IMPDH inhibition activates TLR-VCAM1 pathway and suppresses the development of MLL-fusion leukemia.

Inosine monophosphate dehydrogenase (IMPDH) is a rate-limiting enzyme in de novo guanine nucleotide synthesis pathway. Although IMPDH inhibitors are widely used as effective immunosuppressants, their antitumor effects have not been proven in the clinical setting. Here, we found that acute myeloid leukemias (AMLs) with MLL-fusions are susceptible to IMPDH inhibitors in vitro. We also showed that alternate-day administration of IMPDH inhibitors suppressed the development of MLL-AF9-driven AML in vivo without having a devastating effect on immune function. Mechanistically, IMPDH inhibition induced overactivation of Toll-like receptor (TLR)-TRAF6-NF-κB signaling and upregulation of an adhesion molecule VCAM1, which contribute to the antileukemia effect of IMPDH inhibitors. Consequently, combined treatment with IMPDH inhibitors and the TLR1/2 agonist effectively inhibited the development of MLL-fusion AML. These findings provide a rational basis for clinical testing of IMPDH inhibitors against MLL-fusion AMLs and potentially other aggressive tumors with active TLR signaling.

Detailed analysis of social support and proactive coping with depressive symptoms in Japanese HIV-infected individuals.

The aim of this study was to determine the association of the type of social support and proactive coping with depressive symptoms (DS) in Japanese people living with human immunodeficiency virus (PLHIV), in order to select effective psychosocial care or intervention. Questionnaires were anonymously collected from randomly recruited participants. The questionnaire included items on demographic characteristics, HIV treatment-related factors, DS, social support, and coping. Hierarchical binary logistic regression was used to identify factors associated with DS. A total of 564 patients completed the questionnaire and 207 (37%) patients reported DS. Demographic factors, such as drug-use-related disorders [adjusted odds ratio (AOR) 7.21, 95% confidence interval (95%CI) 1.95-26.70], unemployment (AOR 3.06, 95%CI 1.50-6.27) and younger age (AOR 0.96, 95%CI 0.94-0.99) were significantly associated with DS. With regard to coping, higher levels of instrumental support seeking (AOR 1.09, 95%CI 1.01-1.18), lower levels of proactive coping (AOR 0.91, 95%CI 0.87-0.96) and lower levels of emotional support seeking (AOR 0.82, 95%CI 0.72-0.92) were significantly associated with DS. Our results highlight the need for psychosocial care to enhance or compensate proactive coping and emotional support seeking abilities in DS. Healthcare workers should pay attention to the mental health of young unemployed PLHIV with drug-use-related disorders.

Neurocognitive dysfunction and brain FDG-PET/CT findings in HIV-infected hemophilia patients and HIV-infected non-hemophilia patients.

This single-institution cross-sectional study aimed to grasp the prevalence and features of neurocognitive dysfunction in HIV-infected hemophilia patients in Japan. We conducted neuropsychological tests and medical examinations in 56 HIV-infected hemophilia patients who received outpatient treatment at the AIDS Clinical Center, National Center for Global Health and Medicine. A total of 388 HIV-infected non-hemophilia patients who received outpatient treatment at the same institution were included as a control group. To investigate sites responsible for neurocognitive dysfunction in HIV-infected hemophilia patients using brain FDG-PET/CT scans, the accumulation of FDG in each brain region was compared. Approximately 50% of HIV-infected hemophilia patients had neurocognitive dysfunction. The prevalence of asymptomatic neurocognitive impairment was high (34%). Neurocognitive dysfunction was associated with educational level in HIV-infected hemophilia patients. In the symptomatic group, hemophilic arthropathy and history of cerebrovascular disorders were associated with neurocognitive dysfunction. Left temporal lobe function was reduced in the symptomatic group.

Author Correction: Warm hole in Pacific Arctic sea ice cover forced mid-latitude Northern Hemisphere cooling during 2017-18.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Warm hole in Pacific Arctic sea ice cover forced mid-latitude Northern Hemisphere cooling during 2017-18.

In North America and Asia, extreme cold weather characterized the winter of 2017-18. At the same time, the Pacific, the Bering Sea, and the Atlantic Arctic regions experienced anomalously low sea ice extent in the early winter. The jet stream dividing cold Arctic air from warm air deviated from normal zonal patterns northward into the ice-free areas north of the Bering Strait. Large southward jet stream pathways formed over Asia and America, allowing cold air to spread into Asia and the southern areas of North America. We hypothesise that the late autumn Bering Strait sea-ice anomaly and Pacific atmospheric rivers were partially responsible for the cold winter. We used data analyses and numerical experiments to test this hypothesis. We propose a positive feedback mechanism between the sea ice anomaly and atmospheric river activity, with anomalous south winds toward the sea ice anomaly potentially leading to more warm water injected by the wind-driven current through the Bering Strait. Our findings suggest that Poleward propagation of the atmospheric rivers made upper air warm, leading to their upgliding, which further heated the overlying air, causing poleward jet meanders. As a part of this response the jet stream meandered southward over Asia and North America, resulting in cold intrusions. We speculate that the positive feedback mechanism observed during the 2017-18 winter could recur in future years when the sea-ice reduction in the Pacific Arctic interacts with enhanced atmospheric river activity.

Various associations of aging and long-term HIV infection with different neurocognitive functions: detailed analysis of a Japanese nationwide multicenter study.

Detailed information of the effects of age and long-term HIV infection on various neurocognitive function have not been fully evaluated yet. In a prospective Japanese nationwide multicenter study of 17 facilities (J-HAND study), 728 HIV-infected individuals completed 14 neuropsychological (NP) tests; Verbal Fluency (VF; category and letter), Digit Span (DS; forward and backward), Trail Making Test (TMT) A-B, Rey-Osterrieth Complex Figure Test (ROCFT; copy, immediate and delayed recall), Story Memory Test (SMT; immediate and delayed recall), Digit Symbol Subset (DSS), and the Grooved Pegboard (GP; dominant and non-dominant). Multivariate analysis identified older age (≥ 50 years) to be associated with lower scores in all three ROCFT and GP dominant [odds ratio (OR) [95% confidence interval (CI)] 1.801 (1.217-2.664), 2402 (1.366-3.055), 2.691 (1.720-4.211), and 2.302 (1.145-4.628), respectively], whereas longer time since diagnosis was associated with a lower score in ROCFT (delayed recall) (OR 1.224, 95%CI 1.045-1.434). In VF letter, older age and longer time since diagnosis were associated with a better score [OR (95%CI) 0.449 (0.234-0.861) and 0.831 (0.692-0.997)]. In DSS and TMT-A, longer time since diagnosis was associated with a better score [OR (95%CI): 0.808 (0.670-0.973) and 0.795 (0.665-0.949), respectively]. Older patients in later years since diagnosis are at higher risk of visuospatial and motor impairments despite ART, whereas they are less likely to develop verbal impairment, suggesting that verbal function is relatively resistant to aging and long history of HIV infection under ART. These findings suggest that customtailored supports should be established based on the individual background.

Poleward upgliding Siberian atmospheric rivers over sea ice heat up Arctic upper air.

We carried out upper air measurements with radiosondes during the summer over the Arctic Ocean from an icebreaker moving poleward from an ice-free region, through the ice edge, and into a region of thick ice. Rapid warming of the Arctic is a significant environmental issue that occurs not only at the surface but also throughout the troposphere. In addition to the widely accepted mechanisms responsible for the increase of tropospheric warming during the summer over the Arctic, we showed a new potential contributing process to the increase, based on our direct observations and supporting numerical simulations and statistical analyses using a long-term reanalysis dataset. We refer to this new process as "Siberian Atmospheric Rivers (SARs)". Poleward upglides of SARs over cold air domes overlying sea ice provide the upper atmosphere with extra heat via condensation of water vapour. This heating drives increased buoyancy and further strengthens the ascent and heating of the mid-troposphere. This process requires the combination of SARs and sea ice as a land-ocean-atmosphere system, the implication being that large-scale heat and moisture transport from the lower latitudes can remotely amplify the warming of the Arctic troposphere in the summer.

Molecular targeting of inosine-5'-monophosphate dehydrogenase by FF-10501 promotes erythropoiesis via ROS/MAPK pathway.

One of the major symptoms of myelodysplastic syndromes (MDS) is severe cytopenia. Despite cytokine therapies, such as erythropoiesis-stimulating agents, many patients still require blood transfusions, and the development of new therapeutic approaches is needed. In this work, we studied the effects of the inosine-5'-monophosphate (IMP) dehydrogenase (IMPDH) inhibitor FF-10501 on erythropoiesis of human hematopoietic cells. Differentiation of K562 chronic myeloid leukemia cells to an erythroid lineage was promoted by FF-10501 in a dose-dependent manner. Interestingly, we found that metabolic conversion of IMP to hypoxanthine leads to elevation of reactive oxygen species (ROS). The differentiative effects of FF-10501 were abolished by the ROS scavenger dimethylthiourea or the p38 MAPK inhibitor SB203580. Furthermore, FF-10501 promoted erythropoiesis from CD34+ hematopoietic stem/progenitor cells, accompanied with ROS accumulation, while high-dose FF-10501 mainly showed cytotoxic effects. These findings denote the potential of IMPDH inhibition therapy with FF-10501 in amelioration of anemia in MDS patients.

Association of age and time of disease with HIV-associated neurocognitive disorders: a Japanese nationwide multicenter study.

There is no detailed information on the association between age, time of disease, and HIV-associated neurocognitive disorders (HAND). In this prospective study involving 17 medical facilities across Japan, we recruited HIV-infected patients to complete a 14-test neuropsychological battery that assess eight neurocognitive domains. HAND were diagnosed by the Frascati criteria. Of 1399 recruited patients, 728 were enrolled. The prevalence of HAND was 25.3% [13.5% asymptomatic neurocognitive impairment, 10.6% mild neurocognitive disorder (MND), and 1.2% HIV-associated dementia (HAD)]. Tests that assess executive and visuospatial functions showed better diagnostic accuracy than other tests for HAND. Multivariate analysis identified age (≥ 50 years) and incomplete virological suppression as risk factors for MND and HAD and current ART as a protective factor. The prevalence of MND and HAD was low in the early stage of infection (6.3% in ≥ 2 to < 6 years), then increased in the later stage [17.3% in ≥ 11 years, p = 0.001 (vs. ≥ 2 to < 6 years)], independent of age or treatment. Older patients were more likely to show MND or HAD in the early stage of HIV infection (26.7 vs. 8.7% for < 2 years and 17.4 vs. 3.1% for ≥ 2 to < 6 years, p = 0.040 and 0.004, respectively) compared to younger ones. In conclusion, MND and HAD were more commonly found in later years since diagnosis of HIV infection and older patients are at risk of neurocognitive impairment at the early stage of HIV infection. Tests for executive and visuospatial functions seem more sensitive than other tests for diagnosing HAND.

Lack of cross-resistance to FF-10501, an inhibitor of inosine-5'-monophosphate dehydrogenase, in azacitidine-resistant cell lines selected from SKM-1 and MOLM-13 leukemia cell lines.

Resistance to azacitidine is a major issue in the treatments of myelodysplastic syndrome and acute myeloid leukemia, and previous studies suggest that changes in drug metabolism are involved in the resistance. Therefore, drugs with mechanisms resistant or alternative to such metabolic changes have been desired for the treatment of resistant disease. We generated azacitidine-resistant cells derived from SKM-1 and MOLM-13 leukemia cell lines in vitro, analyzed the mechanisms, and examined the impact on the efficacy of other antimetabolic drugs. It appeared that the cell growth-inhibitory effect of azacitidine, expression levels of uridine-cytidine kinase 2, and the concentrations of azacitidine triphosphate were remarkably decreased in the resistant cells compared with those in parent cells. These results were consistent with previous observations that azacitidine resistance is derived from metabolic changes. Cross-resistance of greater than 10-fold (shift in IC50 value) was observed in azacitidine-resistant cells for decitabine and for cytarabine, but not for gemcitabine or the inosine-5'-monophosphate dehydrogenase (IMPDH) inhibitors FF-10501 and mycophenolate mofetil (cross-resistance to 5-fluorouracil was cell line dependent). The IMPDH inhibitors maintained their cell growth-inhibitory activities in the azacitidine-resistant cell lines, in which the levels of adenine phosphoribosyltransferase (which converts FF-10501 to its active form, FF-10501 ribosylmonophosphate [FF-10501RMP]), FF-10501RMP, and the target enzyme, IMPDH, were equivalent to those in the parent cell lines. These results suggest that an IMPDH inhibitor such as FF-10501 could be an alternative therapeutic treatment for leukemia patients with acquired resistance to azacitidine.

Mechanism of Protein Molecule Isolation by IR Laser Ablation of Droplet Beam.

Gas-phase isolation of bovine serum albumin (BSA) from aqueous solutions is performed by IR laser ablation of a droplet beam. Multiply charged BSA ions (positive and negative) were produced by the IR laser irradiation onto a droplet beam of aqueous BSA solutions with various pH values prepared by addition of hydrochloric acid or sodium hydroxide to the solution. The isolation mechanism was discussed based on the charge state of the isolated BSA ions. A nanodroplet model explains the gas-phase charge distribution of the BSA ions. This study provides a fundamental basis for further studies of a wide variety of biomolecules in the gas phase isolated directly from solution.

Psychological and mental health problems in patients with thalidomide embryopathy in Japan.

AIM: The aim of the study was to examine the presence of psychological and mental health problems in patients with thalidomide embryopathy in Japan in order to develop and build future support systems. METHODS: The present study examined the presence/absence of electroencephalographic abnormalities, intellectual/cognitive functions, and mental health problems in 22 participants (nine men, 13 women) with thalidomide embryopathy. Participants completed the electroencephalograph instrument. Participants were also assessed using the Wechsler Adult Intelligence Scale-III; the Autism-Spectrum Quotient; the General Health Questionnaire-28, and the Mini-International Neuropsychiatric Interview. RESULTS: The results suggest the following: (i) electroencephalographic abnormality observed in several thalidomide embryopathy participants is unlikely to be the direct result of thalidomide; (ii) the cognitive functions of working memory and processing speed are lower in thalidomide embryopathy patients than in healthy individuals; and (iii) 40.9% of the thalidomide embryopathy participants have possible mental disorders, with more mental problems observed than in healthy individuals. CONCLUSIONS: Deterioration of mental health in patients with thalidomide embryopathy is indicated. Anxiety, insomnia, and physical symptoms were especially remarkable and may have resulted in restriction of social activities. Therefore, careful examination and active support of patients' psychological and mental problems is essential.

Development of an iminocoumarin-based zinc sensor suitable for ratiometric fluorescence imaging of neuronal zinc.

Ratiometric imaging is a technique to reduce artifacts by minimizing the influence of extraneous factors on the fluorescence of a sensor and is particularly useful for cellular imaging studies. Here we characterized the iminocoumarin fluorophore as a new scaffold for sensors for ratiometric imaging. The iminocoumarin 4 showed a high quantum yield in aqueous media on excitation in the visible wavelength region, while its coumarin analogue showed little fluorescence. We therefore developed a novel fluorescence probe, ZnIC, for ratiometric imaging of Zn2+, using iminocoumarin as a fluorophore and (ethylamino)dipicolylamine as a Zn2+ chelator. ZnIC exhibited almost the same fluorescence properties as 4, and the emission spectrum of this probe was red-shifted on addition of Zn2+ under physiological conditions. ZnIC is selective for Zn2+ over other biologically important metal ions, such as Ca2+ and Mg2+, and has high affinity for Zn2+. To confirm the suitability of ZnIC for biological applications, we employed it for the ratiometric detection of changes in intracellular Zn2+ in cultured cells and in rat hippocampal slices. The results indicate that iminocoumarin is a useful fluorophore for fluorescence microscopic imaging and that ZnIC should be useful for studies on the biological functions of Zn2+.

Selective zinc sensor molecules with various affinities for Zn2+, revealing dynamics and regional distribution of synaptically released Zn2+ in hippocampal slices.

We have developed a series of fluorescent Zn(2+) sensor molecules with distinct affinities for Zn(2+), because biological Zn(2+) concentrations vary over a wide range from sub-nanomolar to millimolar. The new sensors have K(d) values in the range of 10(-8)-10(-4) M, compared with 2.7 nM for ZnAF-2. They do not fluoresce in the presence of other biologically important metal ions such as calcium or magnesium, and they can detect Zn(2+) within 100 ms. In cultured cells, the fluorescence intensity of ZnAF-2 was saturated at low Zn(2+) concentration, while that of ZnAF-3 (K(d) = 0.79 muM) was not saturated even at relatively high Zn(2+) concentrations. In hippocampal slices, we measured synaptic release of Zn(2+) in response to high-potassium-induced depolarization. ZnAF-2 showed similar levels of fluorescence increase in dentate gyrus (DG), CA3 and CA1, which were indistinguishable. However, ZnAF-3 showed a fluorescence increase only in DG. Thus, by using a combination of sensor molecules, it was demonstrated for the first time that a higher Zn(2+) concentration is released in DG than in CA3 or CA1 and that we can easily visualize Zn(2+) concentration over a wide range. We believe that the use of various combinations of ZnAF family members will offer unprecedented versatility for fluorescence-microscopic imaging of Zn(2+) in biological applications.

Zinc sensing for cellular application.

Numerous tools for Zn2+ sensing in living cells have become available in the past three years. Among them, fluorescence imaging using fluorescent sensor molecules has been the most popular approach. Some of these sensor molecules can be used to visualize Zn2+ in living cells. Some of the biological functions of Zn2+ have been clarified using these sensor molecules, especially in neuronal cells, which contain a high concentration of free Zn2+.