Is Asian flushing syndrome a disadvantage in the labor market?

A large fraction of people in East Asia are incapable of digesting alcohol because of a genetic deficiency. This study examines whether the variation in alcohol tolerance contributes to inequality in the labor market. We conduct our original surveys in Japan, Taiwan, and Korea with the measurement of respondents' degree of alcohol tolerance by a bio-marker test. We find that alcohol-tolerant men consume significantly more alcohol, but their earnings and hours worked do not differ from those of alcohol-intolerant men. Despite a prevalent view that drinking alcohol is indispensable to establish good relationships with colleagues and business partners, our results suggest that there is no systematic impact of alcohol tolerance on labor market outcomes.

The financial health of "swing hospitals" during the first COVID-19 outbreak.

The hospitals in Japan have hitherto had complete autonomy in deciding whether to admit COVID-19 patients. In fact, they were "swinging" between admitting or not COVID-19 patients, especially during the initial COVID-19 outbreak. To address endogenous decision making, we estimated the effect of admitting COVID-19 patients on hospital profits using instrumental variable (IV) regression. We derived the IVs from the guidelines of the national government on which hospital types should admit COVID-19 patients. Our empirical results revealed that the monthly profits per bed decreased by approximately JPY 600,000 ( ≈ USD 4615), which is 15 times the average monthly profit in 2019. This overwhelming financial damage indicates it is costly for some hospitals to treat COVID-19 patients because of their low suitability in admitting such patients. Based on the implications of our main results, we propose an alternative strategy to handling patient surges in case of new infectious disease outbreaks.

SARS-CoV-2 suppression and early closure of bars and restaurants: a longitudinal natural experiment.

Despite severe economic damage, full-service restaurants and bars have been closed in hopes of suppressing the spread of SARS-CoV-2 worldwide. This paper explores whether the early closure of restaurants and bars in February 2021 reduced symptoms of SARS-CoV-2 in Japan. Using a large-scale nationally representative longitudinal survey, we found that the early closure of restaurants and bars decreased the utilization rate among young persons (OR 0.688; CI95 0.515-0.918) and those who visited these places before the pandemic (OR 0.754; CI95 0.594-0.957). However, symptoms of SARS-CoV-2 did not decrease in these active and high-risk subpopulations. Among the more inactive and low-risk subpopulations, such as elderly persons, no discernible impacts are observed in both the utilization of restaurants and bars and the symptoms of SARS-CoV-2. These results suggest that the early closure of restaurants and bars without any other concurrent measures does not contribute to the suppression of SARS-CoV-2.

Increment in the volcanic unrest and number of eruptions after the 2012 large earthquakes sequence in Central America.

Understanding the relationship cause/effect between tectonic earthquakes and volcanic eruptions is a striking topic in Earth Sciences. Volcanoes erupt with variable reaction times as a consequence of the impact of seismic waves (i.e. dynamic stress) and changes in the stress field (i.e. static stress). In 2012, three large (Mw ≥ 7.3) subduction earthquakes struck Central America within a period of 10 weeks; subsequently, some volcanoes in the region erupted a few days after, while others took months or even years to erupt. Here, we show that these three earthquakes contributed to the increase in the number of volcanic eruptions during the 7 years that followed these seismic events. We found that only those volcanoes that were already in a critical state of unrest eventually erupted, which indicates that the earthquakes only prompted the eruptions. Therefore, we recommend the permanent monitoring of active volcanoes to reveal which are more susceptible to culminate into eruption in the aftermath of the next large-magnitude earthquake hits a region.

What the COVID-19 school closure left in its wake: Evidence from a regression discontinuity analysis in Japan.

To control the spread of COVID-19, the national government of Japan abruptly started the closure of elementary schools on March 2, 2020, but preschools were exempted from this nationwide school closure. Taking advantage of this natural experiment, we examined how the proactive closure of elementary schools affected various outcomes related to children and family well-being. To identify the causal effects of the school closure, we exploited the discontinuity in the probability of going to school at a certain threshold of age in months and conducted fuzzy regression discontinuity analyses. The data are from a large-scale online survey of mothers whose firstborn children were aged 4 to 10 years. The results revealed a large increase in children's weight and in mothers' anxiety over how to raise their children. On the outcomes related to marital relationships, such as the incidence of domestic violence and the quality of marriage, we did not find statistically significant changes. These findings together suggest that school closures could have large unintended detrimental effects on non-academic outcomes among children.

DNA analysis of benign adult familial myoclonic epilepsy reveals associations between the pathogenic TTTCA repeat insertion in SAMD12 and the nonpathogenic TTTTA repeat expansion in TNRC6A.

Benign adult familial myoclonic epilepsy (BAFME) is an autosomal dominant disease characterized by adult-onset tremulous hand movement, myoclonus, and infrequent epileptic seizures. Recently, intronic expansion of unstable TTTCA/TTTTA pentanucleotide repeats in SAMD12, TNRC6A, or RAPGEF2 was identified as pathological mutations in Japanese BAFME pedigrees. To confirm these mutations, we performed a genetic analysis on 12 Japanese BAFME pedigrees. A total of 143 participants, including 43 familial patients, 5 suspected patients, 3 sporadic nonfamilial patients, 22 unaffected familial members, and 70 unrelated controls, were screened for expanded abnormal pentanucleotide repeats in SAMD12, TNRC6A, RAPGEF2, YEAT2, MARCH6, and STARD7. DNA samples were analyzed using Southern blotting, long-range polymerase chain reaction (PCR), repeat-primed PCR, and long-range PCR followed by Southern blotting. Of the 51 individuals with clinically diagnosed or suspected BAFME, 49 carried a SAMD12 allele with an expanded TTTCA/TTTTA pentanucleotide repeat. Genetic and clinical anticipation was observed. As in previous reports, the one patient with homozygous mutant alleles showed more severe symptoms than the heterozygous carriers. In addition, screening for expanded pentanucleotide repeats in TNRC6A revealed that the frequency of expanded TTTTA repeat alleles in the BAFME group was significantly higher than in the control group. All patients who were clinically diagnosed with BAFME, including those in the original family reported by Yasuda, carried abnormally expanded TTTCA/TTTTA repeat alleles of SAMD12. Patients with BAFME also frequently carried a TTTTA repeat expansion in TNRC6A, suggesting that there may be unknown factors in the ancestry of patients with BAFME that make pentanucleotide repeats unstable.

Novel pathogenic VPS13A gene mutations in Japanese patients with chorea-acanthocytosis.

OBJECTIVE: To identify mutations in vacuolar protein sorting 13A (VPS13A) for Japanese patients with suspected chorea-acanthocytosis (ChAc). METHODS: We performed a comprehensive mutation screen, including sequencing and copy number variation (CNV) analysis of the VPS13A gene, and chorein Western blotting of erythrocyte ghosts. As the results of the analysis, 17 patients were molecularly diagnosed with ChAc. In addition, we investigated the distribution of VPS13A gene mutations and clinical symptoms in a total of 39 molecularly diagnosed Japanese patients with ChAc, including 22 previously reported cases. RESULTS: We identified 11 novel pathogenic mutations, including 1 novel CNV. Excluding 5 patients with the unknown symptoms, 97.1% of patients displayed various neuropsychiatric symptoms or forms of cognitive dysfunction during the course of disease. The patients carrying the 2 major mutations representing over half of the mutations, exon 60-61 deletion and exon 37 c.4411C>T (R1471X), were localized in western Japan. CONCLUSIONS: We identified 13 different mutations in VPS13A, including 11 novel mutations, and verified the clinical manifestations in 39 Japanese patients with ChAc.

Novel pathogenic XK mutations in McLeod syndrome and interaction between XK protein and chorein.

OBJECTIVE: To identify XK pathologic mutations in 6 patients with suspected McLeod syndrome (MLS) and a possible interaction between the chorea-acanthocytosis (ChAc)- and MLS-responsible proteins: chorein and XK protein. METHODS: Erythrocyte membrane proteins from patients with suspected MLS and patients with ChAc, ChAc mutant carriers, and normal controls were analyzed by XK and chorein immunoblotting. We performed mutation analysis and XK immunoblotting to molecularly diagnose the patients with suspected MLS. Lysates of cultured cells were co-immunoprecipitated with anti-XK and anti-chorein antibodies. RESULTS: All suspected MLS cases were molecularly diagnosed with MLS, and novel mutations were identified. The average onset age was 46.8 ± 8 years, which was older than that of the patients with ChAc. The immunoblot analysis revealed remarkably reduced chorein immunoreactivity in all patients with MLS. The immunoprecipitation analysis indicated a direct or indirect chorein-XK interaction. CONCLUSIONS: In this study, XK pathogenic mutations were identified in all 6 MLS cases, including novel mutations. Chorein immunoreactions were significantly reduced in MLS erythrocyte membranes. In addition, we demonstrated a possible interaction between the chorein and XK protein via molecular analysis. The reduction in chorein expression is similar to that between Kell antigens and XK protein, although the chorein-XK interaction is a possibly noncovalent binding unlike the covalent Kell-XK complex. Our results suggest that reduced chorein levels following lack of XK protein are possibly associated with molecular pathogenesis in MLS.

Granulocyte-macrophage colony-stimulating factor neuroprotective activities in Alzheimer's disease mice.

We investigated the effects of granulocyte-macrophage colony stimulating factor (GM-CSF) on behavioral and pathological outcomes in Alzheimer's disease (AD) and non-transgenic mice. GM-CSF treatment in AD mice reduced brain amyloidosis, increased plasma Aß, and rescued cognitive impairment with increased hippocampal expression of calbindin and synaptophysin and increased levels of doublecortin-positive cells in the dentate gyrus. These data extend GM-CSF pleiotropic neuroprotection mechanisms in AD and include regulatory T cell-mediated immunomodulation of microglial function, Aß clearance, maintenance of synaptic integrity, and induction of neurogenesis. Together these data support further development of GM-CSF as a neuroprotective agent for AD.

Phenotypic abnormalities in a chorea-acanthocytosis mouse model are modulated by strain background.

Chorea-acanthocytosis (ChAc) is an autosomal recessive hereditary disease characterized by neurodegeneration in the striatum and acanthocytosis that is caused by mutations in the VPS13A gene. We previously produced a ChAc model mice encoding a human disease mutation with deletion of exons 60-61 in the VPS13A gene. The behavioral and pathological phenotypes of the model mice varied a good deal from individual to individual, indicating that differences between individuals may be caused by the content of a genetic hybrid 129/Sv and C57BL/6J strain background. To establish the effect of the genetic background on phenotype, we backcrossed the ChAc-model mice to different inbred strains: C57BL/6J and 129S6/Sv. Although no significant difference between ChAc-mutant mice and wild-type mice on the C57BL/6J background was observed, the ChAc-mutant mice on the 129S6/Sv showed abnormal motor function and behavior. Furthermore, we produced ChAc-mutant mice on two different inbred strains: BALB/c and FVB. Significant reduction in weight was observed in ChAc mutant mice on the FVB and 129S6 backgrounds. We found a marked increase in the osmotic fragility of red blood cells in the ChAc mutant mice backcrossed to 129S6/Sv and FVB. The phenotypes varied according to strain, with ChAc mutant mice on the FVB and 129S6 backgrounds showing remarkably abnormal motor function and behavior. These results indicate that there are modifying genetic factors of ChAc symptoms.

Angiotensin peptides attenuate platelet-activating factor-induced inflammatory activity in rats.

Angiotensin (Ang)--a peptide that is part of the renin-angiotensin system-induces vasoconstriction and a subsequent increase in blood pressure; Ang peptides, especially AngII, can also act as potent pro-inflammatory mediators. Platelet-activating factor (PAF) is a potent phospholipid mediator that is implicated in many inflammatory diseases. In this study, we investigated the effects of Ang peptides (AngII, AngIII, and AngIV) on PAF-induced inflammatory activity. In experiments using a rat hind-paw oedema model, AngII markedly and dose-dependently attenuated the paw oedema induced by PAF. The inhibitory effects of AngIII and AngIV on PAF-induced paw oedema were lower than that of AngII. Two Ang receptors, the AT1 and AT2 receptors, did not affect the AngII-mediated attenuation of PAF-induced paw oedema. Moreover, intrinsic tyrosine fluorescence studies demonstrated that AngII, AngIII, and AngIV interact with PAF, and that their affinities were closely correlated with their inhibitory effects on PAF-induced rat paw oedema. Also, AngII interacted with metabolite/precursor of PAF (lyso-PAF), and an oxidized phospholipid, 1-palmitoyl-2-(5'-oxo-valeroyl)-sn-glycero-3-phosphocholine (POVPC), which bears a marked structural resemblance to PAF. Furthermore, POVPC dose-dependently inhibited AngII-mediated attenuation of PAF-induced paw oedema. These results suggest that Ang peptides can attenuate PAF-induced inflammatory activity through binding to PAF and lyso-PAF in rats. Therefore, Ang peptides may be closely involved in the regulation of many inflammatory diseases caused by PAF.

Biotinylated heptapeptides substituted with a D-amino acid as platelet-activating factor inhibitors.

Platelet-activating factor (PAF), a potent lipid mediator, is implicated in many inflammatory diseases, and therefore may serve as a direct target for anti-inflammatory drugs. We previously reported that synthetic biotinylated peptides having a Tyr-Lys-Asp-Gly sequence markedly inhibit PAF-induced inflammation by direct binding, and that two synthetic fluorescence-labelled heptapeptides (Lys-Trp-Tyr-Lys-Asp-Gly-Asp and D-Lys-Trp-Tyr-Lys-Asp-Gly-Asp) with high stability in plasma specifically bind to PAF-like lipids (oxidized- and lyso-phosphatidylchoine). In this study, synthetic heptapeptides (Lys-Trp-Tyr-Lys-Asp-Gly-Asp) coupled to a biotin molecule through the N-terminal amino group and ε-amino group of N-terminus Lys, (Btn)KP6 and K(Btn)P6, respectively, and their biotinylated peptides substituted with D-Lys at the N-terminus, (Btn)dKP6 and dK(Btn)P6, respectively, were investigated for their effects on PAF-induced inflammation. In the experiments using a rat model of hind paw oedema, (Btn)KP6, K(Btn)P6, (Btn)dKP6, and dK(Btn)P6 significantly inhibited PAF-induced paw oedema, with the highest inhibitory effect exhibited by dK(Btn)P6. The inhibitory effect of D-Tyr-D-Lys-D-Asp-Gly tetrapeptide on PAF-induced paw oedema was much lower than that of Tyr-Lys-Asp-Gly tetrapeptide. In the experiments using tryptophan fluorescence spectroscopy, (Btn)KP6, K(Btn)P6, (Btn)dKP6, and dK(Btn)P6 bound to PAF dose-dependently, with dK(Btn)P6 showing the strongest binding affinity, indicating that its affinity appears to be closely correlated with its inhibitory effect on PAF-induced inflammation. These results suggest that direct binding of (Btn)KP6, K(Btn)P6, (Btn)dKP6, and dK(Btn)P6 to PAF can lead to marked inhibition of PAF-induced inflammation, and these agents, particularly dK(Btn)P6, may be useful as anti-inflammatory drugs targeting PAF with high stability in plasma.

Highly stable, fluorescence-labeled heptapeptides substituted with a D-amino acid for the specific detection of oxidized low-density lipoprotein in plasma.

Probes that can detect oxidized low-density lipoprotein (ox-LDL) in plasma and in atherosclerotic plaques can be useful for the diagnosis, prevention, and treatment of atherosclerosis. Recently, we have reported that two heptapeptides (Lys-Trp-Tyr-Lys-Asp-Gly-Asp, KP6) coupled to fluorescein isothiocyanate (FITC) through the ε-amino group of N-terminus Lys in the absence/presence of 6-amino-n-caproic acid (AC) linker to FITC-(FITC)KP6 and (FITC-AC)KP6-can be useful as fluorescent probes for the specific detection of ox-LDL. In this study, to develop the fluorescent peptides with high plasma stability for the specific detection of ox-LDL, we investigated the interaction of (FITC)KP6 and (FITC-AC)KP6 substituted with D-Lys at the N-terminus-(FITC)dKP6 and (FITC-AC)dKP6-with ox-LDL, and the in vitro stability of these peptides in mouse plasma. (FITC)dKP6 and (FITC-AC)dKP6 bound with high specificity to ox-LDL in a dose-dependent manner, and also to ox-LDL in the mouse plasma. Furthermore, (FITC)dKP6 was more stable than (FITC)KP6 in mouse plasma (102.1% versus 69.0% remained after 1 h). These findings strongly suggest that (FITC)dKP6 and (FITC-AC)dKP6 may be effective fluorescent probes with higher plasma stability than (FITC)KP6 and (FITC-AC)KP6 for the specific detection of ox-LDL.

C-reactive protein specifically enhances platelet-activating factor-induced inflammatory activity in vivo.

Platelet-activating factor (PAF) is a potent lipid mediator that is implicated in numerous inflammatory diseases. C-reactive protein (CRP) is an acute-phase plasma protein that increases rapidly and dramatically in response to inflammation. In this study, we investigated the effect of the interaction between CRP and PAF on inflammatory responses in vivo. From binding analysis using a time-resolved fluorometric assay, CRP bound to PAF and its precursor/metabolite lyso-PAF in a concentration-dependent manner. In addition, CRP bound to several phospholipids containing lysophosphatidylcholine, which bears structural resemblance to PAF and lyso-PAF, sphingosylphosphorylcholine, and lysophosphatidylethanolamine more readily than to lysophosphatidic acid and lysophosphatidylserine. In in vivo experiments using a rat model of hind paw oedema, CRP increased PAF-induced rat paw oedema in a dose-dependent manner, without causing the oedema itself, but it did not increase histamine and serotonin-induced paw oedema. Furthermore, the receptor for CRP, lectin-like oxidized low-density lipoprotein receptor 1 was not involved in the increase in PAF-induced inflammatory responses caused by CRP. These results indicate that CRP can specifically enhance PAF-induced inflammatory activity through binding to PAF and lyso-PAF. Therefore, CRP may accelerate the pathogenesis of numerous inflammatory diseases caused by PAF.

Muon radiography and deformation analysis of the lava dome formed by the 1944 eruption of Usu, Hokkaido--contact between high-energy physics and volcano physics--.

Lava domes are one of the conspicuous topographic features on volcanoes. The subsurface structure of the lava dome is important to discuss its formation mechanism. In the 1944 eruption of Volcano Usu, Hokkaido, a new lava dome was formed at its eastern foot. After the completion of the lava dome, various geophysical methods were applied to the dome to study its subsurface structure, but resulted in a rather ambiguous conclusion. Recently, from the results of the levelings, which were repeated during the eruption, "pseudo growth curves" of the lava dome were obtained. The curves suggest that the lava dome has a bulbous shape. In the present work, muon radiography, which previously proved effective in imaging the internal structure of Volcano Asama, has been applied to the Usu lava dome. The muon radiography measures the distribution of the "density length" of volcanic bodies when detectors are arranged properly. The result obtained is consistent with the model deduced from the pseudo growth curves. The measurement appears to afford useful method to clarify the subsurface structure of volcanoes and its temporal changes, and in its turn to discuss volcanic processes. This is a point of contact between high-energy physics and volcano physics.

The 1969-1985 Pozzuoli event and active volcanisms.

Pozzuoli is located at the center of the Campi Flegrei caldera, near Naples and is famous for its anomalous subsidence and upheaval documented since the Roman period. Its secular and gradual subsidence can be interpreted as self-loading compaction of the caldera fills while abrupt upheavals are geologically suspected to be caused by magmagenic movements or steam forces. In order to interpret the origin and the process of the Pozzuoli upheavals, they are compared with active volcanisms represented by the 1977-1982 eruption of Usu volcano in Hokkaido. Usu volcano outburst in 1977 in major pumice eruptions and repeated magmatic and phreatomagmatic eruptions, and manifested remarkable ground deformations accompanying earthquake swarms. In 1969, the ground of Pozzuoli began to upheave with increases in seismicity but finally failed to cause any eruptive phenomena at the surface; nevertheless there are common characteristics of their motives and processes between the two events. The motive of the Usu deformation is clearly due to magma movements while that of the Pozzuoli upheaval has not been completely settled. A quantitative relationship between seismicity and deformation gives a clue for discussing the motive of the Pozzuoli deformations. The discharge rates of seismic energy and the deformation rates are compared between the two events and a certain similarity is found. This suggests that the origin of the Pozzuoli event may be partly magmatic as well as the Usu eruption, but its behavior largely depends on the property of the caldera deposits. When their deformation volumes are taken into consideration, their characteristics become quantitatively conspicuous. The ground at Pozzuoli is much more easily deformed by the upward motive force than Usu volcano. This is due to the rheological property of the caldera deposits of Campi Flegrei, and agrees to the theory that interprets the secular subsidence observed in historical times, as self-loading compaction. It is interesting that there is a point of contact between anomalous movements of the ground along the seashore in Italy and remarkable magmatic movements at the active volcano in Japan.