Viral entry and translation in brain endothelia provoke influenza-associated encephalopathy

The version of record of this article, first published in Acta Neuropathologica, is available online at Publisher’s website: https://doi.org/10.1007/s00401-024-02723-z.Influenza-associated encephalopathy (IAE) is extremely acute in onset, with high lethality and morbidity within a few days, while the direct pathogenesis by influenza virus in this acute phase in the brain is largely unknown. Here we show that influenza virus enters into the cerebral endothelium and thereby induces IAE. Three-weeks-old young mice were inoculated with influenza A virus (IAV). Physical and neurological scores were recorded and temporal-spatial analyses of histopathology and viral studies were performed up to 72 h post inoculation. Histopathological examinations were also performed using IAE human autopsy brains. Viral infection, proliferation and pathogenesis were analyzed in cell lines of endothelium and astrocyte. The effects of anti-influenza viral drugs were tested in the cell lines and animal models. Upon intravenous inoculation of IAV in mice, the mice developed encephalopathy with brain edema and pathological lesions represented by micro bleeding and injured astrocytic process (clasmatodendrosis) within 72 h. Histologically, massive deposits of viral nucleoprotein were observed as early as 24 h post infection in the brain endothelial cells of mouse models and the IAE patients. IAV inoculated endothelial cell lines showed deposition of viral proteins and provoked cell death, while IAV scarcely amplified. Inhibition of viral transcription and translation suppressed the endothelial cell death and the lethality of mouse models. These data suggest that the onset of encephalopathy should be induced by cerebral endothelial infection with IAV. Thus, IAV entry into the endothelium, and transcription and/or translation of viral RNA, but not viral proliferation, should be the key pathogenesis of IAE

松前公園(北海道) のシロバナタンポポの核型

摘要 北海道松前町の松前公園・龍雲院にはシロバナタンポポが生育している。シロバナタンポポは本州（関東・北陸以西），四国，九州に自生し，東北以北では松前公園だけに存在することから移入されたと考えられている。シロバナタンポポには，四倍体 （2n=32）と五倍体（2n=40）があり，五倍体には核型の異なる2型 （Type I, TypeⅡ）が存在することが知られていることから，松前公園のシロバナタンポポがどのタイプかを明らかにするために，種子から育てた2個体について染色体観察を行った。その結果，松前公園のシロバナタンポポは五倍体（2n=40）であり，核型はSato et al. （2011）で報告した五倍体の2つの型の内のType Iであることが判った

Glycolysis Inhibition Inactivates ABC Transporters to Restore Drug Sensitivity in Malignant Cells

Cancer cells eventually acquire drug resistance largely via the aberrant expression of ATP-binding cassette (ABC) transporters, ATP-dependent efflux pumps. Because cancer cells produce ATP mostly through glycolysis, in the present study we explored the effects of inhibiting glycolysis on the ABC transporter function and drug sensitivity of malignant cells. Inhibition of glycolysis by 3-bromopyruvate (3BrPA) suppressed ATP production in malignant cells, and restored the retention of daunorubicin or mitoxantrone in ABC transporter-expressing, RPMI8226 (ABCG2), KG-1 (ABCB1) and HepG2 cells (ABCB1 and ABCG2). Interestingly, although side population (SP) cells isolated from RPMI8226 cells exhibited higher levels of glycolysis with an increased expression of genes involved in the glycolytic pathway, 3BrPA abolished Hoechst 33342 exclusion in SP cells. 3BrPA also disrupted clonogenic capacity in malignant cell lines including RPMI8226, KG-1, and HepG2. Furthermore, 3BrPA restored cytotoxic effects of daunorubicin and doxorubicin on KG-1 and RPMI8226 cells, and markedly suppressed subcutaneous tumor growth in combination with doxorubicin in RPMI8226-implanted mice. These results collectively suggest that the inhibition of glycolysis is able to overcome drug resistance in ABC transporter-expressing malignant cells through the inactivation of ABC transporters and impairment of SP cells with enhanced glycolysis as well as clonogenic cells

Redefining Diastolic Dysfunction Grading Combination of E/A ≤0.75 and Deceleration Time >140 ms and E/ε′ ≥10

AbstractObjectivesThis study sought to examine left atrial (LA) mechanics and the prognostic impact of patients with echocardiographic findings of E/A ratio ≤0.75, deceleration time (DcT) of mitral E-wave >140 ms, but E/ε′ ≥10.BackgroundTraditional diastolic dysfunction (DD) grading system could not classify every patient into a specific group. We considered the group of patients with E/A ≤0.75, DcT >140 ms, but E/ε′ ≥10 (proposed new DD grade) as a new group in the DD grading system.MethodsA total of 1,362 consecutive patients were stratified according to the new DD grading system, and the LA volumes, strain, and strain rates were measured by 2-dimensional speckle-tracking analysis. All patients were followed up to determine cardiac death and major adverse cardiac events.ResultsAn E/A ≤0.75, DcT >140 ms, but E/ε′ ≥10 was observed in 227 patients (17%). LA volumes in patients with the new DD grade were between those of the impaired relaxation group and the pseudonormal group. LA strain of the new DD grade was similar to that of the pseudonormal group, whereas LA booster function was preserved as in the impaired relaxation group. During a mean follow-up of 3.0 ± 1.1 years, 25 patients had cardiac death and 61 had major adverse cardiac events. Event-free survival for major adverse cardiac events of the new DD grade was worse than that of the impaired relaxation group but similar to that of the pseudonormal group.ConclusionsThe new DD grade is frequently observed and has a prognosis similar to that of the pseudonormal group but significantly worse than that of the impaired relaxation group. However, LA booster function was maintained at the expense of LA volume enlargement. Thus, the new grade should be a distinct entity for routine DD grading

CO(JJ=1-0) mapping survey of 64 galaxies in the Fornax cluster with the ALMA Morita array

We conduct a $^{12}$C$^{16}$O($J$=1-0) (hereafter CO) mapping survey of 64 galaxies in the Fornax cluster using the ALMA Morita array in cycle 5. CO emission is detected from 23 out of the 64 galaxies. Our sample includes dwarf, spiral and elliptical galaxies with stellar masses of $M_{\rm star}\sim10^{6.3-11.6}$~M$_\odot$. The achieved beam size and sensitivity are $15''\times8''$ and $\sim12$~mJy~beam$^{-1}$ at the velocity resolution of $\sim10$~km~s$^{-1}$, respectively. We study the cold-gas (molecular- and atomic-gas) properties of 38 subsamples with $M_{\rm star}>10^9$~M$_\odot$ combined with literature HI data. We find that: (1) the low star-formation (SF) activity in the Fornax galaxies is caused by the decrease in the cold-gas mass fraction with respect to stellar mass (hereafter, gas fraction) rather than the decrease of the SF efficiency from the cold gas; (2) the atomic-gas fraction is more heavily reduced than the molecular-gas fraction of such galaxies with low SF activity. A comparison between the cold-gas properties of the Fornax galaxies and their environmental properties suggests that the atomic gas is stripped tidally and by the ram pressure, which leads to the molecular gas depletion with an aid of the strangulation and consequently SF quenching. Pre-processes in the group environment would also play a role in reducing cold-gas reservoirs in some Fornax galaxies.Comment: 53 pages, 41 figures, accepted for publication in ApJ

Pim-2 in myeloma cells

Bone marrow stromal cells (BMSCs) and osteoclasts (OCs) confer multiple myeloma (MM) cell survival through elaborating factors. We demonstrate herein that IL-6 and TNF family cytokines, TNFα, BAFF and APRIL, but not IGF-1 cooperatively enhance the expression of the serine/threonine kinase Pim-2 in MM cells. BMSCs and OCs upregulate Pim-2 expression in MM cells largely via the IL-6/STAT3 and NF-ｋB pathway, respectively. Pim-2 short interfering RNA reduces MM cell viability in cocultures with BMSCs or OCs. Thus, upregulation of Pim-2 appears to be a novel anti-apoptotic mechanism for MM cell survival. Interestingly, the mammalian target of rapamycin inhibitor rapamycin further suppresses the MM cell viability in combination with the Pim-2 silencing. The Pim inhibitor (Z)-5-(4-propoxybenzylidene) thiazolidine-2, 4-dione and the PI3K inhibitor LY294002 cooperatively enhance MM cell death. The Pim inhibitor suppresses 4E-BP1 phosphorylation along with the reduction of Mcl-1 and c-Myc. Pim-2 may therefore become a new target for MM treatment