We prove a finiteness theorem and a comparison theorem in the theory of étale cohomology of rigid analytic varieties. By a result of Huber, for a quasi-compact separated morphism of rigid analytic ...varieties with target being of dimension
≤
1
, the compactly supported higher direct image preserves quasi-constructibility. Though the analogous statement for morphisms with higher dimensional target fails in general, we prove that, in the algebraizable case, it holds after replacing the target with a modification. We deduce it from a known finiteness result in the theory of nearby cycles over general bases and a new comparison result, which gives an identification of the compactly supported higher direct image sheaves, up to modification of the target, in terms of nearby cycles over general bases.
Ferroptosis is an iron-dependent programmed cell death event, whose regulation and physiological significance remain to be elucidated. Analyzing transcriptional responses of mouse embryonic ...fibroblasts exposed to the ferroptosis inducer erastin, here we found that a set of genes related to oxidative stress protection is induced upon ferroptosis. We considered that up-regulation of these genes attenuates ferroptosis induction and found that the transcription factor BTB domain and CNC homolog 1 (BACH1), a regulator in heme and iron metabolism, promotes ferroptosis by repressing the transcription of a subset of the erastin-induced protective genes. We noted that these genes are involved in the synthesis of GSH or metabolism of intracellular labile iron and include glutamate-cysteine ligase modifier subunit (Gclm), solute carrier family 7 member 11 (Slc7a11), ferritin heavy chain 1 (Fth1), ferritin light chain 1 (Ftl1), and solute carrier family 40 member 1 (Slc40a1). Ferroptosis has also been previously shown to induce cardiomyopathy, and here we observed that Bach1−/− mice are more resistant to myocardial infarction than WT mice and that the severity of ischemic injury is decreased by the iron-chelator deferasirox, which suppressed ferroptosis. Our findings suggest that BACH1 represses genes that combat labile iron-induced oxidative stress, and ferroptosis is stimulated at the transcriptional level by BACH1 upon disruption of the balance between the transcriptional induction of protective genes and accumulation of iron-mediated damage. We propose that BACH1 controls the threshold of ferroptosis induction and may represent a therapeutic target for alleviating ferroptosis-related diseases, including myocardial infarction.
For a family of varieties, we prove that the alternating sum of the traces of “local” monodromy acting on the
ℓ
-adic étale cohomology groups of the generic fiber is an integer that is independent of
...ℓ
. In the course of the proof, we also establish a result on fixed points.
Viral infection results in the generation of non‐self RNA species in the cells, which is recognized by retinoic acid inducible gene‐I‐like receptors (RLRs), and initiates innate antiviral responses, ...including the production of proinflammatory cytokines and type I interferon. In this review, we summarize reports on virus‐specificity of RLRs, structures of non‐self RNA patterns, structural biology of RLRs, and the signaling adapter molecules involved in antiviral innate immunity.
Differentiation of hematopoietic stem and progenitor cells is tightly regulated depending on environmental changes in order to maintain homeostasis. Transcription factors direct the development of ...hematopoietic cells, such as GATA-1 for erythropoiesis and PU.1 for myelopoiesis. However, recent findings obtained from single-cell analyses raise the question of whether these transcription factors are "initiators" or just "executors" of differentiation, leaving the initiation of hematopoietic stem and progenitor cell differentiation (i.e. lineage commitment) unclear. While a stochastic process is likely involved in commitment, it cannot fully explain the homeostasis of hematopoiesis nor "on-demand" hematopoiesis in response to environmental changes. Transcription factors BACH1 and BACH2 may regulate both commitment and on-demand hematopoiesis because they control erythroid-myeloid and lymphoid-myeloid differentiation by repressing the myeloid program, and their activities are repressed in response to infectious and inflammatory conditions. We summarize possible mechanisms of lineage commitment of hematopoietic stem and progenitor cells suggested by recent findings and discuss the erythroid and lymphoid commitment of hematopoietic stem and progenitor cells, focusing on the gene regulatory network composed of genes encoding key transcription factors. Surprising similarity exists between commitment to erythroid and lymphoid lineages, including repression of the myeloid program by BACH factors. The suggested gene regulatory network of BACH factors sheds light on the myeloid-based model of hematopoiesis. This model will help to understand the tuning of hematopoiesis in higher eukaryotes in the steady-state condition as well as in emergency conditions, the evolutional history of the system, aging and hematopoietic disorders.
To determine the efficacy of acotiamide, an acetylcholinesterase inhibitor, in patients with functional dyspepsia (FD) in a 4-week trial.
A multicentre, randomised, placebo-controlled, ...parallel-group, phase III trial was carried out, in which patients with FD received 100 mg of acotiamide or placebo three times a day for 4 weeks, with 4 weeks post-treatment follow-up. The primary efficacy end points were global assessment of overall treatment efficacy (OTE) and elimination rate of all three meal-related symptoms (postprandial fullness, upper abdominal bloating and early satiation), as derived from daily diaries. Secondary efficacy end points were individual symptom scores and quality of life. Adverse events were monitored.
52.2% of those receiving acotiamide and 34.8% in the placebo group (p<0.001) were classified as responders according to a global assessment of OTE. Over 4 weeks, the elimination rate for all three meal-related symptoms was 15.3% among patients receiving acotiamide compared with 9.0% in the placebo group (p=0.004). The significant benefit of acotiamide over placebo in OTE and elimination rate was maintained during the 4 week post-treatment follow-up. All other secondary efficacy end points, including quality of life, were significantly improved with 100 mg of acotiamide as compared with placebo. The number needed to treat was 6 for OTE and 16 for symptom elimination rate. The incidence of adverse events was similar between the acotiamide group and placebo group and no significant cardiovascular effects due to treatment were seen.
Over 4 weeks, acotiamide significantly improved symptom severity and eliminated meal-related symptoms in patients with FD.
http://ClinicalTrials.gov number, NCT00761358.
The effects of stem cells from human exfoliated deciduous teeth (SHED) on mechanical allodynia were examined in mice. A single intravenous injection of SHED and conditioned medium from SHED (SHED-CM) ...through the left external jugular vein significantly reversed the established mechanical allodynia induced by spinal nerve transection at 6 days after injection. SHED or SHED-CM significantly decreased the mean numbers of activating transcription factor 3-positive neurons and macrophages in the ipsilateral side of the dorsal root ganglion (DRG) at 20 days after spinal nerve transection. SHED or SHED-CM also suppressed activation of microglia and astrocytes in the ipsilateral side of the dorsal spinal cord. A single intravenous injection of secreted ectodomain of sialic acid-binding Ig-like lectin-9 and monocyte chemoattractant protein-1 had no effect on the established mechanical allodynia, whereas a single intravenous injection of protein component(s) contained in SHED-CM with molecular weight of between 30 and 50 kDa reversed the pain. Therefore, it may be concluded that protein component(s) with molecular mass of 30-50 kDa secreted by SHED could protect and/or repair DRG neurons damaged by nerve transection, thereby ameliorating mechanical allodynia.
Objectives
To evaluate the image quality and iodine concentration (IC) measurements in pancreatic protocol dual-energy computed tomography (DECT) reconstructed using deep learning image ...reconstruction (DLIR) and compare them with those of images reconstructed using hybrid iterative reconstruction (IR).
Methods
The local institutional review board approved this prospective study. Written informed consent was obtained from all participants. Thirty consecutive participants with pancreatic cancer (PC) underwent pancreatic protocol DECT for initial evaluation. DECT data were reconstructed at 70 keV using 40% adaptive statistical iterative reconstruction–Veo (hybrid-IR) and DLIR at medium and high levels (DLIR-M and DLIR-H, respectively). The diagnostic acceptability and conspicuity of PC were qualitatively assessed using a 5-point scale. IC values of the abdominal aorta, pancreas, PC, liver, and portal vein; standard deviation (SD); and coefficient of variation (CV) were calculated. Qualitative and quantitative parameters were compared between the hybrid-IR, DLIR-M, and DLIR-H groups.
Results
The diagnostic acceptability and conspicuity of PC were significantly better in the DLIR-M group compared with those in the other groups (
p
< .001–.001). The IC values of the anatomical structures were almost comparable between the three groups (
p
= .001–.9). The SD of IC values was significantly lower in the DLIR-H group (
p
< .001) and resulted in the lowest CV (
p
< .001–.002) compared with those in the hybrid-IR and DLIR-M groups.
Conclusions
DLIR could significantly improve image quality and reduce the variability of IC values than could hybrid-IR.
Key Points
Image quality and conspicuity of pancreatic cancer were the best in DLIR-M.
DLIR significantly reduced background noise and improved SNR and CNR.
The variability of iodine concentration was reduced in DLIR.
Objective
18
F-labeled prostate-specific membrane antigen (PSMA) ligand,
18
FPSMA-1007, has the benefit of a higher synthetic yield and minimal excretion in the urine. High detection efficacy was ...reported in biochemical recurrence (BCR) of prostate cancer after radical prostatectomy. Thus, we evaluated the preliminary diagnostic utility of
18
FPSMA-1007 PET in patients with prostate cancer, focusing on the BCR which is not detected on conventional imaging.
Methods
We enrolled a total of 28 patients (age 51–79 years) with BCR of prostate cancer. BCR was defined as a continuous increase in PSA after radical prostatectomy or radiation therapy without any apparent recurrent lesions on conventional diagnostic imaging (CT and bone scintigraphy). PSMA-PET scanning was performed approximately 60 min after intravenous injection of
18
FPSMA-1007 (259 ± 37 MBq). PSMA-PET images were evaluated for lesion detection as well as its relation to PSA values and location.
Results
Abnormal uptake, which was suspected to be recurrence or metastasis, was detected in 92.9% (26/28) of patients with BCR. The SUVmax was 8.4 ± 6.4 in local recurrence, 11.5 ± 11.8 in pelvic lymph nodes (LN), and 4.1 ± 1.6 in bone metastasis. The detection rates were 66.7% in the PSA group-1 (0.1–0.5 ng/mL), 85.7% in the PSA group-2 (0.5–1.0 ng/mL), and 100% in the PSA group-3 (above 1.0 ng/mL). Among the PET-positive BCR patients (
n
= 26), local recurrence was detected in 57.7% (15/26), pelvic LN in 42.3% (11/26), and bone metastasis in 15.4% (4/26). In 53% (8/15) of BCR patients who were suspected of local recurrence, focal uptake was detected adjacent to the bladder on
18
FPSMA-1007 PET. This suggested the significant advantage of having minimal physiological urine excretion.
Conclusions
18
FPSMA-1007 PET showed a high detection rate in recurrent and metastatic lesions. In patients with BCR, its high detection led to suitable treatment strategies, such as salvage radiation therapy or surgical removal of recurrent lymph nodes.
Trial registration
(UMIN Clinical Trials Registry) UMIN000037697.
RNA virus infection is recognized by retinoic acid-inducible gene (RIG)-I-like receptors (RLRs), RIG-I, and melanoma differentiation-associated gene 5 (MDA5) in the cytoplasm. RLRs are comprised of ...N-terminal caspase-recruitment domains (CARDs) and a DExD/H-box helicase domain. The third member of the RLR family, LGP2, lacks any CARDs and was originally identified as a negative regulator of RLR signaling. In the present study, we generated mice lacking LGP2 and found that LGP2 was required for RIG-I- and MDA5-mediated antiviral responses. In particular, LGP2 was essential for type I IFN production in response to picornaviridae infection. Overexpression of the CARDs from RIG-I and MDA5 in Lgp2 ⁻/⁻ fibroblasts activated the IFN-β promoter, suggesting that LGP2 acts upstream of RIG-I and MDA5. We further examined the role of the LGP2 helicase domain by generating mice harboring a point mutation of Lys-30 to Ala (Lgp2 K³⁰A/K³⁰A) that abrogated the LGP2 ATPase activity. Lgp2 K³⁰A/K³⁰A dendritic cells showed impaired IFN-β productions in response to various RNA viruses to extents similar to those of Lgp2 ⁻/⁻ cells. Lgp2 ⁻/⁻ and Lgp2 K³⁰A/K³⁰A mice were highly susceptible to encephalomyocarditis virus infection. Nevertheless, LGP2 and its ATPase activity were dispensable for the responses to synthetic RNA ligands for MDA5 and RIG-I. Taken together, the present data suggest that LGP2 facilitates viral RNA recognition by RIG-I and MDA5 through its ATPase domain.
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