h. The induction level of p53 phophorylation at ser18 was not different between wild-type and Parg(-/-) cells. The augmented level of poly(ADP-ribose) accumulation was noted after carbon-ion irradiation compared to γ-irradiation even in the wild-type cells. An enhanced poly(ADP-ribose) accumulation was further observed in Parg(-/-) cells. Both Parg(-/-) cells and Parp-1(-/-) cells did not show sensitization to Fe-ion irradiation. Parg deficiency sensitizes mouse ES cells to a wide therapeutic range of LET radiation through the effects on DNA double strand break repair responses and enhanced cell death.

Rapid degradation of poly(ADP-ribose) after injection into the mouse bloodstream.

Extensive DNA damage leads to the activation of poly(ADP-ribose) polymerase and subsequently to the formation of poly(ADP-ribose). When the damage is severe or leads to cell death, poly(ADP-ribose) may leak into the blood circulation. The metabolism of poly(ADP-ribose) in the bloodstream is not well understood. Thus, in the present study, the metabolism of P-labeled poly(ADP-ribose) was followed in mice after injection of this labeled compound into the tail vein. The results showed that 5 min after injection more than half of the radioactivity was concentrated in acid-soluble fractions, namely in low molecular weight compounds in the blood, liver, and kidneys. Most of this radioactivity was in the form of inorganic phosphate, detected 5 min post-injection in the blood, kidneys, and urine. By contrast, the metabolites ADP-ribose and phosphoribosyl-AMP were not detected in any of the tissues nor in blood or urine. Taken together, these findings suggest that once poly(ADP-ribose) enters the bloodstream it is rapidly degraded, thereby preventing its accumulation in the blood.