Anti-programmed cell death-1 (PD-1) antibodies can cause thyroid dysfunction. However, no predictive biomarkers enabling stratification of thyroid dysfunction risk have been identified.
A total of ...209 patients treated with an anti-PD-1 antibody were evaluated for anti-thyroid antibodies at baseline and prospectively for thyroid function every 6 weeks for 24 weeks after treatment initiation, and then observed until the visits stopped. Thyroid ultrasonography was performed if the patient was positive for anti-thyroid antibodies at baseline.
Of the 209 patients, 19 (9.1%) developed thyroid dysfunction (destructive thyroiditis or hypothyroidism). The cumulative incidence of thyroid dysfunction was significantly higher in patients who were positive vs. negative for anti-thyroid antibodies (15/44 34.1% vs. 4/165 2.4%, p < 0.001). Forty-two patients positive for anti-thyroid antibodies at baseline were divided into two groups according to the presence of an irregular echo pattern. The cumulative incidence of thyroid dysfunction was significantly higher in those with an irregular vs. a regular echo pattern (13/23 56.5% vs. 1/19 5.3%, p = 0.001). None of the patients developed thyroid dysfunction after the initial 24-week period.
The risk of thyroid dysfunction induced by anti-PD-1 antibodies can be predicted by evaluation of anti-thyroid antibodies and the thyroid echo pattern at baseline.
UMIN000019024.
In this study, 42 years of tidal records and landfall TC best tracks in Japan were used to demonstrate that TC pre-landfall forward speed is significantly correlated with maximum storm surge height. ...Coastal morphology was the determining factor for the correlation between storm surge and TC forward speed. Fast-moving TCs tended to amplify the storm surge along open coastlines (Pearson correlation coefficient, R = 0.62), but reduce it in semi-enclosed bays (R = −0.52). The negative correlation contrasts with the general perception that the coincidence of TC wind speed and forward speed vectors generates a larger storm surge. The influence of coastal morphology was most prominent for TCs with a central pressure lower than 956 hPa. Tropical cyclone (TC) operational forecasts are continuously improving; however, there is still scope to improve the precision of storm surge predictions. These findings could contribute to the improvement of storm surge forecasting and provide emergency management personnel with more precise early warnings of dangerous storm surges.
Proline is the most abundant amino acid in wine and beer, because the yeast Saccharomyces cerevisiae hardly assimilates proline during fermentation processes. Our previous studies showed that ...arginine induces endocytosis of the proline transporter Put4, resulting in inhibition of proline utilization. We here report a possible role of arginine sensing in the inhibition of proline utilization. We first found that two basic amino acids, ornithine, and lysine, inhibit proline utilization by inducing Put4 endocytosis in a manner similar to arginine, but citrulline does not. Our genetic screening revealed that the arginine transporter Can1 is involved in the inhibition of proline utilization by arginine. Intriguingly, the arginine uptake activity of Can1 was not required for the arginine‐dependent inhibition of proline utilization, suggesting that Can1 has a function beyond its commonly known function of transporting arginine. More importantly, our biochemical analyses revealed that Can1 activates signaling cascades of protein kinase A in response to extracellular arginine. Hence, we proposed that Can1 regulates proline utilization by functioning as a transceptor possessing the activity of both a transporter and receptor of arginine.
Proline is mainly transported to the cells by the proline‐specific transporter Put4. In the presence of basic amino acids, Put4 is endocytosed dependent on the ubiquitin ligase Rsp5 and its adaptor Art3, leading to the inhibition of proline utilization. The transceptor function of Can1 plays a role in the mechanism for sensing basic amino acids that regulate the inhibition of proline utilization.
Take‐away
Basic amino acids inhibit proline utilization by inducing Put4 endocytosis.
Can1 is involved in the inhibition of proline utilization in yeast.
Can1 is a transceptor acting as both a transporter and receptor of arginine.
Sea level rise and land subsidence — induced flooding are projected to have severe impacts on highly populated Asian deltaic cities. These cities are already suffering from frequent floods, though ...few comparative analyses have been conducted on the similarities and differences of their adaptation approaches. Thus, this study aims to investigate the current adaptation pathways of Asian deltaic cities to flooding induced by slow onset events such as urbanization-induced land subsidence and sea level rise, by looking at Tokyo, Jakarta, Manila, and Ho Chi Minh City as case studies. Evidence from them shows that an engineering approach towards flooding adaptation is shaping the future of Asian deltaic cities. However, emerging challenges question the sustainability of this approach. Recommendations on how to improve current adaptation pathways and direction for future research are also provided.
Typhoon Lionrock, also known as the national number 1610 in Japan, caused severe flooding in east Japan in August 28–31, 2016, leaving a death toll of 22. With a maximum sustained wind speed of ~ ...220 km/h from the Joint Typhoon Warning Center’s best track, Lionrock was classified as a category 4 hurricane in Saffir–Simpson Hurricane Wind Scale and as a typhoon in Japan Meteorological Agency’s scale. Lionrock was among unique typhoons as it started its landfall from north of Japan. Here, we studied the characteristics of this typhoon through tide gauge data analysis, field surveys and numerical modeling. Tide gauge analysis showed that the surges generated by Lionrock were in the ranges of 15–55 cm with surge duration of 0.8–3.1 days. Our field surveys revealed that the damage to coastal communities/structures was moderate although it caused severe flooding inland. We measured a maximum coastal wave runup of 4.3 m in Iwaisaki. Such a runup was smaller than that generated by other category 4 typhoons hitting Japan in the past. Our numerical model was able to reproduce the storm surge generated by the 2016 Typhoon Lionrock. This validated numerical model can be used in the future for typhoon-hazard studies along the coast of northeastern Japan. Despite relatively small surge/wave runups in coastal areas, Lionrock’s death toll was more than that of some other category 4 typhoons. We attribute this to various primary (e.g., flooding, surges, waves, strong winds) and secondary (e.g., landslides, coastal erosions, debris flows, wind-blown debris) mechanisms and their combinations and interactions that contribute to damage/death during a typhoon event.
ABSTRACT
Proline is a predominant amino acid in grape must, but it is poorly utilized by the yeast Saccharomyces cerevisiae in wine-making processes. This sometimes leads to a nitrogen deficiency ...during fermentation and proline accumulation in wine. In this study, we clarified that a glucose response is involved in an inhibitory mechanism of proline utilization in yeast. Our genetic screen showed that strains with a loss-of-function mutation on the CDC25 gene can utilize proline even under fermentation conditions. Cdc25 is a regulator of the glucose response consisting of the Ras/cAMP-dependent protein kinase A (PKA) pathway. Moreover, we found that activation of the Ras/PKA pathway is necessary for the inhibitory mechanism of proline utilization. The present data revealed that crosstalk exists between the carbon and proline metabolisms. Our study could hold promise for the development of wine yeast strains that can efficiently assimilate proline during the fermentation processes.
In the fission yeast Schizosaccharomyces pombe, we found that the putative NO dioxygenase SPAC869.02c (named Yhb1) and the S-nitrosoglutathione reductase Fmd2 cooperatively reduced intracellular NO ...levels as NO-detoxification enzymes. Although both mRNA and protein levels were increased with exogenous NO, their expression patterns were different during growth phases. While treatment with an NO synthase inhibitor in the log phase abrogated both NO production and Yhb1 expression, induction of Fmd2 in the stationary phase was correlated with elevated mitochondrial respiratory chain (MRC) activity, confirmed by the fact that inhibition of MRC complex III led to a decrease in Fmd2 and NO levels. Moreover, NO was localized in the mitochondria in the stationary phase, suggesting that there are two distinctive types of NO signaling in S. pombe. For mitochondria, pretreatment with an NO donor rescued cell growth by repressing generation of reactive oxygen species (ROS) under oxidative stress. DNA microarray analysis revealed that exogenous NO contributes to tolerance to hydrogen peroxide (H2O2) by (i) inhibition of Fe3+ to Fe2+ conversion, (ii) upregulation of the H2O2-detoxifying enzymes, and (iii) downregulation of the MRC genes, suggesting that NO plays a pivotal role in the negative feedback system to regulate ROS levels in S. pombe.
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•We investigate the regulatory mechanisms of NO signaling in the fission yeast.•There are two NO-detoxifying enzymes with distinct expression patterns.•Complex III of mitochondrial respiratory chain is responsible for generation of NO.•NO plays a pivotal role in the negative feedback system to regulate ROS levels.
Nitric oxide (NO) functions in cell protection or cell death, depending on its concentration. Therefore, regulation of the intracellular concentrations of NO by its degradation systems is important ...for cellular functions. One of the NO degrading enzymes, flavohemoglobin (FHb), which has NO dioxygenase (NOD) activity, is a promising target for antibiotics, based on the finding that FHb-deficient pathogens exhibited reduced host toxicity. Here, we developed a high-throughput method to measure the NOD activity. Our newly developed method could contribute to the screening of potential antibiotics with NOD inhibitory activity.
This study investigated tidal records and landfall tropical cyclone (TC) best tracks from 1980 to 2019 to determine changes in storm surge heights in coastal regions of Central Japan, including ...Tokyo. The results indicate that annual mean storm surge heights have increased in the last 20 years (2000–2019) compared with those in 1980–1999, and that these changes are noteworthy, particularly in Tokyo Bay. The TC wind intensity and size during landfall have become stronger and larger, respectively, corresponding to increasing storm surge magnitudes from 1980 to 2019. The increased frequency of TCs with more northeastward tracks is another factor that may have contributed to the increased surge hazards around Tokyo. Additionally, a positive correlation between surge heights and a hazard index supports these statistical findings. The central coast of Japan will likely experience increasing numbers of extreme storm surge events in the future if the current increasing tendency continues.
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