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To assess temporal changes to the risk of death in COVID-19 cases caused by the Omicron variant, we calculated age-standardized case fatality rates (CFR) in patients aged ≥40 years over nine diagnostic periods (3 January to 28 August 2022) in ten Japanese prefectures (14.8 million residents). Among 552,581 study subjects, we found that there were 1836 fatalities during the isolation period (up to 28 days from date of onset). The highest age-standardized CFR (0.85%, 95% confidence interval (CI):0.78–0.92) was observed in cases diagnosed in the second 4-week period (January 31 to February 27), after which it declined significantly up to the 6th 4-week period (0.23%, 95% CI: 0.13–0.33, May 23 to June 19). The CFR then increased again but remained at 0.39% in the eighth period (July 18 to August 28). The CFR in cases with the BA.2 or BA.5 sublineages in the age range 60–80 years was significantly lower than that with BA.1 infections (60 years: 0.19%, 0.02%, 0.053%, respectively; 70 years: 0.91%, 0.33%, 0.39%; ≥80 years: 3.78%, 1.96%, 1.81%, respectively). We conclude that the risk of death in Japanese COVID-19 patients infected with Omicron variants declined through February to mid-June 2022.

Flavonoids are a subclass of polyphenols which are attractive, due to possessing various physiological activities, including a radioprotective effect. Tumor suppressor p53 is a primary regulator in the radiation response and is involved in the pathogenesis of radiation injuries. In this study, we revealed that isorhamnetin inhibited radiation cell death, and investigated its action mechanism focusing on DNA damage response. Although isorhamnetin moderated p53 activity, it promoted phosphorylation of ataxia telangiectasia mutated (ATM) and enhanced 53BP1 recruitment in irradiated cells. The radioprotective effect of isorhamnetin was not observed in the presence of ATM inhibitor, indicating that its protective effect was dependent on ATM. Furthermore, isorhamnetin-treated mice survived gastrointestinal death caused by a lethal dose of abdominal irradiation. These findings suggested that isorhamnetin enhances the ATM-dependent DNA repair process, which is presumably associated with the suppressive effect against GI syndrome.

In April 2020, a coronavirus disease (COVID-19) outbreak occurred on the cruise ship Costa Atlantica in Nagasaki, Japan. Our outbreak investigation included 623 multinational crewmembers onboard on April 20. Median age was 31 years; 84% were men. Each crewmember was isolated or quarantined in a single room inside the ship, and monitoring of health status was supported by a remote health monitoring system. Crewmembers with more severe illness were hospitalized. The investigation found that the outbreak started in late March and peaked in late April, resulting in 149 laboratory-confirmed and 107 probable cases of infection with severe acute respiratory syndrome coronavirus 2. Six case-patients were hospitalized for COVID-19 pneumonia, including 1 in severe condition and 2 who required oxygen administration, but no deaths occurred. Although the virus can spread rapidly on a cruise ship, we describe how prompt isolation and quarantine combined with a sensitive syndromic surveillance system can control a COVID-19 outbreak., Emerging Infectious Diseases, 27(9), pp. 2251-2260; 2021

Caffeic acid β-phenethyl ester (CAPE), an antioxidative bioactive catechol isolated from propolis, was semisynthesized from chlorogenic acid and related compounds in an extract of raw (unroasted) Robusta coffee (Coffea canephora) beans in 5 steps and a total yield of 31%. Oxidative degradation of the intermediates and target molecule was prevented by alkaline hydrolysis of the chlorogenic acids in the presence of sodium dithionite (Na2S2O4) and deprotection of the catecholic diacetate precursor by Candida antarctica lipase B-mediated transesterification as the final step.

A formal total synthesis of (−)-hamigeran B was achieved in 17 steps from commercially available ethyl 2-oxocyclopentanecarboxylate. Carbonyl reductase-catalyzed asymmetric reduction and the subsequent chemical transformations furnished an enantiomerically pure synthetic intermediate, (R)-5-formyl-2-isopropyl-5-methylcyclopent-1-en-1-yl trifluoromethylsulfonate. Suzuki-Miyaura coupling with Gao's arylboronate [2-(2-formyl-3-methoxy-5-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane], under PdCl2(dppf)•CH2Cl2 catalysis, and the subsequent cyclization by way of intramolecular reductive SmI2-mediated 1,2-diol formation provided a tricyclic skeleton with a tetrasubstituted double bond between C-1 and C-9b. Upon hydrogenation of this double bond, the proper stereochemistry of the remaining chiral centers was established. Exclusive addition of the hydrogen atom from the β-face occurred, owing to the shielding of the α-face with a bulky TBS protective group on the C-4 alcohol. The hydrogenation products were transformed into Clive's synthetic precursor for (−)-hamigeran B.

Scientific Data, 4, ISSN:2052-4463

MafG and p45 possess basic region-leucine zipper (bZip) domains and form a heterodimer called NF-E2, a key regulator of megakaryopoiesis. NF-E2 binds to the Maf recognition element (MARE) and activates transcription of many platelet genes. Since the bZip domain, which mediates DNA binding and heterodimerization, is the only functional domain established for MafG, it has been assumed that MafG is required only for p45 binding to MARE and to facilitate p45-mediated transcriptional activation. Analysis of the C-terminal region of MafG, which is distinct from the bZip domain, revealed that this region contains a nuclear matrix-targeting signal. We used a transgenic complementation rescue assay to delineate the function of the MafG C terminus in vivo. Transgenic mice expressing a mutant MafG protein lacking the C terminus (MafGΔC) were crossed into a MafG-null background. The compound mutant mice displayed severe thrombocytopenia and splenomegaly, which phenocopied p45-null mice. The MafG C terminus is essential for proplatelet formation and platelet gene activation but not for p45 binding to MARE. These results demonstrate that the MafG C terminus is required for NF-E2 function and suggest that efficient targeting of NF-E2 to a specific nuclear scaffold is important to achieve high-level activity.

Cell differentiation is uniquely regulated by lineage-specific transcription factors. Efforts have been made to understand the function of each transcription factor from the viewpoint of context-dependent and hierarchical relationships with other transcription factors. Recent studies have revealed critical regulatory networks among key transcription factors regulating differentiation of hematopoietic cells (8, 51). However, such interrelations between transcription factors are usually validated in cell culture but not by in vivo experimental systems. Recent studies have shown that the latter approach is more informative than in vitro or in transfecto approaches because various physiological parameters are present for validation. Several key transcription factors regulating megakaryocytic differentiation have been described. c-Myb is a critical regulator at the bifurcation of erythroid and megakaryocytic differentiation from the megakaryocytic-erythroid bipotential progenitor (MEP). Decreased c-Myb activity in MEP was found to enhance megakaryocytic differentiation (27). The other factors regulating megakaryocytic differentiation, especially after lineage commitment, include GATA1, GATA2, SCL/Tal1, Runx1, and the Ets family factors Fli-1 and TEL (32, 38, 41). In contrast, terminal maturation of megakaryocytes depends heavily on NF-E2, a heterodimer of the cap'n'collar (CNC) transcription factor p45 and a small Maf protein (24, 31, 34, 36). GATA1 has been shown to be an indispensable regulator of erythroid and megakaryocytic cell differentiation. Disruption of the Gata1 gene in mouse results in lethality at the midgestation stage due to the failure of primitive hematopoiesis (10, 42). In contrast, a megakaryocyte-specific knockdown of the Gata1 gene (Gata1ΔneoΔHS/Y) was reported not to be lethal but to result in severe thrombocytopenia and accumulation of immature megakaryocytes (37). The temporal and spatial expression pattern of Gata1 conforms with these contributions of GATA1 to erythroid and megakaryocytic cell differentiation (43). Regulatory regions recapitulating endogenous Gata1 gene expression in hematopoietic cells have been delineated (30), and we refer to the regulatory region as the Gata1 gene hematopoietic regulatory domain (G1HRD). It has been shown that impaired function of NF-E2 affects terminal maturation of megakaryopoiesis, resulting in the accumulation of mature megakaryocytes with higher ploidy (34, 36) and defective proplatelet formation (16, 31). As the small Maf proteins lack any canonical transactivation domains, the transcription activation ability of NF-E2 resides solely in the p45 subunit (3, 24, 29), suggesting that p45 abundance may be a primary determinant of NF-E2 activity. In this regard, the N-terminal half of p45 has been identified as a transactivation domain (3, 29), which recruits TAFII130 and CBP (1, 12). Another structural feature of the p45 N-terminal region is the presence of two WW domain-binding motifs (or PPXY motifs), which are necessary for β-Globin gene transcription (15, 22). In addition to the PPXY motifs, the very end of the N-terminal region is also necessary for β-Globin gene transcription (3). It should be noted that all of these studies examined the domain function of p45 in immortalized erythroid cells but not in the megakaryocytic lineage. Three lines of evidence suggest that GATA1 directly activates p45 gene expression in megakaryocytes. First, genetic analyses revealed that GATA1 dysfunction causes a reduction of p45 expression in megakaryocytes (35, 49). Second, a well-conserved tandem palindromic GATA-binding site has been found in the p45 gene 1b promoter, which was shown to be functional in a reporter assay using K562 cells (21). Third, GATA1 appears to be required at earlier stages of megakaryopoiesis than p45 (5, 36, 37, 49). In addition to GATA1, it has also been shown that other factors, such as GATA2 and SCL, participate in p45 gene regulation in megakaryocytes (4, 19). To validate the GATA1-p45 regulatory axis in megakaryocytes, we adopted a transgenic complementation rescue approach. We examined whether G1HRD directs sufficient expression of p45 to sustain normal megakaryopoiesis. We generated transgenic mouse lines expressing p45 under the control of G1HRD, and these lines were crossed into the p45-null background. The compound mutant mice showed normal platelet counts and no sign of hemorrhage, indicating that G1HRD-driven p45 rescued the defective megakaryopoiesis and thrombogenesis of p45-null mice. In contrast, a p45 mutant lacking 38 amino acids of the N-terminal region could not rescue thrombogenesis in p45-null mice, suggesting the presence of essential transactivation activity in this region. We also evaluated the contribution of p45 to the GATA1-directed regulatory hierarchy by crossing the G1HRD-p45 mice with Gata1ΔneoΔHS mice. Whereas Gata1ΔneoΔHS/Y megakaryocytes express reduced amounts of p45, the p45 transgene rescued p45 levels to normal levels in megakaryocytes from compound mutant mice. Of the phenotypes observed in Gata1ΔneoΔHS/Y megakaryocytes, decreased expression of platelet genes and an abnormal increase in immature megakaryocytes were partially restored by the transgene-derived p45 expression, but thrombocytopenia in peripheral blood was not substantially improved. This study is a unique in vivo validation of the hierarchical relationship between GATA1 and p45, demonstrating that the GATA1-p45 regulatory axis is operative in megakaryopoiesis.

In megakaryocytes, the maturation process and oxidative stress response appear to be closely related. It has been suggested that increased oxygen tension and reactive oxygen species (ROS) promote megakaryopoiesis and that the expression of stress-responsive genes responsible for ROS elimination declines during megakaryocytic maturation. NF-E2 p45 is an essential regulator of megakaryopoiesis, whereas Nrf2 is a key activator of stress-responsive genes. Because p45 and Nrf2 have similar DNA-binding specificities, we hypothesized that p45 competes with Nrf2 to repress stress-responsive genes and achieves favorable intracellular conditions to allow ROS to be efficiently used as signaling molecules. We conducted comprehensive gene expression profiling with wild-type and p45-null megakaryocytes and examined the functional relationship between p45 and Nrf2. We found that 2 characteristic gene clusters are defined within p45 target genes: platelet genes and cytoprotective genes. The former are unique targets activated by p45, whereas the latter are common targets of p45 and Nrf2. Further analysis suggested that, as a less efficacious activator, p45 maintains moderate expression of cytoprotective genes through competing with Nrf2 and promotes ROS accumulation. Increased ROS enhanced platelet gene expression. These results suggest that p45 dominates over Nrf2 to enhance megakaryocytic maturation by promoting ROS accumulation.

Hepatocyte transplantation and use of bioartificial liver support systems have been suggested as potential therapies for fulminant hepatic failure. Cryopreservation in liquid nitrogen is presently the major method of long-term storage of isolated hepatocytes. However, cryopreservation can result in low cell recovery and reduction in differentiated function. Several possible mechanisms of cell death during cryopreservation have been proposed. The most important mechanisms appear to be oxidative stress and apoptosis. In this study, we isolated fresh rat hepatocytes and cryopreserved them in three media: University of Wisconsin (UW) solution, an antioxidant-containing medium, and medium containing a caspase inhibitor. Viability and function of hepatocytes cryopreserved in these media were examined. Cryopreservation conditions had no effect on hepatocyte viability after thawing. However, after culture we found significant improvements in viability and function in both antioxidant- and caspase inhibitor-treated hepatocytes at 6 and 24 h.

This study aimed to investigate the maximum depth imaging and optical properties of the dentin near the pulp by using optical coherence tomography (OCT) and to explore the possibility of measuring the remaining dentin thickness (RDT). Human third molars were used. In experiment 1, the cuspal dentin blocks (0.50-mm to 1.75-mm thickness) were prepared. Each specimen was scanned using OCT. OCT images could be obtained for all specimens with 1.00-mm or less thicknesses. In experiment 2, dentin-pulp complex slices (0.50-mm and 1.00-mm RDT) were prepared. Each specimen was scanned using OCT and micro-computed tomography, and compared. The resulting length change rates of OCT images for the 0.50-mm RDTs were significantly lower than those of the 1.00-mm RDTs. Within the limitations of this study, OCT was effective for measuring the 1.00-mm or less RDT and preventing pulpal injury, while considering the length change rate of OCT image as a variable.

Thirty-nine hypertensive patients with type 2 diabetes mellitus were followed under long-term treatment (mean, 20.7 months) with manidipine hydrochloride, a Ca antagonist, or delapril hydrochloride, an ACE inhibitor, at nine institutions. Both the treatments showed similar antihypertensive effects, although slight but significantly larger decreases were observed in systolic and mean blood pressures at months 12 and 24 in the patients treated with manidipine (P0.02). The urinary albumin excretion index (AEI) tended to increase throughout the study in both treatment groups, but no significant difference in AEI was observed between the two treatment groups at any time point. Overt albuminuria developed in four patients on manidipine but did not appear in any of the patients on delapril. The risk of progression to overt albuminuria was significantly different between manidipine and delapril groups (P = 0.011). No increase in serum creatinine (Cr) was observed with delapril. The average excretion indexes of tubular markers such as beta2-microglobulin, alpha1-microglobulin, and NAG tended to be higher in the patients on manidipine than in those on delapril. Taken in sum, these findings suggest that the ACE inhibitor delapril is more beneficial than the Ca antagonist manidipine in the treatment of diabetic renal diseases via mechanisms other than the blood pressure regulation, partly through their different effects on tubular function. In conclusion, delapril was significantly more effective than manidipine in inhibiting progression to overt albuminuria in hypertensive type 2 diabetes mellitus patients.

This paper deals with a case of superior mesenteric vein thrombosis diagnosed by an abdominal CT scan, causing small bowel stricture 2 months after intraarterial thrombolytic method with resultant symptomatic remission, which demanded a laparotomy. A 68-year-old man was brought to the hospital with a 7-day history of increasing nausea, vomiting. Contrast-enhanced CT scanning comfirmed mesenteric venous thrombosis. An arteriogram was obtained with injections into the superior mesentery, and the patient was given urokinase 240, 000 units daily for 5 consecutive days through an endhole catheter. The patient appeared stable without any symptoms. On the following day, 2 months after the therapy, the patient became worse with increasing pain and nausea. Partial resection of the small intestine was performed. Resected specimen showed severe stenosis 5 cm in length with necrotic change in the ileum. Microscopically, penetrated ulcer with granulomatous panniculitis and submucosal hemorrhage were observed. Postoperative course was uneventful.

Vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) is a secreted mitogen for vascular endothelial cells, and it promotes vascular permeability and neovascularization in vivo. We investigated the mechanisms by which low oxygen tension modulates the expression of VEGF in human aortic vascular smooth muscle cells (h-SMC) in vitro. Moreover, we measured VEGF levels in the cultured medium with or without endothelin-1 (ET-1) using a newly developed, highly sensitive, enzyme-linked immunosorbent assay. Hypoxia resulted in a substantial induction of VEGF transcripts at 3 and 24 hr. VEGF levels were significantly higher when h-SMC were cultured in medium containing ET-1 than when cultured in medium without ET-1. In conclusion, hypoxia and ET-1 constitute potent stimuli for VEGF production in h-SMC.

The oxidative rearrangement of pentaalkoxychalcones using the hypervalent iodine compound, phenyliodine(III) bis(trifluoroacetate) (PIFA), has been examined. Treatment of 2,2′-bis(benzyloxy)-4′-methoxy-4,5-methylenedioxychalcone with PIFA gives a rearrangement product in low yield, but 2,2′-bis(benzyloxy)-3-bromo-4′-methoxy-4,5-methylenedioxychalcone yields the rearrangement product, which leads to (±)-bromopterocarpin and (±)-pterocarpin.

The oxidative rearrangement of pentaalkoxychalcones using the hypervalent iodine compound, phenyliodine(III) bis(trifluoroacetate) (PIFA), has been examined. Treatment of 2,2′-bis(benzyloxy)-4′-methoxy-4,5-methylenedioxychalcone with PIFA gives a rearrangement product in low yield, but 2,2′-bis(benzyloxy)-3-bromo-4′-methoxy-4,5-methylenedioxychalcone yields the rearrangement product, which leads to (±)-bromopterocarpin and (±)-pterocarpin.

Leptospirosis, a zoonotic infection with worldwide prevalence, is caused by pathogenic spirochaetes of Leptospira spp., and exhibits an extremely broad clinical spectrum in human patients. Although previous studies indicated that specific serovars or genotypes of Leptospira spp. were associated with severe leptospirosis or its outbreak, the mechanism underlying the difference in virulence of the various Leptospira serotypes or genotypes remains unclear. The present study addresses this question by measuring and comparing bacterial burden and cytokine gene expression in hamsters infected with strains of two L. interrogans serovars Manilae (highly virulent) and Hebdomadis (less virulent). The histopathology of kidney, liver, and lung tissues was also investigated in infected hamsters. A significantly higher bacterial burden was observed in liver tissues of hamsters infected with serovar Manilae than those infected with serovar Hebdomadis (p < 0.01). The average copy number of the leptospiral genome was 1,302 and 20,559 in blood and liver, respectively, of hamsters infected with serovar Manilae and 1,340 and 4,896, respectively, in hamsters infected with serovar Hebdomadis. The expression levels of mip1alpha in blood; tgfbeta, il1beta, mip1alpha, il10, tnfalpha and cox2 in liver; and tgfbeta, il6, tnfalpha and cox2 in lung tissue were significantly higher in hamsters infected with serovar Manilae than those infected with serovar Hebdomadis (p < 0.05). In addition, infection with serovar Manilae resulted in a significantly larger number of hamsters with tnfalpha upregulation (p = 0.04). Severe distortion of tubular cell arrangement and disruption of renal tubules in kidney tissues and hemorrhage in lung tissues were observed in Manilae-infected hamsters. These results demonstrate that serovar Manilae multiplied more efficiently in liver tissues and induced significantly higher expression of genes encoding pro- and anti-inflammatory cytokines than serovar Hebdomadis even in tissues for which a significant difference in leptospiral load was not observed. In addition, our results suggest a serovar Manilae-specific mechanism responsible for inducing severe damage in kidneys and hemorrhage in lung.

Unlike laparoscopic cholecystectomy, laparoscopic hepatectomy has been slow to gain acceptance because of its association with technical difficulties. Many surgeons feel there are few advantages in laparoscopic hepatectomy when compared to open surgery. The liver is the organ most susceptible to bleeding while dissecting the parenchyma and the resected liver usually requires a wide abdominal incision to deliver the resected specimen. Both the improvement of surgeons' skills and the development of technology have improved results, however, the indication of laparoscopic hepatectomy for malignancy is still controversial. This article focuses on the current status of minimally invasive treatment for liver malignancy.

Regulated transcription controls the diversity, developmental pathways and spatial organization of the hundreds of cell types that make up a mammal. Using single-molecule cDNA sequencing, we mapped transcription start sites (TSSs) and their usage in human and mouse primary cells, cell lines and tissues to produce a comprehensive overview of mammalian gene expression across the human body. We find that few genes are truly 'housekeeping', whereas many mammalian promoters are composite entities composed of several closely separated TSSs, with independent cell-type-specific expression profiles. TSSs specific to different cell types evolve at different rates, whereas promoters of broadly expressed genes are the most conserved. Promoter-based expression analysis reveals key transcription factors defining cell states and links them to binding-site motifs. The functions of identified novel transcripts can be predicted by coexpression and sample ontology enrichment analyses. The functional annotation of the mammalian genome 5 (FANTOM5) project provides comprehensive expression profiles and functional annotation of mammalian cell-type-specific transcriptomes with wide applications in biomedical research.

Vol 350 • November 15, 1997 1449 had secondary DVT and six cancers were diagnosed among these patients during their hospital stay (1·2%). When thrombosis was idiopathic, the rate of occult cancer was significantly higher (3·9%, p