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1. MondoA and AKI and AKI-to-CKD Transition

Author

Maeda, Shihomi, Sakai, Shinsuke, Takabatake, Yoshitsugu, Yamamoto, Takeshi, Minami, Satoshi, Nakamura, Jun, Namba-Hamano, Tomoko, Takahashi, Atsushi, Matsuda, Jun, Yonishi, Hiroaki, Matsui, Sho, Imai, Atsuhiro, Edahiro, Ryuya, Yamamoto-Imoto, Hitomi, Matsui, Isao, Takashima, Seiji, Imamura, Ryoichi, Nonomura, Norio, Yanagita, Motoko, Okada, Yukinori, Ballabio, Andrea, Nakamura, Shuhei, Yoshimori, Tamotsu, and Isaka, Yoshitaka

Published
2024
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2. The Rubicon–WIPI axis regulates exosome biogenesis during ageing

Author

Yanagawa, Kyosuke, Kuma, Akiko, Hamasaki, Maho, Kita, Shunbun, Yamamuro, Tadashi, Nishino, Kohei, Nakamura, Shuhei, Omori, Hiroko, Kaminishi, Tatsuya, Oikawa, Satoshi, Kato, Yoshio, Edahiro, Ryuya, Kawagoe, Ryosuke, Taniguchi, Takako, Tanaka, Yoko, Shima, Takayuki, Tabata, Keisuke, Iwatani, Miki, Bekku, Nao, Hanayama, Rikinari, Okada, Yukinori, Akimoto, Takayuki, Kosako, Hidetaka, Takahashi, Akiko, Shimomura, Iichiro, Sakata, Yasushi, and Yoshimori, Tamotsu

Abstract

Cells release intraluminal vesicles in multivesicular bodies as exosomes to communicate with other cells. Although recent studies suggest an intimate link between exosome biogenesis and autophagy, the detailed mechanism is not fully understood. Here we employed comprehensive RNA interference screening for autophagy-related factors and discovered that Rubicon, a negative regulator of autophagy, is essential for exosome release. Rubicon recruits WIPI2d to endosomes to promote exosome biogenesis. Interactome analysis of WIPI2d identified the ESCRT components that are required for intraluminal vesicle formation. Notably, we found that Rubicon is required for an age-dependent increase of exosome release in mice. In addition, small RNA sequencing of serum exosomes revealed that Rubicon determines the fate of exosomal microRNAs associated with cellular senescence and longevity pathways. Taken together, our current results suggest that the Rubicon–WIPI axis functions as a key regulator of exosome biogenesis and is responsible for age-dependent changes in exosome quantity and quality.

Published
2024
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3. Extension of multi-site analogue series with potent compounds using a bidirectional transformer-based chemical language model

Author

Chen, Hengwei, Yoshimori, Atsushi, and Bajorath, Jürgen

Abstract

Generating potent compounds for evolving analogue series (AS) is a key challenge in medicinal chemistry. The versatility of chemical language models (CLMs) makes it possible to formulate this challenge as an off-the-beaten-path prediction task. In this work, we have devised a coding and tokenization scheme for evolving AS with multiple substitution sites (multi-site AS) and implemented a bidirectional transformer to predict new potent analogues for such series. Scientific foundations of this approach are discussed and, as a benchmark, the transformer model is compared to a recurrent neural network (RNN) for the prediction of analogues of AS with single substitution sites. Furthermore, the transformer is shown to successfully predict potent analogues with varying R-group combinations for multi-site AS having activity against many different targets. Prediction of R-group combinations for extending AS with potent compounds represents a novel approach for compound optimization.

Published
2024
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4. Next questions in autophagy

Author

Cuervo, Ana Maria, Elazar, Zvulun, Evans, Chantell, Ge, Liang, Hansen, Malene, Jäättelä, Marja, Liang, Jin Rui (Amos), Loos, Ben, Mizushima, Noboru, Simon, Anna Katharina, Tooze, Sharon, Yoshimori, Tamotsu, and Nakamura, Shuhei

Abstract

Our understanding of the basic mechanisms of autophagy is growing, but many questions remain about the types of autophagy cells use, when they use them, and how they function in different contexts. We asked emerging and established leaders in the field to discuss the questions and areas that they are most excited about to deepen our understanding of autophagy.

Published
2024
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5. The mechanisms of arterial signal intensity profile in non-contrast coronary MRA (NC-MRCA): a 3D printed phantom investigation and clinical translations

Author

Kato, Yoko, Noda, Chikara, Ambale-Venkatesh, Bharath, Ortman, Jason M., Kassai, Yoshimori, Lima, Joao A. C., and Liu, Chia-Ying

Abstract

Signal intensity (SI) drop has been proposed as an indirect stenosis assessment in non-contrast coronary MRA (NC-MRCA) but it uses unproven assumptions.We aimed to clarify the mechanisms that govern the SI in vitro and develop a stenosis detection method in vivo. Flow phantom tubes with/without stenosis were scanned under two spatial resolutions (0.5/1.0 mm3) on a 3.0 T MRI. Thirty-two coronary arteries from 11 volunteers were prospectively scanned with an EKG- and respiratory-gated 3D NC-MRCA with a resolution of 1.0 mm3, with coronary computed tomography angiography (CTA) as reference. The normalized SI along the centerline of the tubes or the coronary arteries was assessed against the distance from the orifice using a linear regression model. Its coefficient (SI decay slope) and goodness-of-fit (R2) were extracted to assess the effect of flow velocity and stenosis on the SI profile curve. The R2 was utilized for the stenosis detection. Phantom study: A slow flow velocity caused a steep SI decay slope. The SI drop revealed only at the inlet and outlet of stenosis due to the flow turbulence/vortex and yielded low R2, in which shape changed by the resolution. Clinical study: The R2 cutoff to detect ≥ 50% stenosis for the left and right coronary arteries were 0.64 and 0.20 with a sensitivity/specificity of 71.5/71.5 and 66.7/100 (%), respectively. The SI drop did not reflect the actual stenosis position and not suitable for the stenosis localization. The R2 cutoff represents an alternative method to detect stenoses on NC-MRCA at vessel level.

Published
2024
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6. Proteinuria is independently associated with heart failure events in patients with atrial fibrillation: the Fushimi AF registry

Author

Ikeda, Syuhei, An, Yoshimori, Iguchi, Moritake, Ogawa, Hisashi, Nakanishi, Yumiko, Minami, Kimihito, Ishigami, Kenjiro, Aono, Yuya, Doi, Kosuke, Hamatani, Yasuhiro, Yoshizawa, Takashi, Ide, Yuya, Fujino, Akiko, Ishii, Mitsuru, Masunaga, Nobutoyo, Esato, Masahiro, Tsuji, Hikari, Wada, Hiromichi, Hasegawa, Koji, Abe, Mitsuru, and Akao, Masaharu

Abstract

Graphical AbstractProteinuria can stratify the risk of HF events in patients with AF.

Published
2023
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7. Comparison of the thickness of the erector spinae muscles between aspiration pneumonia and bacterial pneumonia patients

Author

Shimoda, Masafumi, Tanaka, Yoshiaki, Morimoto, Kozo, Nomura, Sakika, Yoshimori, Kozo, and Ohta, Ken

Abstract

Background and Aims: Aspiration pneumonia is generally associated with deterioration of skeletal muscle mass, which is usually evaluated by the erector spinae muscle cross-sectional area (ESMCSA); however, no report has assessed ESMCSAin patients with aspiration pneumonia. Furthermore, erector spinae muscle thickness (ESMT) was developed to be easier to measure than ESMCSA. Therefore, this study investigated the relationship between ESMTand ESMCSAin aspiration pneumonia patients compared to bacterial pneumonia patients. Methods: We retrospectively collected data for 164 patients with aspiration pneumonia and 480 patients with bacterial pneumonia who were hospitalized at Fukujuji Hospital between September 2018 and May 2022. We assessed the correlations between ESMCSAand ESMTand compared the data between the two groups. Results: ESMThad a strong, proportional relationship with ESMCSAin all patients (r = 0.908, p< 0.001) and those with aspiration pneumonia (r = 0.896, p< 0.001). ESMCSA(median 671.8 mm2[range 164.0–1636.7] vs. median 1057.0 mm2[range 161.3–2412.5], p< 0.001) and ESMT(median 17.1 mm [range 6.95–34.4] vs. median 23.8 mm [range 6.95–43.7], p< 0.001) were significantly lower in patients with aspiration pneumonia. A multivariate analysis of aspiration pneumonia diagnosis showed significant independent differences from bacterial pneumonia in ESMCSA(odds ratio 0.998 [95% CI: 0.996–0.999], p= 0.001) and ESMT(odds ratio 0.90 [95% CI: 0.84–0.96], p= 0.002). Conclusion: This study demonstrates a strong correlation between ESMCSAand ESMT. ESMTcan be more easily used to evaluate skeletal muscle mass and can help in diagnosing aspiration pneumonia.

Published
2023
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9. The mechanisms and roles of selective autophagy in mammals

Author

Vargas, Jose Norberto S., Hamasaki, Maho, Kawabata, Tsuyoshi, Youle, Richard J., and Yoshimori, Tamotsu

Abstract

Autophagy is a process that targets various intracellular elements for degradation. Autophagy can be non-selective — associated with the indiscriminate engulfment of cytosolic components — occurring in response to nutrient starvation and is commonly referred to as bulk autophagy. By contrast, selective autophagy degrades specific targets, such as damaged organelles (mitophagy, lysophagy, ER-phagy, ribophagy), aggregated proteins (aggrephagy) or invading bacteria (xenophagy), thereby being importantly involved in cellular quality control. Hence, not surprisingly, aberrant selective autophagy has been associated with various human pathologies, prominently including neurodegeneration and infection. In recent years, considerable progress has been made in understanding mechanisms governing selective cargo engulfment in mammals, including the identification of ubiquitin-dependent selective autophagy receptors such as p62, NBR1, OPTN and NDP52, which can bind cargo and ubiquitin simultaneously to initiate pathways leading to autophagy initiation and membrane recruitment. This progress opens the prospects for enhancing selective autophagy pathways to boost cellular quality control capabilities and alleviate pathology.

Published
2023
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10. Loss of RUBCN/rubicon in adipocytes mediates the upregulation of autophagy to promote the fasting response

Author

Yamamuro, Tadashi, Nakamura, Shuhei, Yanagawa, Kyosuke, Tokumura, Ayaka, Kawabata, Tsuyoshi, Fukuhara, Atsunori, Teranishi, Hirofumi, Hamasaki, Maho, Shimomura, Iichiro, and Yoshimori, Tamotsu

Abstract

ABSTRACTUpon fasting, adipocytes release their lipids that accumulate in the liver, thus promoting hepatic steatosis and ketone body production. However, the mechanisms underlying this process are not fully understood. In this study, we found that fasting caused a substantial decrease in the adipose levels of RUBCN/rubicon, a negative regulator of macroautophagy/autophagy, along with an increase in autophagy. Adipose-specific rubcn-knockout mice exhibited systemic fat loss that was not accelerated by fasting. Genetic inhibition of autophagy in adipocytes in fasted mice led to a reduction in fat loss, hepatic steatosis, and ketonemia. In terms of mechanism, autophagy decreased the levels of its substrates NCOA1/SRC-1 and NCOA2/TIF2, which are also coactivators of PPARG/PPARγ, leading to a fasting-induced reduction in the mRNA levels of adipogenic genes in adipocytes. Furthermore, RUBCN in adipocytes was degraded through the autophagy pathway, suggesting that autophagic degradation of RUBCN serves as a feedforward system for autophagy induction during fasting. Collectively, we propose that loss of adipose RUBCN promotes a metabolic response to fasting via increasing autophagic activity.

Published
2022
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11. Degradation of the NOTCH intracellular domain by elevated autophagy in osteoblasts promotes osteoblast differentiation and alleviates osteoporosis

Author

Yoshida, Gota, Kawabata, Tsuyoshi, Takamatsu, Hyota, Saita, Shotaro, Nakamura, Shuhei, Nishikawa, Keizo, Fujiwara, Mari, Enokidani, Yusuke, Yamamuro, Tadashi, Tabata, Keisuke, Hamasaki, Maho, Ishii, Masaru, Kumanogoh, Atsushi, and Yoshimori, Tamotsu

Abstract

ABSTRACTMaintenance of bone integrity is mediated by the balanced actions of osteoblasts and osteoclasts. Because macroautophagy/autophagy regulates osteoblast mineralization, osteoclast differentiation, and their secretion from osteoclast cells, autophagy deficiency in osteoblasts or osteoclasts can disrupt this balance. However, it remains unclear whether upregulation of autophagy becomes beneficial for suppression of bone-associated diseases. In this study, we found that genetic upregulation of autophagy in osteoblasts facilitated bone formation. We generated mice in which autophagy was specifically upregulated in osteoblasts by deleting the gene encoding RUBCN/Rubicon, a negative regulator of autophagy. The rubcnflox/flox;Sp7/Osterix-Cremice showed progressive skeletal abnormalities in femur bones. Consistent with this, RUBCN deficiency in osteoblasts resulted in elevated differentiation and mineralization, as well as an increase in the elevated expression of key transcription factors involved in osteoblast function such as Runx2and Bglap/Osteocalcin. Furthermore, RUBCN deficiency in osteoblasts accelerated autophagic degradation of NOTCH intracellular domain (NICD) and downregulated the NOTCH signaling pathway, which negatively regulates osteoblast differentiation. Notably, osteoblast-specific deletion of RUBCN alleviated the phenotype in a mouse model of osteoporosis. We conclude that RUBCN is a key regulator of bone homeostasis. On the basis of these findings, we propose that medications targeting RUBCN or autophagic degradation of NICD could be used to treat age-related osteoporosis and bone fracture.Abbreviations: ALPL: alkaline phosphatase, liver/bone/kidney; BCIP/NBT: 5-bromo-4-chloro-3ʹ-indolyl phosphate/nitro blue tetrazolium; BMD: bone mineral density; BV/TV: bone volume/total bone volume; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MTOR: mechanistic target of rapamycin kinase; NICD: NOTCH intracellular domain; RB1CC1/FIP200: RB1-inducible coiled-coil 1; RUBCN/Rubicon: RUN domain and cysteine-rich domain containing, Beclin 1-interacting protein; SERM: selective estrogen receptor modulator; TNFRSF11B/OCIF: tumor necrosis factor receptor superfamily, member 11b (osteoprotegerin)

Published
2022
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12. Mitral valve motion after performing an edge-to-edge repair in an isolated swine heart

Author

Hasegawa, Hiroki, Araki, Yoshimori, Usui, Akihiko, Yokote, Jun, Saito, Shunei, Oshima, Hideki, and Ueda, Yuichi

Subjects
Heart valve diseases, Swine, Health
Abstract

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.jtcvs.2008.03.050 Byline: Hiroki Hasegawa, Yoshimori Araki, Akihiko Usui, Jun Yokote, Shunei Saito, Hideki Oshima, Yuichi Ueda Abbreviations: EtoE, edge-to-edge; LAP, left atrial pressure; LV, left ventricular; MS, mitral stenosis; MVA, mitral valve area; MVOP, mitral valve open phase; NM, normal mode; SV, stroke volume Abstract: Mitral valve motion after performing an edge-to-edge repair is a major concern, but it has not yet been observed directly. Mitral valve motion was assessed by using a high-speed digital video camera and microsonometric analysis in an isolated swine heart, and any changes in the mitral valve area or the development of mitral stenosis symptoms were evaluated. Author Affiliation: Department of Cardiothoracic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan Article History: Received 21 November 2007; Revised 2 February 2008; Accepted 7 March 2008

Published
2008

13. How cells recognize and remove the perforated lysosome

Author

Tabata, Keisuke, Saeki, Marika, Yoshimori, Tamotsu, and Hamasaki, Maho

Abstract

ABSTRACTMacroautophagy (hereafter autophagy) is a highly conserved intracellular degradation system to maintain cellular homeostasis by degrading cellular components such as misfolded proteins, nonfunctional organelles, pathogens, and cytosol. Conversely, selective autophagy targets and degrades specific cargo, such as organelles, bacteria, etc. We previously reported that damaged lysosomes are autophagy targets, via a process called lysophagy. However, how cells target damaged lysosomes through autophagy is not known. We performed proteomics analysis followed by siRNA screening to identify genes involved in targeting damaged lysosomes and identified a new E3 ligase complex, involving CUL4A (cullin 4A), as a regulatory complex in lysophagy. We also found that this complex mediates K48-linked poly-ubiquitination on lysosome protein LAMP2 during lysosomal damage; particularly, the lumenal side of LAMP2 is important to recruit the complex to damaged lysosomes. This protein modification is thus critical to initiate the clearance of damaged lysosomes.

Published
2023
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14. Changing Role of Horizontal Moisture Advection in the Lower Troposphere Under Extreme Arctic Amplification

Author

Hori, Masatake E., Yoshimori, Masakazu, and Ukita, Jinro

Abstract

Horizontal and vertical moisture advection in the lower troposphere of the Arctic under progressing global warming is examined using a large‐scale ensemble model data set. Advection is decomposed into terms related to the basic state of the atmosphere and transient eddies and compared against a non‐warming experiment. During summer, horizontal moisture advection increases mainly by transient eddies advecting moisture from the lower latitudes. During winter, enhanced evaporation due to reduced sea ice becomes a source of moisture diminishing the role of transient eddies moistening the atmosphere. This effect intensifies under extreme global warming, turning the change in total horizontal advection in the lower troposphere negative. Diminished horizontal advection during winter is counteracted by vertical advection accompanied with enhanced evaporation and upper‐level horizontal advection maintaining the increase in column moisture. These results improve our understanding of how the water cycle in the Arctic responds via atmospheric processes under global warming. This study uses a data set with a large number of members to investigate how the atmosphere is moistened in the Arctic (north of 70˚N) under various stages of global warming. The movement of moisture is summarized in terms of horizontal and vertical components of advection, a measure of how the atmosphere is moistened in a given specific humidity gradient and wind, which is decomposed into parts related to the average state of the atmosphere and parts related to high‐frequency phenomena, such as cyclones. It is found that (a) during summer, moisturization of the Arctic is mainly driven by horizontal movement of moisture from a remote source in the lower latitude, (b) during winter, this moisturization due to horizontal movement of moisture is suppressed and is driven more by vertical movement of moisture due to reduction of sea ice and increased evaporation. As global warming progresses, the role or horizontal movement of moisture is taken over by the local process of evaporation and vertical movement of moisture. This research helps us understand how the water cycle in the Arctic changes with severe global warming and improves our knowledge of the atmospheric processes that govern the climate system through various feedbacks. Moisture advection in the Arctic under progressing global warming is examined using a large‐scale ensemble model simulation data setMoistening effect of horizontal advection in the lower troposphere is enhanced for summer and diminished for winter under extreme warmingEnhanced horizontal advection in the upper layer and surface evaporation are consistent with increased column moisture during winter Moisture advection in the Arctic under progressing global warming is examined using a large‐scale ensemble model simulation data set Moistening effect of horizontal advection in the lower troposphere is enhanced for summer and diminished for winter under extreme warming Enhanced horizontal advection in the upper layer and surface evaporation are consistent with increased column moisture during winter

Published
2024
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16. Application of an indentation sensor for the arthroscopic measurement of articular cartilage stiffness

Author

Kitta, Yuki, Kiriyama, Yoshimori, Harato, Kengo, Kobayashi, Shu, Niki, Yasuo, Matsumoto, Morio, Nakamura, Masaya, and Nagura, Takeo

Abstract

Direct measurement of cartilage stiffness provides useful clinical information and enables us to develop treatment strategies for patients. We applied an indentation sensor to evaluate cartilage stiffness under arthroscopic control. The purpose of this study was to validate the arthroscopic indentation sensor using cadaver knees and to measure cartilage stiffness in clinical cases. The stiffness of a material with known properties was measured at thicknesses from 2 mm to 10 mm with a 2-mm interval. This was repeated three times at each thickness to evaluate repeatability. The articular cartilage stiffness of the medial and lateral femoral condyles of five human cadaveric knees was measured. The sensor was inclined from 0° to 20° with 1° intervals. The stiffness value at each degree of inclination was compared to evaluate the acceptable measuring angle. Additionally, articular cartilage stiffness was measured in 23 adolescent and 11 adult patients under arthroscopy. Young’s moduli of the material were 1.15–1.24 (mean 1.20) MPa. Inter-class correlation coefficients in repeated measurements using the material were 0.83–0.99. There were no differences in the cartilage stiffness between the medial and lateral femoral condyles of the cadaver knees. All condyles showed a nonlinear relationship between force and displacement. The force decreased in all condyles when the tip of the sensor system was tilted. The range of error was < 97.1% within 5° inclination. There was a moderate negative correlation between age and cartilage stiffness in adolescent patients, and a moderate positive correlation in adult patients. Since the sensor system is manually held during measurement, the validity and repeatability to assess material properties of the cartilage may be inaccurate. This study has proven that the instrument can measure the stiffness of joint cartilage reliably and is a useful clinical tool under arthroscopic control.

Published
2022
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18. Efficacy of topical povidone-iodine during the first week after ophthalmic surgery

Author

Isenberg, Sherwin J., Apt, Leonard, Yoshimori, Robert, Pham, Catherine, and Lam, Nam K.

Subjects
Povidone -- Evaluation, Eye, Health
Abstract

PURPOSE: In the first postoperative day, povidone-iodine ophthalmic solution prevents an increase in conjunctival bacterial colony-forming units and decreases the species compared with antibiotic. We sought to determine whether these beneficial effects of povidone-iodine could be sustained during the first postoperative week. METHODS: In 42 eyes of 35 consecutive patients, one or two drops of either a broad-spectrum antibiotic (polymyxin B sulfate - neomycin sulfate-gramicidin) or povidone iodine 1.25% to 2.5% were placed in the treated eye or eyes at the conclusion of surgery and three times daily during the first postoperative week. Bacterial cultures were taken from both eyes at the end of surgery before instillation of either of the eyedrops and again 1 week later. Twenty-eight untreated eyes served as a control group. RESULTS: During the first postoperative week, the number of colony-forming units and species increased in both treatment groups. Relative to the control group, both medications effectively reduced the mean number of colony-forming units at 1 week (P [is less than] .02), but their effects on colony-forming units did not significantly differ from each other (80 [+ or -] 290 for the povidone iodine-treated eyes and 75 [+ or -] 90 for the antibiotic treated eyes). At 1 week, the species count increased 281% in the antibiotic group but only 106% in the povidone-iodine group. Compared to the control group, eyes that received povidone-iodine had a significantly lower species count (P = .0097). CONCLUSION: Povidone-iodine ophthalmic solution is an alternative to postoperative topical antibiotics because of its effectiveness in controlling conjunctival bacterial colony-forming units and species, its relatively low cost, and its availability.

Published
1997

21. Whose company is it? The concept of the corporation in Japan and the West

Author

Yoshimori, Masaru

Subjects
Corporations -- Analysis, Corporations, Japanese -- Management, Corporations -- Management, Corporations, European -- Management, Business, Business, international
Abstract

Significant differences underlie the concept of the corporation in Japan and the West, particularly the US and Europe. The Japanese corporation follows the pluralistic approach of corporate governance, which looks at the firm as belonging to stakeholders and where the interest of employees is of prime importance. In the US and the UK, the monistic outlook is more prevalent, where the firm is assumed to be the private property of its owners. The dualistic concept takes precedence in Germany and in France, where shareholder interest is important, but employee interest is considered as well. The advantages and disadvantages of each concept are discussed.

Published
1996

22. Author Correction: LC3 lipidation is essential for TFEB activation during the lysosomal damage response to kidney injury

Author

Nakamura, Shuhei, Shigeyama, Saki, Minami, Satoshi, Shima, Takayuki, Akayama, Shiori, Matsuda, Tomoki, Esposito, Alessandra, Napolitano, Gennaro, Kuma, Akiko, Namba-Hamano, Tomoko, Nakamura, Jun, Yamamoto, Kenichi, Sasai, Miwa, Tokumura, Ayaka, Miyamoto, Mika, Oe, Yukako, Fujita, Toshiharu, Terawaki, Seigo, Takahashi, Atsushi, Hamasaki, Maho, Yamamoto, Masahiro, Okada, Yukinori, Komatsu, Masaaki, Nagai, Takeharu, Takabatake, Yoshitsugu, Xu, Haoxing, Isaka, Yoshitaka, Ballabio, Andrea, and Yoshimori, Tamotsu

Published
2022
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23. Bevacizumab plus erlotinib versus erlotinib alone in Japanese patients with advanced, metastatic, EGFR-mutant non-small-cell lung cancer (NEJ026): overall survival analysis of an open-label, randomised, multicentre, phase 3 trial

Author

Kawashima, Yosuke, Fukuhara, Tatsuro, Saito, Haruhiro, Furuya, Naoki, Watanabe, Kana, Sugawara, Shunichi, Iwasawa, Shunichiro, Tsunezuka, Yoshio, Yamaguchi, Ou, Okada, Morihito, Yoshimori, Kozo, Nakachi, Ichiro, Seike, Masahiro, Azuma, Koichi, Kurimoto, Futoshi, Tsubata, Yukari, Fujita, Yuka, Nagashima, Hiromi, Asai, Gyo, Watanabe, Satoshi, Miyazaki, Masaki, Hagiwara, Koichi, Nukiwa, Toshihiro, Morita, Satoshi, Kobayashi, Kunihiko, and Maemondo, Makoto

Abstract

Bevacizumab is a promising candidate for combination treatment with epidermal growth factor receptor tyrosine-kinase inhibitors (eg, erlotinib), which could improve outcomes for patients with metastatic EGFR-mutant non-small-cell lung cancer (NSCLC). We have previously shown in NEJ026, a phase 3 trial, that the combination of bevacizumab plus erlotinib significantly prolonged progression-free survival compared with erlotinib alone in these patients. In further analyses, we aimed to examine the effects of bevacizumab–erlotinib on overall survival, time from enrolment to progressive disease during second-line treatment or death, and quality of life.

Published
2022
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24. TP53/p53-FBXO22-TFEB controls basal autophagy to govern hormesis

Author

Suzuki, Narumi, Johmura, Yoshikazu, Wang, Teh-Wei, Migita, Toshiro, Wu, Wenwen, Noguchi, Rei, Yamaguchi, Kiyoshi, Furukawa, Yoichi, Nakamura, Shuhei, Miyoshi, Ichiro, Yoshimori, Tamotsu, Ohta, Tomohiko, and Nakanishi, Makoto

Abstract

ABSTRACTPreconditioning with a mild stressor such as fasting is a promising way to reduce severe side effects from subsequent chemo- or radiotherapy. However, the underlying mechanisms have been largely unexplored. Here, we demonstrate that the TP53/p53-FBXO22-TFEB (transcription factor EB) axis plays an essential role in this process through upregulating basal macroautophagy/autophagy. Mild stress-activated TP53 transcriptionally induced FBXO22, which in turn ubiquitinated KDM4B (lysine-specific demethylase 4B) complexed with MYC-NCOR1 suppressors for degradation, leading to transcriptional induction of TFEB. Upregulation of autophagy-related genes by increased TFEB dramatically enhanced autophagic activity and cell survival upon following a severe stressor. Mitogen-induced AKT1 activation counteracted this process through the phosphorylation of KDM4B, which inhibited FBXO22-mediated ubiquitination. Additionally, fbxo22−/−mice died within 10 h of birth, and their mouse embryonic fibroblasts (MEFs) showed a lowered basal autophagy, whereas FBXO22-overexpressing mice were resistant to chemotherapy. Taken together, these results suggest that TP53 upregulates basal autophagy through the FBXO22-TFEB axis, which governs the hormetic effect in chemotherapy.Abbreviations: BBC3/PUMA: BCL2 binding component 3; CDKN1A/p21: cyclin dependent kinase inhibitor 1A; ChIP-seq: chromatin immunoprecipitation followed by sequencing; DDB2: damage specific DNA binding protein 2; DRAM: DNA damage regulated autophagy modulator; ESR/ER: estrogen receptor 1; FMD: fasting mimicking diet; HCQ: hydroxychloroquine; KDM4B: lysine-specific demethylase 4B; MAP1LC3/LC3: microtubule associated protein 1 light chain 3 alpha; MEFs: mouse embryonic fibroblasts; MTOR: mechanistic target of rapamycin kinase; NCOR1: nuclear receptor corepressor 1; SCF: SKP1-CUL-F-box protein; SQSTM1: sequestosome 1; TFEB: transcription factor EB

Published
2021
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25. Whose company is it? The concept of the corporation in Japan and the West

Author

Yoshimori, Masaru

Subjects
Corporations, Japanese -- Management, Corporate governance -- Analysis, Business, Business, general, Economics
Abstract

This article examines the differences in the concept of the corporation and their possible implications for corporate performance, between Japan on the one hand and the United States and Europe (Germany, UK and France) on the other. The Japanese concept is used as the standard against which the other models are compared. The concept of the corporation is defined here as the answer to the question: 'In whose interest should the firm be managed?' This is the foundation on which corporate governance and the monitoring system for the CEO is built. The analysis is focused on large publicly-held corporations with widely diffused ownership.

Published
1995

27. Intratumoral DNA heterogeneity of small hepatocellular carcinoma

Author

Okada, Shuichi, Ishii, Hiroshi, Nose, Haruhiko, Okusaka, Takuji, Kyogoku, Akiko, Yoshimori, Masayoshi, Sakamoto, Michiie, and Hirohashi, Setsuo

Subjects
Liver cancer -- Genetic aspects, Ploidy -- Physiological aspects, Health
Abstract

Background. Intratumoral DNA heterogeneity provides important information regarding biologic and clinical behavior. The purpose of this study was to evaluate the incidence of DNA heterogeneity in small hepatocellular carcinoma (HCC) nodules. Methods. The DNA content of 28 surgically resected small HCC nodules ([less than or equal to] 3.0 cm) was measured using flow cytometry of fresh or frozen samples taken from different parts of each nodule with reference to the macroscopic features. Results. Of the 28 small HCC nodules, 14 (50.0%) had only DNA diploid stemline characteristics. Five nodules (17.9%) manifested DNA diploid and DNA aneuploidy within the same tumor. Of the remaining nine nodules (32.1%) that showed only DNA aneuploidy, two contained tumor tissues with apparently different DNA content. Thus, DNA heterogeneity was found in 7 (25.0%) of 28 nodules. DNA heterogeneity correlated well with macroscopic histologic features. All four early HCC were composed of only DNA diploid cells, whereas three of six nodule-in-nodule lesions were composed of DNA heterogeneous cells, in which the inner obviously cancerous nodule showed DNA aneuploidy and the outer well differentiated HCC portion demonstrated DNA diploid. Four of 18 overt HCC nodules showed DNA heterogeneity; 2 of these 4 nodules showed both diploid and aneuploid peaks, and the other 2 two showed different aneuploid peaks within the same nodule. Conclusions. DNA heterogeneity correlating with macroscopic features is found frequently even in small HCC nodules. Therefore, multiple sampling based on macroscopic features is required for the accurate assessment of DNA ploidy, particularly when the information about DNA ploidy is used as a prognostic indicator.

Published
1995

28. Povidone-iodine for ophthalmia neonatorum prophylaxis

Author

Isenberg, Sherwin J., Apt, Leonard, Yoshimori, Robert, Leake, Rosemary D., and Rich, Roberta

Subjects
Conjunctivitis, Infantile -- Drug therapy, Povidone -- Usage, Iodine -- Usage, Health
Published
1994

29. Sources of Japanese competitiveness

Author

Yoshimori, Masaru

Subjects
International competition (Commerce) -- Analysis, Industrial management -- Japan, Free trade -- Analysis, Business, Business, international
Abstract

US protectionist measures against Japanese competition have greatly affected consumer welfare. Although import restrictions have been perceived to be detrimental to consumer interest, a number of US companies have used such time-periods to learn effective managerial processes from their Japanese competitors. Industries may then be able to gain much knowledge through foreign competition without necessarily ignoring consumer welfare.

Published
1992

30. Alternative mitochondrial quality control mediated by extracellular release

Author

Choong, Chi-Jing, Okuno, Tatsusada, Ikenaka, Kensuke, Baba, Kousuke, Hayakawa, Hideki, Koike, Masato, Yokota, Mutsumi, Doi, Junko, Kakuda, Keita, Takeuchi, Toshihide, Kuma, Akiko, Nakamura, Shuhei, Nagai, Yoshitaka, Nagano, Seiichi, Yoshimori, Tamotsu, and Mochizuki, Hideki

Abstract

ABSTRACTMitochondrial quality control, which is crucial for maintaining cellular homeostasis, has been considered to be achieved exclusively through mitophagy. Here we report an alternative mitochondrial quality control pathway mediated by extracellular mitochondria release. By performing time-lapse confocal imaging on a stable cell line with fluorescent-labeled mitochondria, we observed release of mitochondria from cells into the extracellular space. Correlative light-electron microscopy revealed that majority of the extracellular mitochondria are in free form and, on rare occasions, some are enclosed in membrane-surrounded vesicles. Rotenone- and carbonyl cyanide m-chlorophenylhydrazone-induced mitochondrial quality impairment promotes the extracellular release of depolarized mitochondria. Overexpression of PRKN (parkin RBR E3 ubiquitin protein ligase), which has a pivotal role in mitophagy regulation, suppresses the extracellular mitochondria release under basal and stress condition, whereas its knockdown exacerbates it. Correspondingly, overexpression of PRKN-independent mitophagy regulators, BNIP3 (BCL2 interacting protein 3) and BNIP3L/NIX (BCL2 interacting protein 3 like), suppress extracellular mitochondria release. Autophagy-deficient cell lines show elevated extracellular mitochondria release. These results imply that perturbation of mitophagy pathway prompts mitochondria expulsion. Presence of mitochondrial protein can also be detected in mouse sera. Sera of PRKN-deficient mice contain higher level of mitochondrial protein compared to that of wild-type mice. More importantly, fibroblasts and cerebrospinal fluid samples from Parkinson disease patients carrying loss-of-function PRKNmutations show increased extracellular mitochondria compared to control subjects, providing evidence in a clinical context. Taken together, our findings suggest that extracellular mitochondria release is a comparable yet distinct quality control pathway from conventional mitophagy.Abbreviations:ACTB: actin beta; ANXA5: annexin A5; ATP5F1A/ATP5A: ATP synthase F1 subunit alpha; ATG: autophagy related; BNIP3: BCL2 interacting protein 3; BNIP3L/NIX: BCL2 interacting protein 3 like; CCCP: carbonyl cyanide m-chlorophenylhydrazone; CM: conditioned media; CSF: cerebrospinal fluid; DMSO: dimethyl sulfoxide; EM: electron microscopy; HSPD1/Hsp60: heat shock protein family D (Hsp60) member 1; KD: knockdown; KO: knockout; MAP1LC3A/LC3: microtubule associated protein 1 light chain 3 alpha; MT-CO1: mitochondrially encoded cytochrome c oxidase I; NDUFB8: NADH:ubiquinone oxidoreductase subunit B8; OE: overexpression; OPA1: OPA1 mitochondrial dynamin like GTPase; OXPHOS: oxidative phosphorylation; PBS: phosphate-buffered saline; PB: phosphate buffer; PD: Parkinson disease; PINK1: PTEN induced kinase 1; PRKN: parkin RBR E3 ubiquitin protein ligase; RB1CC1/FIP200: RB1 inducible coiled-coil 1; SDHB: succinate dehydrogenase complex iron sulfur subunit B; TOMM20: translocase of outer mitochondrial membrane 20; TOMM40: translocase of outer mitochondrial membrane 40; UQCRC2: ubiquinol-cytochrome c reductase core protein 2; WT: wild-type

Published
2021
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31. A cross-population atlas of genetic associations for 220 human phenotypes

Author

Sakaue, Saori, Kanai, Masahiro, Tanigawa, Yosuke, Karjalainen, Juha, Kurki, Mitja, Koshiba, Seizo, Narita, Akira, Konuma, Takahiro, Yamamoto, Kenichi, Akiyama, Masato, Ishigaki, Kazuyoshi, Suzuki, Akari, Suzuki, Ken, Obara, Wataru, Yamaji, Ken, Takahashi, Kazuhisa, Asai, Satoshi, Takahashi, Yasuo, Suzuki, Takao, Shinozaki, Nobuaki, Yamaguchi, Hiroki, Minami, Shiro, Murayama, Shigeo, Yoshimori, Kozo, Nagayama, Satoshi, Obata, Daisuke, Higashiyama, Masahiko, Masumoto, Akihide, Koretsune, Yukihiro, Ito, Kaoru, Terao, Chikashi, Yamauchi, Toshimasa, Komuro, Issei, Kadowaki, Takashi, Tamiya, Gen, Yamamoto, Masayuki, Nakamura, Yusuke, Kubo, Michiaki, Murakami, Yoshinori, Yamamoto, Kazuhiko, Kamatani, Yoichiro, Palotie, Aarno, Rivas, Manuel A., Daly, Mark J., Matsuda, Koichi, and Okada, Yukinori

Abstract

Current genome-wide association studies do not yet capture sufficient diversity in populations and scope of phenotypes. To expand an atlas of genetic associations in non-European populations, we conducted 220 deep-phenotype genome-wide association studies (diseases, biomarkers and medication usage) in BioBank Japan (n= 179,000), by incorporating past medical history and text-mining of electronic medical records. Meta-analyses with the UK Biobank and FinnGen (ntotal= 628,000) identified ~5,000 new loci, which improved the resolution of the genomic map of human traits. This atlas elucidated the landscape of pleiotropy as represented by the major histocompatibility complex locus, where we conducted HLA fine-mapping. Finally, we performed statistical decomposition of matrices of phenome-wide summary statistics, and identified latent genetic components, which pinpointed responsible variants and biological mechanisms underlying current disease classifications across populations. The decomposed components enabled genetically informed subtyping of similar diseases (for example, allergic diseases). Our study suggests a potential avenue for hypothesis-free re-investigation of human diseases through genetics.

Published
2021
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33. Antineoplastic and anti-inflammatory effects of bortezomib on systemic chronic active EBV infection

Author

Yoshimori, Mayumi, Shibayama, Haruna, Imadome, Ken-Ichi, Kawano, Fuyuko, Ohashi, Ayaka, Nishio, Miwako, Shimizu, Norio, Kurata, Morito, Fujiwara, Shigeyoshi, and Arai, Ayako

Abstract

Systemic chronic active Epstein-Barr virus (EBV; sCAEBV) infection, T- and natural killer (NK)-cell type (sCAEBV), is a fatal disorder accompanied by persisting inflammation harboring clonal proliferation of EBV-infected T or NK cells. Today's chemotherapy is insufficient to resolve disease activity and to rid infected cells of sCAEBV. The currently established treatment strategy for eradicating infected cells is allogeneic hematopoietic stem cell transplantation. In this study, we focused on the effects of proteasome inhibitor bortezomib on the disease. Bortezomib suppressed survival and induced apoptosis of EBV+T- or NK-cell lines and peripheral mononuclear cells containing EBV-infected T or NK cells of sCAEBV patients. Bortezomib enhanced binding immunoglobulin protein/78-kDa glucose-regulated protein (Bip/GRP78) expression induced by endoplasmic reticulum stress and activated apoptosis-promoting molecules JNK and p38 in the cell lines. Bortezomib suppressed the activation of survival-promoting molecule NF-κB, which was constitutively activated in EBV+T- or NK-cell lines. Furthermore, quantitative reverse transcription–polymerase chain reaction demonstrated that bortezomib suppressed messenger RNA expression of proinflammatory cytokines tumor necrosis factor α (TNF-α) and interferon γ (IFN-γ) in EBV+T or NK cells from the patients. Finally, we examined the effects of bortezomib using xenograft models of sCAEBV generated by IV injection of patients' cells. The intraperitoneal administration of bortezomib significantly reduced EBV-DNA load in peripheral blood and the infiltration of EBV-infected cells in the models' livers. Moreover, the serum concentration of TNF-α and IFN-γ decreased after bortezomib treatment to the models. Our findings will be translated into the treatment of sCAEBV not only to reduce the number of tumor cells but also to suppress inflammation.

Published
2021
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35. Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)1

Author

Klionsky, Daniel J., Abdel-Aziz, Amal Kamal, Abdelfatah, Sara, Abdellatif, Mahmoud, Abdoli, Asghar, Abel, Steffen, Abeliovich, Hagai, Abildgaard, Marie H., Abudu, Yakubu Princely, Acevedo-Arozena, Abraham, Adamopoulos, Iannis E., Adeli, Khosrow, Adolph, Timon E., Adornetto, Annagrazia, Aflaki, Elma, Agam, Galila, Agarwal, Anupam, Aggarwal, Bharat B., Agnello, Maria, Agostinis, Patrizia, Agrewala, Javed N., Agrotis, Alexander, Aguilar, Patricia V., Ahmad, S. Tariq, Ahmed, Zubair M., Ahumada-Castro, Ulises, Aits, Sonja, Aizawa, Shu, Akkoc, Yunus, Akoumianaki, Tonia, Akpinar, Hafize Aysin, Al-Abd, Ahmed M., Al-Akra, Lina, Al-Gharaibeh, Abeer, Alaoui-Jamali, Moulay A., Alberti, Simon, Alcocer-Gómez, Elísabet, Alessandri, Cristiano, Ali, Muhammad, Alim Al-Bari, M. Abdul, Aliwaini, Saeb, Alizadeh, Javad, Almacellas, Eugènia, Almasan, Alexandru, Alonso, Alicia, Alonso, Guillermo D., Altan-Bonnet, Nihal, Altieri, Dario C., Álvarez, Élida M. C., Alves, Sara, Alves da Costa, Cristine, Alzaharna, Mazen M., Amadio, Marialaura, Amantini, Consuelo, Amaral, Cristina, Ambrosio, Susanna, Amer, Amal O., Ammanathan, Veena, An, Zhenyi, Andersen, Stig U., Andrabi, Shaida A., Andrade-Silva, Magaiver, Andres, Allen M., Angelini, Sabrina, Ann, David, Anozie, Uche C., Ansari, Mohammad Y., Antas, Pedro, Antebi, Adam, Antón, Zuriñe, Anwar, Tahira, Apetoh, Lionel, Apostolova, Nadezda, Araki, Toshiyuki, Araki, Yasuhiro, Arasaki, Kohei, Araújo, Wagner L., Araya, Jun, Arden, Catherine, Arévalo, Maria-Angeles, Arguelles, Sandro, Arias, Esperanza, Arikkath, Jyothi, Arimoto, Hirokazu, Ariosa, Aileen R., Armstrong-James, Darius, Arnauné-Pelloquin, Laetitia, Aroca, Angeles, Arroyo, Daniela S., Arsov, Ivica, Artero, Rubén, Asaro, Dalia Maria Lucia, Aschner, Michael, Ashrafizadeh, Milad, Ashur-Fabian, Osnat, Atanasov, Atanas G., Au, Alicia K., Auberger, Patrick, Auner, Holger W., Aurelian, Laure, Autelli, Riccardo, Avagliano, Laura, Ávalos, Yenniffer, Aveic, Sanja, Aveleira, Célia Alexandra, Avin-Wittenberg, Tamar, Aydin, Yucel, Ayton, Scott, Ayyadevara, Srinivas, Azzopardi, Maria, Baba, Misuzu, Backer, Jonathan M., Backues, Steven K., Bae, Dong-Hun, Bae, Ok-Nam, Bae, Soo Han, Baehrecke, Eric H., Baek, Ahruem, Baek, Seung-Hoon, Baek, Sung Hee, Bagetta, Giacinto, Bagniewska-Zadworna, Agnieszka, Bai, Hua, Bai, Jie, Bai, Xiyuan, Bai, Yidong, Bairagi, Nandadulal, Baksi, Shounak, Balbi, Teresa, Baldari, Cosima T., Balduini, Walter, Ballabio, Andrea, Ballester, Maria, Balazadeh, Salma, Balzan, Rena, Bandopadhyay, Rina, Banerjee, Sreeparna, Banerjee, Sulagna, Bánréti, Ágnes, Bao, Yan, Baptista, Mauricio S., Baracca, Alessandra, Barbati, Cristiana, Bargiela, Ariadna, Barilà, Daniela, Barlow, Peter G., Barmada, Sami J., Barreiro, Esther, Barreto, George E., Bartek, Jiri, Bartel, Bonnie, Bartolome, Alberto, Barve, Gaurav R., Basagoudanavar, Suresh H., Bassham, Diane C., Bast, Robert C., Basu, Alakananda, Batoko, Henri, Batten, Isabella, Baulieu, Etienne E., Baumgarner, Bradley L., Bayry, Jagadeesh, Beale, Rupert, Beau, Isabelle, Beaumatin, Florian, Bechara, Luiz R.G., Beck, George R., Beers, Michael F., Begun, Jakob, Behrends, Christian, Behrens, Georg M.N., Bei, Roberto, Bejarano, Eloy, Bel, Shai, Behl, Christian, Belaid, Amine, Belgareh-Touzé, Naïma, Bellarosa, Cristina, Belleudi, Francesca, Belló Pérez, Melissa, Bello-Morales, Raquel, Beltran, Jackeline Soares de Oliveira, Beltran, Sebastián, Benbrook, Doris Mangiaracina, Bendorius, Mykolas, Benitez, Bruno A., Benito-Cuesta, Irene, Bensalem, Julien, Berchtold, Martin W., Berezowska, Sabina, Bergamaschi, Daniele, Bergami, Matteo, Bergmann, Andreas, Berliocchi, Laura, Berlioz-Torrent, Clarisse, Bernard, Amélie, Berthoux, Lionel, Besirli, Cagri G., Besteiro, Sebastien, Betin, Virginie M., Beyaert, Rudi, Bezbradica, Jelena S., Bhaskar, Kiran, Bhatia-Kissova, Ingrid, Bhattacharya, Resham, Bhattacharya, Sujoy, Bhattacharyya, Shalmoli, Bhuiyan, Md. Shenuarin, Bhutia, Sujit Kumar, Bi, Lanrong, Bi, Xiaolin, Biden, Trevor J., Bijian, Krikor, Billes, Viktor A., Binart, Nadine, Bincoletto, Claudia, Birgisdottir, Asa B., Bjorkoy, Geir, Blanco, Gonzalo, Blas-Garcia, Ana, Blasiak, Janusz, Blomgran, Robert, Blomgren, Klas, Blum, Janice S., Boada-Romero, Emilio, Boban, Mirta, Boesze-Battaglia, Kathleen, Boeuf, Philippe, Boland, Barry, Bomont, Pascale, Bonaldo, Paolo, Bonam, Srinivasa Reddy, Bonfili, Laura, Bonifacino, Juan S., Boone, Brian A., Bootman, Martin D., Bordi, Matteo, Borner, Christoph, Bornhauser, Beat C., Borthakur, Gautam, Bosch, Jürgen, Bose, Santanu, Botana, Luis M., Botas, Juan, Boulanger, Chantal M., Boulton, Michael E., Bourdenx, Mathieu, Bourgeois, Benjamin, Bourke, Nollaig M., Bousquet, Guilhem, Boya, Patricia, Bozhkov, Peter V., Bozi, Luiz H. M., Bozkurt, Tolga O., Brackney, Doug E., Brandts, Christian H., Braun, Ralf J., Braus, Gerhard H., Bravo-Sagua, Roberto, Bravo-San Pedro, José M., Brest, Patrick, Bringer, Marie-Agnès, Briones-Herrera, Alfredo, Broaddus, V. Courtney, Brodersen, Peter, Brodsky, Jeffrey L., Brody, Steven L., Bronson, Paola G., Bronstein, Jeff M., Brown, Carolyn N., Brown, Rhoderick E., Brum, Patricia C., Brumell, John H., Brunetti-Pierri, Nicola, Bruno, Daniele, Bryson-Richardson, Robert J., Bucci, Cecilia, Buchrieser, Carmen, Bueno, Marta, Buitrago-Molina, Laura Elisa, Buraschi, Simone, Buch, Shilpa, Buchan, J. Ross, Buckingham, Erin M., Budak, Hikmet, Budini, Mauricio, Bultynck, Geert, Burada, Florin, Burgoyne, Joseph R., Burón, M. Isabel, Bustos, Victor, Büttner, Sabrina, Butturini, Elena, Byrd, Aaron, Cabas, Isabel, Cabrera-Benitez, Sandra, Cadwell, Ken, Cai, Jingjing, Cai, Lu, Cai, Qian, Cairó, Montserrat, Calbet, Jose A., Caldwell, Guy A., Caldwell, Kim A., Call, Jarrod A., Calvani, Riccardo, Calvo, Ana C., Calvo-Rubio Barrera, Miguel, Camara, Niels OS, Camonis, Jacques H., Camougrand, Nadine, Campanella, Michelangelo, Campbell, Edward M., Campbell-Valois, François-Xavier, Campello, Silvia, Campesi, Ilaria, Campos, Juliane C., Camuzard, Olivier, Cancino, Jorge, Candido de Almeida, Danilo, Canesi, Laura, Caniggia, Isabella, Canonico, Barbara, Cantí, Carles, Cao, Bin, Caraglia, Michele, Caramés, Beatriz, Carchman, Evie H., Cardenal-Muñoz, Elena, Cardenas, Cesar, Cardenas, Luis, Cardoso, Sandra M., Carew, Jennifer S., Carle, Georges F., Carleton, Gillian, Carloni, Silvia, Carmona-Gutierrez, Didac, Carneiro, Leticia A., Carnevali, Oliana, Carosi, Julian M., Carra, Serena, Carrier, Alice, Carrier, Lucie, Carroll, Bernadette, Carter, A. Brent, Carvalho, Andreia Neves, Casanova, Magali, Casas, Caty, Casas, Josefina, Cassioli, Chiara, Castillo, Eliseo F., Castillo, Karen, Castillo-Lluva, Sonia, Castoldi, Francesca, Castori, Marco, Castro, Ariel F., Castro-Caldas, Margarida, Castro-Hernandez, Javier, Castro-Obregon, Susana, Catz, Sergio D., Cavadas, Claudia, Cavaliere, Federica, Cavallini, Gabriella, Cavinato, Maria, Cayuela, Maria L., Cebollada Rica, Paula, Cecarini, Valentina, Cecconi, Francesco, Cechowska-Pasko, Marzanna, Cenci, Simone, Ceperuelo-Mallafré, Victòria, Cerqueira, João J., Cerutti, Janete M., Cervia, Davide, Cetintas, Vildan Bozok, Cetrullo, Silvia, Chae, Han-Jung, Chagin, Andrei S., Chai, Chee-Yin, Chakrabarti, Gopal, Chakrabarti, Oishee, Chakraborty, Tapas, Chakraborty, Trinad, Chami, Mounia, Chamilos, Georgios, Chan, David W., Chan, Edmond Y. W., Chan, Edward D., Chan, H.Y. Edwin, Chan, Helen H., Chan, Hung, Chan, Matthew T.V., Chan, Yau Sang, Chandra, Partha K., Chang, Chih-Peng, Chang, Chunmei, Chang, Hao-Chun, Chang, Kai, Chao, Jie, Chapman, Tracey, Charlet-Berguerand, Nicolas, Chatterjee, Samrat, Chaube, Shail K., Chaudhary, Anu, Chauhan, Santosh, Chaum, Edward, Checler, Frédéric, Cheetham, Michael E., Chen, Chang-Shi, Chen, Guang-Chao, Chen, Jian-Fu, Chen, Liam L., Chen, Leilei, Chen, Lin, Chen, Mingliang, Chen, Mu-Kuan, Chen, Ning, Chen, Quan, Chen, Ruey-Hwa, Chen, Shi, Chen, Wei, Chen, Weiqiang, Chen, Xin-Ming, Chen, Xiong-Wen, Chen, Xu, Chen, Yan, Chen, Ye-Guang, Chen, Yingyu, Chen, Yongqiang, Chen, Yu-Jen, Chen, Yue-Qin, Chen, Zhefan Stephen, Chen, Zhi, Chen, Zhi-Hua, Chen, Zhijian J., Chen, Zhixiang, Cheng, Hanhua, Cheng, Jun, Cheng, Shi-Yuan, Cheng, Wei, Cheng, Xiaodong, Cheng, Xiu-Tang, Cheng, Yiyun, Cheng, Zhiyong, Chen, Zhong, Cheong, Heesun, Cheong, Jit Kong, Chernyak, Boris V., Cherry, Sara, Cheung, Chi Fai Randy, Cheung, Chun Hei Antonio, Cheung, King-Ho, Chevet, Eric, Chi, Richard J., Chiang, Alan Kwok Shing, Chiaradonna, Ferdinando, Chiarelli, Roberto, Chiariello, Mario, Chica, Nathalia, Chiocca, Susanna, Chiong, Mario, Chiou, Shih-Hwa, Chiramel, Abhilash I., Chiurchiù, Valerio, Cho, Dong-Hyung, Choe, Seong-Kyu, Choi, Augustine M.K., Choi, Mary E., Choudhury, Kamalika Roy, Chow, Norman S., Chu, Charleen T., Chua, Jason P., Chua, John Jia En, Chung, Hyewon, Chung, Kin Pan, Chung, Seockhoon, Chung, So-Hyang, Chung, Yuen-Li, Cianfanelli, Valentina, Ciechomska, Iwona A., Cifuentes, Mariana, Cinque, Laura, Cirak, Sebahattin, Cirone, Mara, Clague, Michael J., Clarke, Robert, Clementi, Emilio, Coccia, Eliana M., Codogno, Patrice, Cohen, Ehud, Cohen, Mickael M., Colasanti, Tania, Colasuonno, Fiorella, Colbert, Robert A., Colell, Anna, Čolić, Miodrag, Coll, Nuria S., Collins, Mark O., Colombo, María I., Colón-Ramos, Daniel A., Combaret, Lydie, Comincini, Sergio, Cominetti, Márcia R., Consiglio, Antonella, Conte, Andrea, Conti, Fabrizio, Contu, Viorica Raluca, Cookson, Mark R., Coombs, Kevin M., Coppens, Isabelle, Corasaniti, Maria Tiziana, Corkery, Dale P., Cordes, Nils, Cortese, Katia, Costa, Maria do Carmo, Costantino, Sarah, Costelli, Paola, Coto-Montes, Ana, Crack, Peter J., Crespo, Jose L., Criollo, Alfredo, Crippa, Valeria, Cristofani, Riccardo, Csizmadia, Tamas, Cuadrado, Antonio, Cui, Bing, Cui, Jun, Cui, Yixian, Cui, Yong, Culetto, Emmanuel, Cumino, Andrea C., Cybulsky, Andrey V., Czaja, Mark J., Czuczwar, Stanislaw J., D’Adamo, Stefania, D’Amelio, Marcello, D’Arcangelo, Daniela, D’Lugos, Andrew C., D’Orazi, Gabriella, da Silva, James A., Dafsari, Hormos Salimi, Dagda, Ruben K., Dagdas, Yasin, Daglia, Maria, Dai, Xiaoxia, Dai, Yun, Dai, Yuyuan, Dal Col, Jessica, Dalhaimer, Paul, Dalla Valle, Luisa, Dallenga, Tobias, Dalmasso, Guillaume, Damme, Markus, Dando, Ilaria, Dantuma, Nico P., Darling, April L., Das, Hiranmoy, Dasarathy, Srinivasan, Dasari, Santosh K., Dash, Srikanta, Daumke, Oliver, Dauphinee, Adrian N., Davies, Jeffrey S., Dávila, Valeria A., Davis, Roger J., Davis, Tanja, Dayalan Naidu, Sharadha, De Amicis, Francesca, De Bosscher, Karolien, De Felice, Francesca, De Franceschi, Lucia, De Leonibus, Chiara, de Mattos Barbosa, Mayara G., De Meyer, Guido R.Y., De Milito, Angelo, De Nunzio, Cosimo, De Palma, Clara, De Santi, Mauro, De Virgilio, Claudio, De Zio, Daniela, Debnath, Jayanta, DeBosch, Brian J., Decuypere, Jean-Paul, Deehan, Mark A., Deflorian, Gianluca, DeGregori, James, Dehay, Benjamin, Del Rio, Gabriel, Delaney, Joe R., Delbridge, Lea M. D., Delorme-Axford, Elizabeth, Delpino, M. Victoria, Demarchi, Francesca, Dembitz, Vilma, Demers, Nicholas D., Deng, Hongbin, Deng, Zhiqiang, Dengjel, Joern, Dent, Paul, Denton, Donna, DePamphilis, Melvin L., Der, Channing J., Deretic, Vojo, Descoteaux, Albert, Devis, Laura, Devkota, Sushil, Devuyst, Olivier, Dewson, Grant, Dharmasivam, Mahendiran, Dhiman, Rohan, di Bernardo, Diego, Di Cristina, Manlio, Di Domenico, Fabio, Di Fazio, Pietro, Di Fonzo, Alessio, Di Guardo, Giovanni, Di Guglielmo, Gianni M., Di Leo, Luca, Di Malta, Chiara, Di Nardo, Alessia, Di Rienzo, Martina, Di Sano, Federica, Diallinas, George, Diao, Jiajie, Diaz-Araya, Guillermo, Díaz-Laviada, Inés, Dickinson, Jared M., Diederich, Marc, Dieudé, Mélanie, Dikic, Ivan, Ding, Shiping, Ding, Wen-Xing, Dini, Luciana, Dinić, Jelena, Dinic, Miroslav, Dinkova-Kostova, Albena T., Dionne, Marc S., Distler, Jörg H.W., Diwan, Abhinav, Dixon, Ian M.C., Djavaheri-Mergny, Mojgan, Dobrinski, Ina, Dobrovinskaya, Oxana, Dobrowolski, Radek, Dobson, Renwick C.J., Đokić, Jelena, Dokmeci Emre, Serap, Donadelli, Massimo, Dong, Bo, Dong, Xiaonan, Dong, Zhiwu, 2nd Dorn, Gerald W., Dotsch, Volker, Dou, Huan, Dou, Juan, Dowaidar, Moataz, Dridi, Sami, Drucker, Liat, Du, Ailian, Du, Caigan, Du, Guangwei, Du, Hai-Ning, Du, Li-Lin, du Toit, André, Duan, Shao-Bin, Duan, Xiaoqiong, Duarte, Sónia P., Dubrovska, Anna, Dunlop, Elaine A., Dupont, Nicolas, Durán, Raúl V., Dwarakanath, Bilikere S., Dyshlovoy, Sergey A., Ebrahimi-Fakhari, Darius, Eckhart, Leopold, Edelstein, Charles L., Efferth, Thomas, Eftekharpour, Eftekhar, Eichinger, Ludwig, Eid, Nabil, Eisenberg, Tobias, Eissa, N. Tony, Eissa, Sanaa, Ejarque, Miriam, El Andaloussi, Abdeljabar, El-Hage, Nazira, El-Naggar, Shahenda, Eleuteri, Anna Maria, El-Shafey, Eman S., Elgendy, Mohamed, Eliopoulos, Aristides G., Elizalde, María M., Elks, Philip M., Elsasser, Hans-Peter, Elsherbiny, Eslam S., Emerling, Brooke M., Emre, N. C. Tolga, Eng, Christina H., Engedal, Nikolai, Engelbrecht, Anna-Mart, Engelsen, Agnete S.T., Enserink, Jorrit M., Escalante, Ricardo, Esclatine, Audrey, Escobar-Henriques, Mafalda, Eskelinen, Eeva-Liisa, Espert, Lucile, Eusebio, Makandjou-Ola, Fabrias, Gemma, Fabrizi, Cinzia, Facchiano, Antonio, Facchiano, Francesco, Fadeel, Bengt, Fader, Claudio, Faesen, Alex C., Fairlie, W. 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Razaul, Karmakar, Parimal, Katare, Rajesh G., Kato, Masaru, Kaufmann, Stefan H.E., Kauppinen, Anu, Kaushal, Gur P., Kaushik, Susmita, Kawasaki, Kiyoshi, Kazan, Kemal, Ke, Po-Yuan, Keating, Damien J., Keber, Ursula, Kehrl, John H., Keller, Kate E., Keller, Christian W., Kemper, Jongsook Kim, Kenific, Candia M., Kepp, Oliver, Kermorgant, Stephanie, Kern, Andreas, Ketteler, Robin, Keulers, Tom G., Khalfin, Boris, Khalil, Hany, Khambu, Bilon, Khan, Shahid Y., Khandelwal, Vinoth Kumar Megraj, Khandia, Rekha, Kho, Widuri, Khobrekar, Noopur V., Khuansuwan, Sataree, Khundadze, Mukhran, Killackey, Samuel A., Kim, Dasol, Kim, Deok Ryong, Kim, Do-Hyung, Kim, Dong-Eun, Kim, Eun Young, Kim, Eun-Kyoung, Kim, Hak-Rim, Kim, Hee-Sik, Kim, Hyung-Ryong, Kim, Jeong Hun, Kim, Jin Kyung, Kim, Jin-Hoi, Kim, Joungmok, Kim, Ju Hwan, Kim, Keun Il, Kim, Peter K., Kim, Seong-Jun, Kimball, Scot R., Kimchi, Adi, Kimmelman, Alec C., Kimura, Tomonori, King, Matthew A., Kinghorn, Kerri J., Kinsey, Conan G., Kirkin, Vladimir, Kirshenbaum, Lorrie A., Kiselev, Sergey L., Kishi, Shuji, Kitamoto, Katsuhiko, Kitaoka, Yasushi, Kitazato, Kaio, Kitsis, Richard N., Kittler, Josef T., Kjaerulff, Ole, Klein, Peter S., Klopstock, Thomas, Klucken, Jochen, Knævelsrud, Helene, Knorr, Roland L., Ko, Ben C.B., Ko, Fred, Ko, Jiunn-Liang, Kobayashi, Hotaka, Kobayashi, Satoru, Koch, Ina, Koch, Jan C., Koenig, Ulrich, Kögel, Donat, Koh, Young Ho, Koike, Masato, Kohlwein, Sepp D., Kocaturk, Nur M., Komatsu, Masaaki, König, Jeannette, Kono, Toru, Kopp, Benjamin T., Korcsmaros, Tamas, Korkmaz, Gözde, Korolchuk, Viktor I., Korsnes, Mónica Suárez, Koskela, Ali, Kota, Janaiah, Kotake, Yaichiro, Kotler, Monica L., Kou, Yanjun, Koukourakis, Michael I., Koustas, Evangelos, Kovacs, Attila L., Kovács, Tibor, Koya, Daisuke, Kozako, Tomohiro, Kraft, Claudine, Krainc, Dimitri, Krämer, Helmut, Krasnodembskaya, Anna D., Kretz-Remy, Carole, Kroemer, Guido, Ktistakis, Nicholas T., Kuchitsu, Kazuyuki, Kuenen, Sabine, Kuerschner, Lars, Kukar, Thomas, Kumar, Ajay, Kumar, Ashok, Kumar, Deepak, Kumar, Dhiraj, Kumar, Sharad, Kume, Shinji, Kumsta, Caroline, Kundu, Chanakya N., Kundu, Mondira, Kunnumakkara, Ajaikumar B., Kurgan, Lukasz, Kutateladze, Tatiana G., Kutlu, Ozlem, Kwak, SeongAe, Kwon, Ho Jeong, Kwon, Taeg Kyu, Kwon, Yong Tae, Kyrmizi, Irene, La Spada, Albert, Labonté, Patrick, Ladoire, Sylvain, Laface, Ilaria, Lafont, Frank, Lagace, Diane C., Lahiri, Vikramjit, Lai, Zhibing, Laird, Angela S., Lakkaraju, Aparna, Lamark, Trond, Lan, Sheng-Hui, Landajuela, Ane, Lane, Darius J. R., Lane, Jon D., Lang, Charles H., Lange, Carsten, Langel, Ülo, Langer, Rupert, Lapaquette, Pierre, Laporte, Jocelyn, LaRusso, Nicholas F., Lastres-Becker, Isabel, Lau, Wilson Chun Yu, Laurie, Gordon W., Lavandero, Sergio, Law, Betty Yuen Kwan, Law, Helen Ka-wai, Layfield, Rob, Le, Weidong, Le Stunff, Herve, Leary, Alexandre Y., Lebrun, Jean-Jacques, Leck, Lionel Y.W., Leduc-Gaudet, Jean-Philippe, Lee, Changwook, Lee, Chung-Pei, Lee, Da-Hye, Lee, Edward B., Lee, Erinna F., Lee, Gyun Min, Lee, He-Jin, Lee, Heung Kyu, Lee, Jae Man, Lee, Jason S., Lee, Jin-A, Lee, Joo-Yong, Lee, Jun Hee, Lee, Michael, Lee, Min Goo, Lee, Min Jae, Lee, Myung-Shik, Lee, Sang Yoon, Lee, Seung-Jae, Lee, Stella Y., Lee, Sung Bae, Lee, Won Hee, Lee, Ying-Ray, Lee, Yong-ho, Lee, Youngil, Lefebvre, Christophe, Legouis, Renaud, Lei, Yu L., Lei, Yuchen, Leikin, Sergey, Leitinger, Gerd, Lemus, Leticia, Leng, Shuilong, Lenoir, Olivia, Lenz, Guido, Lenz, Heinz Josef, Lenzi, Paola, León, Yolanda, Leopoldino, Andréia M., Leschczyk, Christoph, Leskelä, Stina, Letellier, Elisabeth, Leung, Chi-Ting, Leung, Po Sing, Leventhal, Jeremy S., Levine, Beth, Lewis, Patrick A., Ley, Klaus, Li, Bin, Li, Da-Qiang, Li, Jianming, Li, Jing, Li, Jiong, Li, Ke, Li, Liwu, Li, Mei, Li, Min, Li, Min, Li, Ming, Li, Mingchuan, Li, Pin-Lan, Li, Ming-Qing, Li, Qing, Li, Sheng, Li, Tiangang, Li, Wei, Li, Wenming, Li, Xue, Li, Yi-Ping, Li, Yuan, Li, Zhiqiang, Li, Zhiyong, Li, Zhiyuan, Lian, Jiqin, Liang, Chengyu, Liang, Qiangrong, Liang, Weicheng, Liang, Yongheng, Liang, YongTian, Liao, Guanghong, Liao, Lujian, Liao, Mingzhi, Liao, Yung-Feng, Librizzi, Mariangela, Lie, Pearl P. Y., Lilly, Mary A., Lim, Hyunjung J., Lima, Thania R.R., Limana, Federica, Lin, Chao, Lin, Chih-Wen, Lin, Dar-Shong, Lin, Fu-Cheng, Lin, Jiandie D., Lin, Kurt M., Lin, Kwang-Huei, Lin, Liang-Tzung, Lin, Pei-Hui, Lin, Qiong, Lin, Shaofeng, Lin, Su-Ju, Lin, Wenyu, Lin, Xueying, Lin, Yao-Xin, Lin, Yee-Shin, Linden, Rafael, Lindner, Paula, Ling, Shuo-Chien, Lingor, Paul, Linnemann, Amelia K., Liou, Yih-Cherng, Lipinski, Marta M., Lipovšek, Saška, Lira, Vitor A., Lisiak, Natalia, Liton, Paloma B., Liu, Chao, Liu, Ching-Hsuan, Liu, Chun-Feng, Liu, Cui Hua, Liu, Fang, Liu, Hao, Liu, Hsiao-Sheng, Liu, Hua-feng, Liu, Huifang, Liu, Jia, Liu, Jing, Liu, Julia, Liu, Leyuan, Liu, Longhua, Liu, Meilian, Liu, Qin, Liu, Wei, Liu, Wende, Liu, Xiao-Hong, Liu, Xiaodong, Liu, Xingguo, Liu, Xu, Liu, Xuedong, Liu, Yanfen, Liu, Yang, Liu, Yang, Liu, Yueyang, Liu, Yule, Livingston, J. Andrew, Lizard, Gerard, Lizcano, Jose M., Ljubojevic-Holzer, Senka, LLeonart, Matilde E., Llobet-Navàs, David, Llorente, Alicia, Lo, Chih Hung, Lobato-Márquez, Damián, Long, Qi, Long, Yun Chau, Loos, Ben, Loos, Julia A., López, Manuela G., López-Doménech, Guillermo, López-Guerrero, José Antonio, López-Jiménez, Ana T., López-Pérez, Óscar, López-Valero, Israel, Lorenowicz, Magdalena J., Lorente, Mar, Lorincz, Peter, Lossi, Laura, Lotersztajn, Sophie, Lovat, Penny E., Lovell, Jonathan F., Lovy, Alenka, Lőw, Péter, Lu, Guang, Lu, Haocheng, Lu, Jia-Hong, Lu, Jin-Jian, Lu, Mengji, Lu, Shuyan, Luciani, Alessandro, Lucocq, John M., Ludovico, Paula, Luftig, Micah A., Luhr, Morten, Luis-Ravelo, Diego, Lum, Julian J., Luna-Dulcey, Liany, Lund, Anders H., Lund, Viktor K., Lünemann, Jan D., Lüningschrör, Patrick, Luo, Honglin, Luo, Rongcan, Luo, Shouqing, Luo, Zhi, Luparello, Claudio, Lüscher, Bernhard, Luu, Luan, Lyakhovich, Alex, Lyamzaev, Konstantin G., Lystad, Alf Håkon, Lytvynchuk, Lyubomyr, Ma, Alvin C., Ma, Changle, Ma, Mengxiao, Ma, Ning-Fang, Ma, Quan-Hong, Ma, Xinliang, Ma, Yueyun, Ma, Zhenyi, MacDougald, Ormond A., Macian, Fernando, MacIntosh, Gustavo C., MacKeigan, Jeffrey P., Macleod, Kay F., Maday, Sandra, Madeo, Frank, Madesh, Muniswamy, Madl, Tobias, Madrigal-Matute, Julio, Maeda, Akiko, Maejima, Yasuhiro, Magarinos, Marta, Mahavadi, Poornima, Maiani, Emiliano, Maiese, Kenneth, Maiti, Panchanan, Maiuri, Maria Chiara, Majello, Barbara, Major, Michael B., Makareeva, Elena, Malik, Fayaz, Mallilankaraman, Karthik, Malorni, Walter, Maloyan, Alina, Mammadova, Najiba, Man, Gene Chi Wai, Manai, Federico, Mancias, Joseph D., Mandelkow, Eva-Maria, Mandell, Michael A., Manfredi, Angelo A., Manjili, Masoud H., Manjithaya, Ravi, Manque, Patricio, Manshian, Bella B., Manzano, Raquel, Manzoni, Claudia, Mao, Kai, Marchese, Cinzia, Marchetti, Sandrine, Marconi, Anna Maria, Marcucci, Fabrizio, Mardente, Stefania, Mareninova, Olga A., Margeta, Marta, Mari, Muriel, Marinelli, Sara, Marinelli, Oliviero, Mariño, Guillermo, Mariotto, Sofia, Marshall, Richard S., Marten, Mark R., Martens, Sascha, Martin, Alexandre P.J., Martin, Katie R., Martin, Sara, Martin, Shaun, Martín-Segura, Adrián, Martín-Acebes, Miguel A., Martin-Burriel, Inmaculada, Martin-Rincon, Marcos, Martin-Sanz, Paloma, Martina, José A., Martinet, Wim, Martinez, Aitor, Martinez, Ana, Martinez, Jennifer, Martinez Velazquez, Moises, Martinez-Lopez, Nuria, Martinez-Vicente, Marta, Martins, Daniel O., Martins, Joilson O., Martins, Waleska K., Martins-Marques, Tania, Marzetti, Emanuele, Masaldan, Shashank, Masclaux-Daubresse, Celine, Mashek, Douglas G., Massa, Valentina, Massieu, Lourdes, Masson, Glenn R., Masuelli, Laura, Masyuk, Anatoliy I., Masyuk, Tetyana V., Matarrese, Paola, Matheu, Ander, Matoba, Satoaki, Matsuzaki, Sachiko, Mattar, Pamela, Matte, Alessandro, Mattoscio, Domenico, Mauriz, José L., Mauthe, Mario, Mauvezin, Caroline, Maverakis, Emanual, Maycotte, Paola, Mayer, Johanna, Mazzoccoli, Gianluigi, Mazzoni, Cristina, Mazzulli, Joseph R., McCarty, Nami, McDonald, Christine, McGill, Mitchell R., McKenna, Sharon L., McLaughlin, BethAnn, McLoughlin, Fionn, McNiven, Mark A., McWilliams, Thomas G., Mechta-Grigoriou, Fatima, Medeiros, Tania Catarina, Medina, Diego L., Megeney, Lynn A., Megyeri, Klara, Mehrpour, Maryam, Mehta, Jawahar L., Meijer, Alfred J., Meijer, Annemarie H., Mejlvang, Jakob, Meléndez, Alicia, Melk, Annette, Memisoglu, Gonen, Mendes, Alexandrina F., Meng, Delong, Meng, Fei, Meng, Tian, Menna-Barreto, Rubem, Menon, Manoj B., Mercer, Carol, Mercier, Anne E., Mergny, Jean-Louis, Merighi, Adalberto, Merkley, Seth D., Merla, Giuseppe, Meske, Volker, Mestre, Ana Cecilia, Metur, Shree Padma, Meyer, Christian, Meyer, Hemmo, Mi, Wenyi, Mialet-Perez, Jeanne, Miao, Junying, Micale, Lucia, Miki, Yasuo, Milan, Enrico, Milczarek, Małgorzata, Miller, Dana L., Miller, Samuel I., Miller, Silke, Millward, Steven W., Milosevic, Ira, Minina, Elena A., Mirzaei, Hamed, Mirzaei, Hamid Reza, Mirzaei, Mehdi, Mishra, Amit, Mishra, Nandita, Mishra, Paras Kumar, Misirkic Marjanovic, Maja, Misasi, Roberta, Misra, Amit, Misso, Gabriella, Mitchell, Claire, Mitou, Geraldine, Miura, Tetsuji, Miyamoto, Shigeki, Miyazaki, Makoto, Miyazaki, Mitsunori, Miyazaki, Taiga, Miyazawa, Keisuke, Mizushima, Noboru, Mogensen, Trine H., Mograbi, Baharia, Mohammadinejad, Reza, Mohamud, Yasir, Mohanty, Abhishek, Mohapatra, Sipra, Möhlmann, Torsten, Mohmmed, Asif, Moles, Anna, Moley, Kelle H., Molinari, Maurizio, Mollace, Vincenzo, Møller, Andreas Buch, Mollereau, Bertrand, Mollinedo, Faustino, Montagna, Costanza, Monteiro, Mervyn J., Montella, Andrea, Montes, L. Ruth, Montico, Barbara, Mony, Vinod K., Monzio Compagnoni, Giacomo, Moore, Michael N., Moosavi, Mohammad A., Mora, Ana L., Mora, Marina, Morales-Alamo, David, Moratalla, Rosario, Moreira, Paula I., Morelli, Elena, Moreno, Sandra, Moreno-Blas, Daniel, Moresi, Viviana, Morga, Benjamin, Morgan, Alwena H., Morin, Fabrice, Morishita, Hideaki, Moritz, Orson L., Moriyama, Mariko, Moriyasu, Yuji, Morleo, Manuela, Morselli, Eugenia, Moruno-Manchon, Jose F., Moscat, Jorge, Mostowy, Serge, Motori, Elisa, Moura, Andrea Felinto, Moustaid-Moussa, Naima, Mrakovcic, Maria, Muciño-Hernández, Gabriel, Mukherjee, Anupam, Mukhopadhyay, Subhadip, Mulcahy Levy, Jean M., Mulero, Victoriano, Muller, Sylviane, Münch, Christian, Munjal, Ashok, Munoz-Canoves, Pura, Muñoz-Galdeano, Teresa, Münz, Christian, Murakawa, Tomokazu, Muratori, Claudia, Murphy, Brona M., Murphy, J. Patrick, Murthy, Aditya, Myöhänen, Timo T., Mysorekar, Indira U., Mytych, Jennifer, Nabavi, Seyed Mohammad, Nabissi, Massimo, Nagy, Péter, Nah, Jihoon, Nahimana, Aimable, Nakagawa, Ichiro, Nakamura, Ken, Nakatogawa, Hitoshi, Nandi, Shyam S., Nanjundan, Meera, Nanni, Monica, Napolitano, Gennaro, Nardacci, Roberta, Narita, Masashi, Nassif, Melissa, Nathan, Ilana, Natsumeda, Manabu, Naude, Ryno J., Naumann, Christin, Naveiras, Olaia, Navid, Fatemeh, Nawrocki, Steffan T., Nazarko, Taras Y., Nazio, Francesca, Negoita, Florentina, Neill, Thomas, Neisch, Amanda L., Neri, Luca M., Netea, Mihai G., Neubert, Patrick, Neufeld, Thomas P., Neumann, Dietbert, Neutzner, Albert, Newton, Phillip T., Ney, Paul A., Nezis, Ioannis P., Ng, Charlene C.W., Ng, Tzi Bun, Nguyen, Hang T. T., Nguyen, Long T., Ni, Hong-Min, Ní Cheallaigh, Clíona, Ni, Zhenhong, Nicolao, M. Celeste, Nicoli, Francesco, Nieto-Diaz, Manuel, Nilsson, Per, Ning, Shunbin, Niranjan, Rituraj, Nishimune, Hiroshi, Niso-Santano, Mireia, Nixon, Ralph A., Nobili, Annalisa, Nobrega, Clevio, Noda, Takeshi, Nogueira-Recalde, Uxía, Nolan, Trevor M., Nombela, Ivan, Novak, Ivana, Novoa, Beatriz, Nozawa, Takashi, Nukina, Nobuyuki, Nussbaum-Krammer, Carmen, Nylandsted, Jesper, O’Donovan, Tracey R., O’Leary, Seónadh M., O’Rourke, Eyleen J., O’Sullivan, Mary P., O’Sullivan, Timothy E., Oddo, Salvatore, Oehme, Ina, Ogawa, Michinaga, Ogier-Denis, Eric, Ogmundsdottir, Margret H., Ogretmen, Besim, Oh, Goo Taeg, Oh, Seon-Hee, Oh, Young J., Ohama, Takashi, Ohashi, Yohei, Ohmuraya, Masaki, Oikonomou, Vasileios, Ojha, Rani, Okamoto, Koji, Okazawa, Hitoshi, Oku, Masahide, Oliván, Sara, Oliveira, Jorge M. A., Ollmann, Michael, Olzmann, James A., Omari, Shakib, Omary, M. Bishr, Önal, Gizem, Ondrej, Martin, Ong, Sang-Bing, Ong, Sang-Ging, Onnis, Anna, Orellana, Juan A., Orellana-Muñoz, Sara, Ortega-Villaizan, Maria Del Mar, Ortiz-Gonzalez, Xilma R., Ortona, Elena, Osiewacz, Heinz D., Osman, Abdel-Hamid K., Osta, Rosario, Otegui, Marisa S., Otsu, Kinya, Ott, Christiane, Ottobrini, Luisa, Ou, Jing-hsiung James, Outeiro, Tiago F., Oynebraten, Inger, Ozturk, Melek, Pagès, Gilles, Pahari, Susanta, Pajares, Marta, Pajvani, Utpal B., Pal, Rituraj, Paladino, Simona, Pallet, Nicolas, Palmieri, Michela, Palmisano, Giuseppe, Palumbo, Camilla, Pampaloni, Francesco, Pan, Lifeng, Pan, Qingjun, Pan, Wenliang, Pan, Xin, Panasyuk, Ganna, Pandey, Rahul, Pandey, Udai B., Pandya, Vrajesh, Paneni, Francesco, Pang, Shirley Y., Panzarini, Elisa, Papademetrio, Daniela L., Papaleo, Elena, Papinski, Daniel, Papp, Diana, Park, Eun Chan, Park, Hwan Tae, Park, Ji-Man, Park, Jong-In, Park, Joon Tae, Park, Junsoo, Park, Sang Chul, Park, Sang-Youel, Parola, Abraham H., Parys, Jan B., Pasquier, Adrien, Pasquier, Benoit, Passos, João F., Pastore, Nunzia, Patel, Hemal H., Patschan, Daniel, Pattingre, Sophie, Pedraza-Alva, Gustavo, Pedraza-Chaverri, Jose, Pedrozo, Zully, Pei, Gang, Pei, Jianming, Peled-Zehavi, Hadas, Pellegrini, Joaquín M., Pelletier, Joffrey, Peñalva, Miguel A., Peng, Di, Peng, Ying, Penna, Fabio, Pennuto, Maria, Pentimalli, Francesca, Pereira, Cláudia MF, Pereira, Gustavo J.S., Pereira, Lilian C., Pereira de Almeida, Luis, Perera, Nirma D., Pérez-Lara, Ángel, Perez-Oliva, Ana B., Pérez-Pérez, María Esther, Periyasamy, Palsamy, Perl, Andras, Perrotta, Cristiana, Perrotta, Ida, Pestell, Richard G., Petersen, Morten, Petrache, Irina, Petrovski, Goran, Pfirrmann, Thorsten, Pfister, Astrid S., Philips, Jennifer A., Pi, Huifeng, Picca, Anna, Pickrell, Alicia M., Picot, Sandy, Pierantoni, Giovanna M., Pierdominici, Marina, Pierre, Philippe, Pierrefite-Carle, Valérie, Pierzynowska, Karolina, Pietrocola, Federico, Pietruczuk, Miroslawa, Pignata, Claudio, Pimentel-Muiños, Felipe X., Pinar, Mario, Pinheiro, Roberta O., Pinkas-Kramarski, Ronit, Pinton, Paolo, Pircs, Karolina, Piya, Sujan, Pizzo, Paola, Plantinga, Theo S., Platta, Harald W., Plaza-Zabala, Ainhoa, Plomann, Markus, Plotnikov, Egor Y., Plun-Favreau, Helene, Pluta, Ryszard, Pocock, Roger, Pöggeler, Stefanie, Pohl, Christian, Poirot, Marc, Poletti, Angelo, Ponpuak, Marisa, Popelka, Hana, Popova, Blagovesta, Porta, Helena, Porte Alcon, Soledad, Portilla-Fernandez, Eliana, Post, Martin, Potts, Malia B., Poulton, Joanna, Powers, Ted, Prahlad, Veena, Prajsnar, Tomasz K., Praticò, Domenico, Prencipe, Rosaria, Priault, Muriel, Proikas-Cezanne, Tassula, Promponas, Vasilis J., Proud, Christopher G., Puertollano, Rosa, Puglielli, Luigi, Pulinilkunnil, Thomas, Puri, Deepika, Puri, Rajat, Puyal, Julien, Qi, Xiaopeng, Qi, Yongmei, Qian, Wenbin, Qiang, Lei, Qiu, Yu, Quadrilatero, Joe, Quarleri, Jorge, Raben, Nina, Rabinowich, Hannah, Ragona, Debora, Ragusa, Michael J., Rahimi, Nader, Rahmati, Marveh, Raia, Valeria, Raimundo, Nuno, Rajasekaran, Namakkal-Soorappan, Ramachandra Rao, Sriganesh, Rami, Abdelhaq, Ramírez-Pardo, Ignacio, Ramsden, David B., Randow, Felix, Rangarajan, Pundi N., Ranieri, Danilo, Rao, Hai, Rao, Lang, Rao, Rekha, Rathore, Sumit, Ratnayaka, J. Arjuna, Ratovitski, Edward A., Ravanan, Palaniyandi, Ravegnini, Gloria, Ray, Swapan K., Razani, Babak, Rebecca, Vito, Reggiori, Fulvio, Régnier-Vigouroux, Anne, Reichert, Andreas S., Reigada, David, Reiling, Jan H., Rein, Theo, Reipert, Siegfried, Rekha, Rokeya Sultana, Ren, Hongmei, Ren, Jun, Ren, Weichao, Renault, Tristan, Renga, Giorgia, Reue, Karen, Rewitz, Kim, Ribeiro de Andrade Ramos, Bruna, Riazuddin, S. Amer, Ribeiro-Rodrigues, Teresa M., Ricci, Jean-Ehrland, Ricci, Romeo, Riccio, Victoria, Richardson, Des R., Rikihisa, Yasuko, Risbud, Makarand V., Risueño, Ruth M., Ritis, Konstantinos, Rizza, Salvatore, Rizzuto, Rosario, Roberts, Helen C., Roberts, Luke D., Robinson, Katherine J., Roccheri, Maria Carmela, Rocchi, Stephane, Rodney, George G., Rodrigues, Tiago, Rodrigues Silva, Vagner Ramon, Rodriguez, Amaia, Rodriguez-Barrueco, Ruth, Rodriguez-Henche, Nieves, Rodriguez-Rocha, Humberto, Roelofs, Jeroen, Rogers, Robert S., Rogov, Vladimir V., Rojo, Ana I., Rolka, Krzysztof, Romanello, Vanina, Romani, Luigina, Romano, Alessandra, Romano, Patricia S., Romeo-Guitart, David, Romero, Luis C., Romero, Montserrat, Roney, Joseph C., Rongo, Christopher, Roperto, Sante, Rosenfeldt, Mathias T., Rosenstiel, Philip, Rosenwald, Anne G., Roth, Kevin A., Roth, Lynn, Roth, Steven, Rouschop, Kasper M.A., Roussel, Benoit D., Roux, Sophie, Rovere-Querini, Patrizia, Roy, Ajit, Rozieres, Aurore, Ruano, Diego, Rubinsztein, David C., Rubtsova, Maria P., Ruckdeschel, Klaus, Ruckenstuhl, Christoph, Rudolf, Emil, Rudolf, Rüdiger, Ruggieri, Alessandra, Ruparelia, Avnika Ashok, Rusmini, Paola, Russell, Ryan R., Russo, Gian Luigi, Russo, Maria, Russo, Rossella, Ryabaya, Oxana O., Ryan, Kevin M., Ryu, Kwon-Yul, Sabater-Arcis, Maria, Sachdev, Ulka, Sacher, Michael, Sachse, Carsten, Sadhu, Abhishek, Sadoshima, Junichi, Safren, Nathaniel, Saftig, Paul, Sagona, Antonia P., Sahay, Gaurav, Sahebkar, Amirhossein, Sahin, Mustafa, Sahin, Ozgur, Sahni, Sumit, Saito, Nayuta, Saito, Shigeru, Saito, Tsunenori, Sakai, Ryohei, Sakai, Yasuyoshi, Sakamaki, Jun-Ichi, Saksela, Kalle, Salazar, Gloria, Salazar-Degracia, Anna, Salekdeh, Ghasem H., Saluja, Ashok K., Sampaio-Marques, Belém, Sanchez, Maria Cecilia, Sanchez-Alcazar, Jose A., Sanchez-Vera, Victoria, Sancho-Shimizu, Vanessa, Sanderson, J. Thomas, Sandri, Marco, Santaguida, Stefano, Santambrogio, Laura, Santana, Magda M., Santoni, Giorgio, Sanz, Alberto, Sanz, Pascual, Saran, Shweta, Sardiello, Marco, Sargeant, Timothy J., Sarin, Apurva, Sarkar, Chinmoy, Sarkar, Sovan, Sarrias, Maria-Rosa, Sarkar, Surajit, Sarmah, Dipanka Tanu, Sarparanta, Jaakko, Sathyanarayan, Aishwarya, Sathyanarayanan, Ranganayaki, Scaglione, K. Matthew, Scatozza, Francesca, Schaefer, Liliana, Schafer, Zachary T., Schaible, Ulrich E., Schapira, Anthony H.V., Scharl, Michael, Schatzl, Hermann M., Schein, Catherine H., Scheper, Wiep, Scheuring, David, Schiaffino, Maria Vittoria, Schiappacassi, Monica, Schindl, Rainer, Schlattner, Uwe, Schmidt, Oliver, Schmitt, Roland, Schmidt, Stephen D., Schmitz, Ingo, Schmukler, Eran, Schneider, Anja, Schneider, Bianca E., Schober, Romana, Schoijet, Alejandra C., Schott, Micah B., Schramm, Michael, Schröder, Bernd, Schuh, Kai, Schüller, Christoph, Schulze, Ryan J., Schürmanns, Lea, Schwamborn, Jens C., Schwarten, Melanie, Scialo, Filippo, Sciarretta, Sebastiano, Scott, Melanie J., Scotto, Kathleen W., Scovassi, A. Ivana, Scrima, Andrea, Scrivo, Aurora, Sebastian, David, Sebti, Salwa, Sedej, Simon, Segatori, Laura, Segev, Nava, Seglen, Per O., Seiliez, Iban, Seki, Ekihiro, Selleck, Scott B., Sellke, Frank W., Selsby, Joshua T., Sendtner, Michael, Senturk, Serif, Seranova, Elena, Sergi, Consolato, Serra-Moreno, Ruth, Sesaki, Hiromi, Settembre, Carmine, Setty, Subba Rao Gangi, Sgarbi, Gianluca, Sha, Ou, Shacka, John J., Shah, Javeed A., Shang, Dantong, Shao, Changshun, Shao, Feng, Sharbati, Soroush, Sharkey, Lisa M., Sharma, Dipali, Sharma, Gaurav, Sharma, Kulbhushan, Sharma, Pawan, Sharma, Surendra, Shen, Han-Ming, Shen, Hongtao, Shen, Jiangang, Shen, Ming, Shen, Weili, Shen, Zheni, Sheng, Rui, Sheng, Zhi, Sheng, Zu-Hang, Shi, Jianjian, Shi, Xiaobing, Shi, Ying-Hong, Shiba-Fukushima, Kahori, Shieh, Jeng-Jer, Shimada, Yohta, Shimizu, Shigeomi, Shimozawa, Makoto, Shintani, Takahiro, Shoemaker, Christopher J., Shojaei, Shahla, Shoji, Ikuo, Shravage, Bhupendra V., Shridhar, Viji, Shu, Chih-Wen, Shu, Hong-Bing, Shui, Ke, Shukla, Arvind K., Shutt, Timothy E., Sica, Valentina, Siddiqui, Aleem, Sierra, Amanda, Sierra-Torre, Virginia, Signorelli, Santiago, Sil, Payel, Silva, Bruno J. de Andrade, Silva, Johnatas D., Silva-Pavez, Eduardo, Silvente-Poirot, Sandrine, Simmonds, Rachel E., Simon, Anna Katharina, Simon, Hans-Uwe, Simons, Matias, Singh, Anurag, Singh, Lalit P., Singh, Rajat, Singh, Shivendra V., Singh, Shrawan K., Singh, Sudha B., Singh, Sunaina, Singh, Surinder Pal, Sinha, Debasish, Sinha, Rohit Anthony, Sinha, Sangita, Sirko, Agnieszka, Sirohi, Kapil, Sivridis, Efthimios L., Skendros, Panagiotis, Skirycz, Aleksandra, Slaninová, Iva, Smaili, Soraya S., Smertenko, Andrei, Smith, Matthew D., Soenen, Stefaan J., Sohn, Eun Jung, Sok, Sophia P. M., Solaini, Giancarlo, Soldati, Thierry, Soleimanpour, Scott A., Soler, Rosa M., Solovchenko, Alexei, Somarelli, Jason A., Sonawane, Avinash, Song, Fuyong, Song, Hyun Kyu, Song, Ju-Xian, Song, Kunhua, Song, Zhiyin, Soria, Leandro R., Sorice, Maurizio, Soukas, Alexander A., Soukup, Sandra-Fausia, Sousa, Diana, Sousa, Nadia, Spagnuolo, Paul A., Spector, Stephen A., Srinivas Bharath, M. M., St. Clair, Daret, Stagni, Venturina, Staiano, Leopoldo, Stalnecker, Clint A., Stankov, Metodi V., Stathopulos, Peter B., Stefan, Katja, Stefan, Sven Marcel, Stefanis, Leonidas, Steffan, Joan S., Steinkasserer, Alexander, Stenmark, Harald, Sterneckert, Jared, Stevens, Craig, Stoka, Veronika, Storch, Stephan, Stork, Björn, Strappazzon, Flavie, Strohecker, Anne Marie, Stupack, Dwayne G., Su, Huanxing, Su, Ling-Yan, Su, Longxiang, Suarez-Fontes, Ana M., Subauste, Carlos S., Subbian, Selvakumar, Subirada, Paula V., Sudhandiran, Ganapasam, Sue, Carolyn M., Sui, Xinbing, Summers, Corey, Sun, Guangchao, Sun, Jun, Sun, Kang, Sun, Meng-xiang, Sun, Qiming, Sun, Yi, Sun, Zhongjie, Sunahara, Karen K.S., Sundberg, Eva, Susztak, Katalin, Sutovsky, Peter, Suzuki, Hidekazu, Sweeney, Gary, Symons, J. David, Sze, Stephen Cho Wing, Szewczyk, Nathaniel J., Tabęcka-Łonczynska, Anna, Tabolacci, Claudio, Tacke, Frank, Taegtmeyer, Heinrich, Tafani, Marco, Tagaya, Mitsuo, Tai, Haoran, Tait, Stephen W. G., Takahashi, Yoshinori, Takats, Szabolcs, Talwar, Priti, Tam, Chit, Tam, Shing Yau, Tampellini, Davide, Tamura, Atsushi, Tan, Chong Teik, Tan, Eng-King, Tan, Ya-Qin, Tanaka, Masaki, Tanaka, Motomasa, Tang, Daolin, Tang, Jingfeng, Tang, Tie-Shan, Tanida, Isei, Tao, Zhipeng, Taouis, Mohammed, Tatenhorst, Lars, Tavernarakis, Nektarios, Taylor, Allen, Taylor, Gregory A., Taylor, Joan M., Tchetina, Elena, Tee, Andrew R., Tegeder, Irmgard, Teis, David, Teixeira, Natercia, Teixeira-Clerc, Fatima, Tekirdag, Kumsal A., Tencomnao, Tewin, Tenreiro, Sandra, Tepikin, Alexei V., Testillano, Pilar S., Tettamanti, Gianluca, Tharaux, Pierre-Louis, Thedieck, Kathrin, Thekkinghat, Arvind A., Thellung, Stefano, Thinwa, Josephine W., Thirumalaikumar, V.P., Thomas, Sufi Mary, Thomes, Paul G., Thorburn, Andrew, Thukral, Lipi, Thum, Thomas, Thumm, Michael, Tian, Ling, Tichy, Ales, Till, Andreas, Timmerman, Vincent, Titorenko, Vladimir I., Todi, Sokol V., Todorova, Krassimira, Toivonen, Janne M., Tomaipitinca, Luana, Tomar, Dhanendra, Tomas-Zapico, Cristina, Tomić, Sergej, Tong, Benjamin Chun-Kit, Tong, Chao, Tong, Xin, Tooze, Sharon A., Torgersen, Maria L., Torii, Satoru, Torres-López, Liliana, Torriglia, Alicia, Towers, Christina G., Towns, Roberto, Toyokuni, Shinya, Trajkovic, Vladimir, Tramontano, Donatella, Tran, Quynh-Giao, Travassos, Leonardo H., Trelford, Charles B., Tremel, Shirley, Trougakos, Ioannis P., Tsao, Betty P., Tschan, Mario P., Tse, Hung-Fat, Tse, Tak Fu, Tsugawa, Hitoshi, Tsvetkov, Andrey S., Tumbarello, David A., Tumtas, Yasin, Tuñón, María J., Turcotte, Sandra, Turk, Boris, Turk, Vito, Turner, Bradley J., Tuxworth, Richard I., Tyler, Jessica K., Tyutereva, Elena V., Uchiyama, Yasuo, Ugun-Klusek, Aslihan, Uhlig, Holm H., Ułamek-Kozioł, Marzena, Ulasov, Ilya V., Umekawa, Midori, Ungermann, Christian, Unno, Rei, Urbe, Sylvie, Uribe-Carretero, Elisabet, Üstün, Suayib, Uversky, Vladimir N, Vaccari, Thomas, Vaccaro, Maria I., Vahsen, Björn F., Vakifahmetoglu-Norberg, Helin, Valdor, Rut, Valente, Maria J., Valko, Ayelén, Vallee, Richard B., Valverde, Angela M., Van den Berghe, Greet, van der Veen, Stijn, Van Kaer, Luc, van Loosdregt, Jorg, van Wijk, Sjoerd J.L., Vandenberghe, Wim, Vanhorebeek, Ilse, Vannier-Santos, Marcos A., Vannini, Nicola, Vanrell, M. Cristina, Vantaggiato, Chiara, Varano, Gabriele, Varela-Nieto, Isabel, Varga, Máté, Vasconcelos, M. Helena, Vats, Somya, Vavvas, Demetrios G., Vega-Naredo, Ignacio, Vega-Rubin-de-Celis, Silvia, Velasco, Guillermo, Velázquez, Ariadna P., Vellai, Tibor, Vellenga, Edo, Velotti, Francesca, Verdier, Mireille, Verginis, Panayotis, Vergne, Isabelle, Verkade, Paul, Verma, Manish, Verstreken, Patrik, Vervliet, Tim, Vervoorts, Jörg, Vessoni, Alexandre T., Victor, Victor M., Vidal, Michel, Vidoni, Chiara, Vieira, Otilia V., Vierstra, Richard D., Viganó, Sonia, Vihinen, Helena, Vijayan, Vinoy, Vila, Miquel, Vilar, Marçal, Villalba, José M., Villalobo, Antonio, Villarejo-Zori, Beatriz, Villarroya, Francesc, Villarroya, Joan, Vincent, Olivier, Vindis, Cecile, Viret, Christophe, Viscomi, Maria Teresa, Visnjic, Dora, Vitale, Ilio, Vocadlo, David J., Voitsekhovskaja, Olga V., Volonté, Cinzia, Volta, Mattia, Vomero, Marta, Von Haefen, Clarissa, Vooijs, Marc A., Voos, Wolfgang, Vucicevic, Ljubica, Wade-Martins, Richard, Waguri, Satoshi, Waite, Kenrick A., Wakatsuki, Shuji, Walker, David W., Walker, Mark J., Walker, Simon A., Walter, Jochen, Wandosell, Francisco G., Wang, Bo, Wang, Chao-Yung, Wang, Chen, Wang, Chenran, Wang, Chenwei, Wang, Cun-Yu, Wang, Dong, Wang, Fangyang, Wang, Feng, Wang, Fengming, Wang, Guansong, Wang, Han, Wang, Hao, Wang, Hexiang, Wang, Hong-Gang, Wang, Jianrong, Wang, Jigang, Wang, Jiou, Wang, Jundong, Wang, Kui, Wang, Lianrong, Wang, Liming, Wang, Maggie Haitian, Wang, Meiqing, Wang, Nanbu, Wang, Pengwei, Wang, Peipei, Wang, Ping, Wang, Ping, Wang, Qing Jun, Wang, Qing, Wang, Qing Kenneth, Wang, Qiong A., Wang, Wen-Tao, Wang, Wuyang, Wang, Xinnan, Wang, Xuejun, Wang, Yan, Wang, Yanchang, Wang, Yanzhuang, Wang, Yen-Yun, Wang, Yihua, Wang, Yipeng, Wang, Yu, Wang, Yuqi, Wang, Zhe, Wang, Zhenyu, Wang, Zhouguang, Warnes, Gary, Warnsmann, Verena, Watada, Hirotaka, Watanabe, Eizo, Watchon, Maxinne, Wawrzyńska, Anna, Weaver, Timothy E., Wegrzyn, Grzegorz, Wehman, Ann M., Wei, Huafeng, Wei, Lei, Wei, Taotao, Wei, Yongjie, Weiergräber, Oliver H., Weihl, Conrad C., Weindl, Günther, Weiskirchen, Ralf, Wells, Alan, Wen, Runxia H., Wen, Xin, Werner, Antonia, Weykopf, Beatrice, Wheatley, Sally P., Whitton, J. Lindsay, Whitworth, Alexander J., Wiktorska, Katarzyna, Wildenberg, Manon E., Wileman, Tom, Wilkinson, Simon, Willbold, Dieter, Williams, Brett, Williams, Robin S.B., Williams, Roger L., Williamson, Peter R., Wilson, Richard A., Winner, Beate, Winsor, Nathaniel J., Witkin, Steven S., Wodrich, Harald, Woehlbier, Ute, Wollert, Thomas, Wong, Esther, Wong, Jack Ho, Wong, Richard W., Wong, Vincent Kam Wai, Wong, W. Wei-Lynn, Wu, An-Guo, Wu, Chengbiao, Wu, Jian, Wu, Junfang, Wu, Kenneth K., Wu, Min, Wu, Shan-Ying, Wu, Shengzhou, Wu, Shu-Yan, Wu, Shufang, Wu, William K.K., Wu, Xiaohong, Wu, Xiaoqing, Wu, Yao-Wen, Wu, Yihua, Xavier, Ramnik J., Xia, Hongguang, Xia, Lixin, Xia, Zhengyuan, Xiang, Ge, Xiang, Jin, Xiang, Mingliang, Xiang, Wei, Xiao, Bin, Xiao, Guozhi, Xiao, Hengyi, Xiao, Hong-tao, Xiao, Jian, Xiao, Lan, Xiao, Shi, Xiao, Yin, Xie, Baoming, Xie, Chuan-Ming, Xie, Min, Xie, Yuxiang, Xie, Zhiping, Xie, Zhonglin, Xilouri, Maria, Xu, Congfeng, Xu, En, Xu, Haoxing, Xu, Jing, Xu, JinRong, Xu, Liang, Xu, Wen Wen, Xu, Xiulong, Xue, Yu, Yakhine-Diop, Sokhna M.S., Yamaguchi, Masamitsu, Yamaguchi, Osamu, Yamamoto, Ai, Yamashina, Shunhei, Yan, Shengmin, Yan, Shian-Jang, Yan, Zhen, Yanagi, Yasuo, Yang, Chuanbin, Yang, Dun-Sheng, Yang, Huan, Yang, Huang-Tian, Yang, Hui, Yang, Jin-Ming, Yang, Jing, Yang, Jingyu, Yang, Ling, Yang, Liu, Yang, Ming, Yang, Pei-Ming, Yang, Qian, Yang, Seungwon, Yang, Shu, Yang, Shun-Fa, Yang, Wannian, Yang, Wei Yuan, Yang, Xiaoyong, Yang, Xuesong, Yang, Yi, Yang, Ying, Yao, Honghong, Yao, Shenggen, Yao, Xiaoqiang, Yao, Yong-Gang, Yao, Yong-Ming, Yasui, Takahiro, Yazdankhah, Meysam, Yen, Paul M., Yi, Cong, Yin, Xiao-Ming, Yin, Yanhai, Yin, Zhangyuan, Yin, Ziyi, Ying, Meidan, Ying, Zheng, Yip, Calvin K., Yiu, Stephanie Pei Tung, Yoo, Young H., Yoshida, Kiyotsugu, Yoshii, Saori R., Yoshimori, Tamotsu, Yousefi, Bahman, Yu, Boxuan, Yu, Haiyang, Yu, Jun, Yu, Jun, Yu, Li, Yu, Ming-Lung, Yu, Seong-Woon, Yu, Victor C., Yu, W. Haung, Yu, Zhengping, Yu, Zhou, Yuan, Junying, Yuan, Ling-Qing, Yuan, Shilin, Yuan, Shyng-Shiou F., Yuan, Yanggang, Yuan, Zengqiang, Yue, Jianbo, Yue, Zhenyu, Yun, Jeanho, Yung, Raymond L., Zacks, David N., Zaffagnini, Gabriele, Zambelli, Vanessa O., Zanella, Isabella, Zang, Qun S., Zanivan, Sara, Zappavigna, Silvia, Zaragoza, Pilar, Zarbalis, Konstantinos S., Zarebkohan, Amir, Zarrouk, Amira, Zeitlin, Scott O., Zeng, Jialiu, Zeng, Ju-deng, Žerovnik, Eva, Zhan, Lixuan, Zhang, Bin, Zhang, Donna D., Zhang, Hanlin, Zhang, Hong, Zhang, Hong, Zhang, Honghe, Zhang, Huafeng, Zhang, Huaye, Zhang, Hui, Zhang, Hui-Ling, Zhang, Jianbin, Zhang, Jianhua, Zhang, Jing-Pu, Zhang, Kalin Y.B., Zhang, Leshuai W., Zhang, Lin, Zhang, Lisheng, Zhang, Lu, Zhang, Luoying, Zhang, Menghuan, Zhang, Peng, Zhang, Sheng, Zhang, Wei, Zhang, Xiangnan, Zhang, Xiao-Wei, Zhang, Xiaolei, Zhang, Xiaoyan, Zhang, Xin, Zhang, Xinxin, Zhang, Xu Dong, Zhang, Yang, Zhang, Yanjin, Zhang, Yi, Zhang, Ying-Dong, Zhang, Yingmei, Zhang, Yuan-Yuan, Zhang, Yuchen, Zhang, Zhe, Zhang, Zhengguang, Zhang, Zhibing, Zhang, Zhihai, Zhang, Zhiyong, Zhang, Zili, Zhao, Haobin, Zhao, Lei, Zhao, Shuang, Zhao, Tongbiao, Zhao, Xiao-Fan, Zhao, Ying, Zhao, Yongchao, Zhao, Yongliang, Zhao, Yuting, Zheng, Guoping, Zheng, Kai, Zheng, Ling, Zheng, Shizhong, Zheng, Xi-Long, Zheng, Yi, Zheng, Zu-Guo, Zhivotovsky, Boris, Zhong, Qing, Zhou, Ao, Zhou, Ben, Zhou, Cefan, Zhou, Gang, Zhou, Hao, Zhou, Hong, Zhou, Hongbo, Zhou, Jie, Zhou, Jing, Zhou, Jing, Zhou, Jiyong, Zhou, Kailiang, Zhou, Rongjia, Zhou, Xu-Jie, Zhou, Yanshuang, Zhou, Yinghong, Zhou, Yubin, Zhou, Zheng-Yu, Zhou, Zhou, Zhu, Binglin, Zhu, Changlian, Zhu, Guo-Qing, Zhu, Haining, Zhu, Hongxin, Zhu, Hua, Zhu, Wei-Guo, Zhu, Yanping, Zhu, Yushan, Zhuang, Haixia, Zhuang, Xiaohong, Zientara-Rytter, Katarzyna, Zimmermann, Christine M., Ziviani, Elena, Zoladek, Teresa, Zong, Wei-Xing, Zorov, Dmitry B., Zorzano, Antonio, Zou, Weiping, Zou, Zhen, Zou, Zhengzhi, Zuryn, Steven, Zwerschke, Werner, Brand-Saberi, Beate, Dong, X. Charlie, Kenchappa, Chandra Shekar, Li, Zuguo, Lin, Yong, Oshima, Shigeru, Rong, Yueguang, Sluimer, Judith C., Stallings, Christina L., and Tong, Chun-Kit

Abstract

ABSTRACTIn 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fideautophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.

Published
2021
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36. Evidence for lysosomal biogenesis proteome defect and impaired autophagy in preeclampsia

Author

Nakashima, Akitoshi, Cheng, Shi-Bin, Ikawa, Masahito, Yoshimori, Tamotsu, Huber, Warren J., Menon, Ramkumar, Huang, Zheping, Fierce, Jamie, Padbury, James F., Sadovsky, Yoel, Saito, Shigeru, and Sharma, Surendra

Abstract

ABSTRACTThe etiology of preeclampsia (PE), a serious pregnancy complication, remains an enigma. We have demonstrated that proteinopathy, a pathologic feature of neurodegenerative diseases, is a key observation in the placenta and serum from PE patients. We hypothesize that the macroautophagy/autophagy machinery that mediates degradation of aggregated proteins and damaged organelles is impaired in PE. Here, we show that TFEB (transcription factor EB), a master transcriptional regulator of lysosomal biogenesis, and its regulated proteins, LAMP1, LAMP2, and CTSD (cathepsin D), were dysregulated in the placenta from early and late onset PE deliveries. Primary human trophoblasts and immortalized extravillous trophoblasts (EVTs) showed reduced TFEB expression and nuclear translocation as well as lysosomal protein content in response to hypoxia. Hypoxia-exposed trophoblasts also showed decreased PPP3/calcineurin phosphatase activity and increased XPO1/CRM1 (exportin 1), events that inhibit TFEB nuclear translocation. These proteins were also dysregulated in the PE placenta. These results are supported by observed lysosomal ultrastructural defects with decreased number of autolysosomes in hypoxia-treated primary human trophoblasts. Autophagy-deficient human EVTs exhibited poor TFEB nuclear translocation, reduced lysosomal protein expression and function, and increased MTORC1 activity. Sera from PE patients induced these features and protein aggregation in EVTs. Importantly, trophoblast-specific conditional atg7knockout mice exhibited reduced TFEB expression with increased deposition of protein aggregates in the placenta. These results provide compelling evidence for a regulatory link between accumulation of protein aggregates and TFEB-mediated impaired lysosomal biogenesis and autophagy in the placenta of PE patients.Abbreviation:atg7: autophagy related 7; CTSD: cathepsin D; ER: endoplasmic reticulum; EVTs: extravillous trophoblasts; KRT7: keratin 7; LAMP1: lysosomal associated membrane protein 1; LAMP2: lysosomal associated membrane protein 2; mSt: mStrawberry; MTORC1: mechanistic target of rapamycin complex 1; NP: normal pregnancy; NPS: normal pregnancy serum; PE: preeclampsia; PES: preeclampsia serum; p-RPS6KB: phosphorylated ribosomal protein S6 kinase B1; SQSTM1/p62: sequestosome 1; TEM: transmission electron microscopy; TFEB: transcription factor EB; XPO1/CRM1: exportin 1

Published
2020
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37. Metabolic effects of RUBCN/Rubicon deficiency in kidney proximal tubular epithelial cells

Author

Matsuda, Jun, Takahashi, Atsushi, Takabatake, Yoshitsugu, Sakai, Shinsuke, Minami, Satoshi, Yamamoto, Takeshi, Fujimura, Ryuta, Namba-Hamano, Tomoko, Yonishi, Hiroaki, Nakamura, Jun, Kimura, Tomonori, Kaimori, Jun-Ya, Matsui, Isao, Takahashi, Masatomo, Nakao, Motonao, Izumi, Yoshihiro, Bamba, Takeshi, Matsusaka, Taiji, Niimura, Fumio, Yanagita, Motoko, Yoshimori, Tamotsu, and Isaka, Yoshitaka

Abstract

ABSTRACTMacroautophagy/autophagy is a lysosomal degradation system which plays a protective role against kidney injury. RUBCN/Rubicon (RUN domain and cysteine-rich domain containing, Beclin 1-interacting protein) inhibits the fusion of autophagosomes and lysosomes. However, its physiological role in kidney proximal tubular epithelial cells (PTECs) remains uncertain. In the current study, we analyzed the phenotype of newly generated PTEC-specific rubcn-deficient (KO) mice. Additionally, we investigated the role of RUBCN in lipid metabolism using isolated rubcn-deficient PTECs. Although KO mice exhibited sustained high autophagic flux in PTECs, they were not protected from acute ischemic kidney injury. Unexpectedly, KO mice exhibited hallmark features of metabolic syndrome accompanied by expanded lysosomes containing multi-layered phospholipids in PTECs. RUBCN deficiency in cultured PTECs promoted the mobilization of phospholipids from cellular membranes to lysosomes via enhanced autophagy. Treatment of KO PTECs with oleic acid accelerated fatty acids transfer to mitochondria. Furthermore, KO PTECs promoted massive triglyceride accumulation in hepatocytes (BNL-CL2 cells) co-cultured in transwell, suggesting accelerated fatty acids efflux from the PTECs contributes to the metabolic syndrome in KO mice. This study shows that sustained high autophagic flux by RUBCN deficiency in PTECs leads to metabolic syndrome concomitantly with an accelerated mobilization of phospholipids from cellular membranes to lysosomes.Abbreviations: ABC: ATP binding cassette; ACADM: acyl-CoA dehydrogenase medium chain; ACTB: actin, beta; ATG: autophagy related; AUC: area under the curve; Baf: bafilomycin A1; BAT: brown adipose tissue; BODIPY: boron-dipyrromethene; BSA: bovine serum albumin; BW: body weight; CAT: chloramphenicol acetyltransferase; CM: complete medium; CPT1A: carnitine palmitoyltransferase 1a, liver; CQ: chloroquine; CTRL: control; EGFP: enhanced green fluorescent protein; CTSD: cathepsin D; EAT: epididymal adipose tissue; EGFR: epidermal growth factor receptor; EIF4EBP1: eukaryotic translation initiation factor 4E binding protein 1; FA: fatty acid; FBS: fetal bovine serum; GTT: glucose tolerance test; HE: hematoxylin and eosin; HFD: high-fat diet; I/R: ischemia-reperfusion; ITT: insulin tolerance test; KAP: kidney androgen regulated protein; KO: knockout; LAMP1: lysosomal associated membrane protein 1; LD: lipid droplet; LRP2: low density lipoprotein receptor related protein 2; MAP1LC3B: microtubule associated protein 1 light chain 3 beta; MAT: mesenteric adipose tissue; MS: mass spectrometry; MTOR: mechanistic target of rapamycin kinase; MTORC1: MTOR complex 1; NDRG1: N-myc downstream regulated 1; NDUFB5: NADH:ubiquinone oxidoreductase subunit B5; NEFA: non-esterified fatty acid; OA: oleic acid; OCT: optimal cutting temperature; ORO: Oil Red O; PAS: Periodic-acid Schiff; PFA: paraformaldehyde; PIK3C3: phosphatidylinositol 3-kinase catalytic subunit type 3; PPARA: peroxisome proliferator activated receptor alpha; PPARGC1A: PPARG coactivator 1 alpha; PTEC: proximal tubular epithelial cell; RAB7A: RAB7A, member RAS oncogene family; RPS6: ribosomal protein S6; RPS6KB1: ribosomal protein S6 kinase B1; RT: reverse transcription; RUBCN: rubicon autophagy regulator; SAT: subcutaneous adipose tissue; SFC: supercritical fluid chromatography; SQSTM1: sequestosome 1; SREBF1: sterol regulatory element binding transcription factor 1; SV-40: simian virus-40; TFEB: transcription factor EB; TG: triglyceride; TS: tissue specific; TUNEL: terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling; UN: urea nitrogen; UQCRB: ubiquinol-cytochrome c reductase binding protein; UVRAG: UV radiation resistance associated; VPS: vacuolar protein sorting; WAT: white adipose tissue.

Published
2020
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38. LC3 lipidation is essential for TFEB activation during the lysosomal damage response to kidney injury

Author

Nakamura, Shuhei, Shigeyama, Saki, Minami, Satoshi, Shima, Takayuki, Akayama, Shiori, Matsuda, Tomoki, Esposito, Alessandra, Napolitano, Gennaro, Kuma, Akiko, Namba-Hamano, Tomoko, Nakamura, Jun, Yamamoto, Kenichi, Sasai, Miwa, Tokumura, Ayaka, Miyamoto, Mika, Oe, Yukako, Fujita, Toshiharu, Terawaki, Seigo, Takahashi, Atsushi, Hamasaki, Maho, Yamamoto, Masahiro, Okada, Yukinori, Komatsu, Masaaki, Nagai, Takeharu, Takabatake, Yoshitsugu, Xu, Haoxing, Isaka, Yoshitaka, Ballabio, Andrea, and Yoshimori, Tamotsu

Abstract

Sensing and clearance of dysfunctional lysosomes is critical for cellular homeostasis. Here we show that transcription factor EB (TFEB)—a master transcriptional regulator of lysosomal biogenesis and autophagy—is activated during the lysosomal damage response, and its activation is dependent on the function of the ATG conjugation system, which mediates LC3 lipidation. In addition, lysosomal damage triggers LC3 recruitment on lysosomes, where lipidated LC3 interacts with the lysosomal calcium channel TRPML1, facilitating calcium efflux essential for TFEB activation. Furthermore, we demonstrate the presence and importance of this TFEB activation mechanism in kidneys in a mouse model of oxalate nephropathy accompanying lysosomal damage. A proximal tubule-specific TFEB-knockout mouse exhibited progression of kidney injury induced by oxalate crystals. Together, our results reveal unexpected mechanisms of TFEB activation by LC3 lipidation and their physiological relevance during the lysosomal damage response.

Published
2020
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39. Identification of Metal-Binding Peptides and Their Conjugation onto Nanoparticles of Superparamagnetic Iron Oxides and Liposomes

Author

Kodama, Tomonobu, Yoshihara, Akifumi, Goel, Isha, Sekino, Masaki, Kuwahata, Akihiro, Yoshimori, Atsushi, Murayama, Yuichi, Ishihara, Kazuhiko, Ekdahl, Kristina N., Nilsson, Bo, and Teramura, Yuji

Abstract

Metallic materials are used for clinical medical devices such as vascular stents and coils to treat both ischemic and hemorrhagic vascular diseases. An antiplatelet drug is required to avoid thromboembolic complication until metallic surface is covered with a neo-endothelial cell layer. It is important to identify endothelial cell coverage on the metallic surface. However, it is difficult since there are no selective ligands. Here, we used the phage display method to identify peptide ligands that had high affinity for the metallic surface of Ni–Ti stents, Pt–W coils, and Co–Cr stents. The binding assay using fluorescence labeling revealed that several synthetic peptides could bind onto those surfaces. We also chose some oligopeptides for the conjugation onto superparamagnetic iron oxide (SPIO) nanoparticles and liposome-encapsulating SPIO nanoparticles and studied their ability to bind to the stent and coils. By SEM and fluorophotometry, we found that those modified SPIOs and liposomes were selectively bound onto those surfaces. In addition, both treated stents and coils could be detected by magnetic resonance imaging due to the magnetic artifact through the SPIOs and liposomes that were immobilized onto the surface. Thus, we identified metal-binding peptides which may enable to stop antiplatelet therapy after vascular stenting or coiling.

Published
2020
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41. Deregulated MTOR (mechanistic target of rapamycin kinase) is responsible for autophagy defects exacerbating kidney stone development

Author

Unno, Rei, Kawabata, Tsuyoshi, Taguchi, Kazumi, Sugino, Teruaki, Hamamoto, Shuzo, Ando, Ryosuke, Okada, Atsushi, Kohri, Kenjiro, Yoshimori, Tamotsu, and Yasui, Takahiro

Abstract

ABSTRACTKidney stone disease is a lifestyle-related disease prevalent in developed countries; however, effective medical treatment for the disease is not yet well established. As cellular damage in renal tubular cells (RTCs) is responsible for the disease, here, we focused on the role of macroautophagy/autophagy in RTCs. We found that autophagic activity was significantly decreased in mouse RTCs exposed to calcium oxalate (CaOx) monohydrate crystals and in the kidneys of GFP-conjugated MAP1LC3B (microtubule- associated protein 1 light chain 3 beta) transgenic mice with CaOx nephrocalcinosis induced by glyoxylate. This caused accumulation of damaged intracellular organelles, such as mitochondria and lysosomes, the normal functioning of which is mediated by functional autophagy. An impairment of autophagy was also observed in the mucosa with plaques of CaOx kidney stone formers. We determined that the decrease in autophagy was caused by an upregulation of MTOR (mechanistic target of rapamycin kinase), which consequently resulted in the suppression of the upstream autophagy regulator TFEB (transcription factor EB). Furthermore, we showed that an MTOR inhibitor could recover a decrease in autophagy and alleviate crystal-cell interactions and the formation of crystals associated with increased inflammatory responses. Taken together, we conclude that autophagy compromised by MTOR deregulation is a fundamental feature in the pathology of kidney stone formation, and propose that chemical inhibition of MTOR could be a prospective strategy for disease suppression.Abbreviations: ACTB: actin, beta; CaOx: calcium oxalate; CKD: chronic kidney disease; COM: calcium oxalate monohydrate; LGALS3/galectin-3: lectin, galactose binding, soluble 3; GFP: green fluorescent protein; GOX: glyoxylate; HE: hematoxylin and eosin; MAPLC3B: microtubule- associated protein 1 light chain 3 beta; MTOR: mechanistic target of rapamycin kinase; NAC: N-acetyl-L-cysteine; ROS: reactive oxygen species; RTC: renal tubular cell; SQSTM1/p62: sequestosome 1; TFEB: transcription factor EB; TEM: transmission electron microscopy; tfLC3: tandem fluorescent-tagged LC3; 3-MA: 3-methyladenine.

Published
2020
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43. Autophagy, Inflammation, and Metabolism (AIM) Center in its second year

Author

Deretic, Vojo, Prossnitz, Eric, Burge, Mark, Campen, Matthew J., Cannon, Judy, Liu, Ke Jian, Liu, Meilian, Hall, Pamela, Sklar, Larry A., Allers, Lee, Mariscal, Luisa, Garcia, Sally Ann, Weaver, John, Baehrecke, Eric H., Behrends, Christian, Cecconi, Francesco, Codogno, Patrice, Chen, Guang-Chao, Elazar, Zvulun, Eskelinen, Eeva-Liisa, Fourie, Bernard, Gozuacik, Devrim, Hong, Wanjin, Jo, Eun-Kyeong, Johansen, Terje, Juhász, Gábor, Kimchi, Adi, Ktistakis, Nicholas, Kroemer, Guido, Mizushima, Noboru, Münz, Christian, Reggiori, Fulvio, Rubinsztein, David, Ryan, Kevin, Schroder, Kate, Shen, Han-Min, Simonsen, Anne, Tooze, Sharon A., Vaccaro, Maria I., Yoshimori, Tamotsu, Yu, Li, Zhang, Hong, and Klionsky, Daniel J.

Abstract

ABSTRACTThe NIH-funded center for autophagy research named Autophagy, Inflammation, and Metabolism (AIM) Center of Biomedical Research Excellence, located at the University of New Mexico Health Science Center is now completing its second year as a working center with a mission to promote autophagy research locally, nationally, and internationally. The center has thus far supported a cadre of 6 junior faculty (mentored PIs; mPIs) at a near-R01 level of funding. Two mPIs have graduated by obtaining their independent R01 funding and 3 of the remaining 4 have won significant funding from NIH in the form of R21 and R56 awards. The first year and a half of setting up the center has been punctuated by completion of renovations and acquisition and upgrades for equipment supporting autophagy, inflammation and metabolism studies. The scientific cores usage, and the growth of new studies is promoted through pilot grants and several types of enablement initiatives. The intent to cultivate AIM as a scholarly hub for autophagy and related studies is manifested in its Vibrant Campus Initiative, and the Tuesday AIM Seminar series, as well as by hosting a major scientific event, the 2019 AIM symposium, with nearly one third of the faculty from the International Council of Affiliate Members being present and leading sessions, giving talks, and conducting workshop activities. These and other events are often videostreamed for a worldwide scientific audience, and information about events at AIM and elsewhere are disseminated on Twitter and can be followed on the AIM web site. AIM intends to invigorate research on overlapping areas between autophagy, inflammation and metabolism with a number of new initiatives to promote metabolomic research. With the turnover of mPIs as they obtain their independent funding, new junior faculty are recruited and appointed as mPIs. All these activities are in keeping with AIM’s intention to enable the next generation of autophagy researchers and help anchor, disseminate, and convey the depth and excitement of the autophagy field.

Published
2019
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44. Method for Systematic Analogue Search Using the Mega SAR Matrix Database

Author

Yoshimori, Atsushi, Horita, Yuichi, Tanoue, Toru, and Bajorath, Jürgen

Abstract

Analogue searching is a typical requirement in hit expansion, hit-to-lead, and lead optimization projects. A new computational methodology is introduced to search for existing and virtual analogues of active compounds. The approach is based upon the SAR matrix (SARM) data structure that was originally developed for the systematic identification and structural organization of analogue series. The SARM-based analogue search algorithm further extends the capacity of current substructure-based methods by (i) simultaneously considering existing and virtual analogues that populate chemical space around query compounds, (ii) permitting not only R-group replacements but also well-defined chemical modifications in core structures to further expand the analogue space, and (iii) automatically extracting all possible analogues from large pools. In addition, as a basis for analogue searching following the SARM concept, the Mega-SARM database is introduced. Mega-SARM is derived from nearly 3.7 million compounds and contains ∼250 000 matrices with structurally related analogue series and more than 1.5 million virtual candidate compounds.

Published
2019
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45. Ostial atresia of the coronary sinus in patients with supraventricular arrhythmias

Author

Hiroshima, Ken‐ichi, Goya, Masahiko, Nagashima, Michio, Fukunaga, Masato, Ohe, Masatsugu, An, Yoshimori, Makihara, Yu, Hayashi, Kentaro, and Ando, Kenji

Abstract

Of 3577 patients with supraventricular arrhythmias, 3 demonstrated an atresia of the coronary sinus (CS) ostium. Two patients had the accessory pathways. One had atrial fibrillation. No unroofed CSor apparent persistent left superior vena cava was observed. Venous drainage through a small cardiac vein located on the lateral portion of the tricuspid annulus was observed in all patients. Those cases demonstrated that the incidence of ostial atresia of the CSwas 0.084%. Accessory pathways were often accompanied by this anomaly. An abnormal venous orifice located on the lateral tricuspid annulus often functioned as the drainage of the CSflow.

Published
2019
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46. Transgenic expression of a ratiometric autophagy probe specifically in neurons enables the interrogation of brain autophagy in vivo

Author

Lee, Ju-Hyun, Rao, Mala V., Yang, Dun-Sheng, Stavrides, Philip, Im, Eunju, Pensalfini, Anna, Huo, Chunfeng, Sarkar, Pallabi, Yoshimori, Tamotsu, and Nixon, Ralph A.

Abstract

ABSTRACTAutophagy-lysosome pathway (ALP) disruption is considered pathogenic in multiple neurodegenerative diseases; however, current methods are inadequate to investigate macroautophagy/autophagy flux in brain in vivoand its therapeutic modulation. Here, we describe a novel autophagy reporter mouse (TRGL6) stably expressing a dual-fluorescence-tagged LC3 (tfLC3, mRFP-eGFP-LC3) by transgenesis selectively in neurons. The tfLC3 probe distributes widely in the central nervous system, including spinal cord. Expression levels were similar to endogenous LC3 and induced no detectable ALP changes. This ratiometric reporter registers differential pH-dependent changes in color as autophagosomes form, fuse with lysosomes, acidify, and degrade substrates within autolysosomes. We confirmed predicted changes in neuronal autophagy flux following specific experimental ALP perturbations. Furthermore, using a third fluorescence label in TRGL6 brains to identify lysosomes by immunocytochemistry, we validated a novel procedure to detect defective autolysosomal acidification in vivo. Thus, TRGL6 mice represent a unique tool to investigate in vivoALP dynamics in specific neuron populations in relation to neurological diseases, aging, and disease modifying agents.Abbreviations: ACTB: actin, beta; AD: Alzheimer disease; AL: autolysosomes; ALP: autophagy-lysosome pathway; AP: autophagosome; APP: amyloid beta (Abeta) precursor protein; ATG5: autophagy related 5; ATG7: autophagy related 7; AV: autophagic vacuoles; CNS: central nervous system; CTSD: cathepsin D; CQ: chloroquine; DMEM: Dulbecco’s modified Eagle’s medium; GFP: green fluorescent protein; GABARAP: gamma-aminobutyric acid receptor associated protein; GABARAPL2/GATE16: gamma-aminobutyric acid (GABA) receptor-associated protein-like 2; ICC: immunocytochemistry; ICV: intra-cerebroventricular; LAMP2: lysosomal-associated membrane protein 2; Leup: leupeptin; LY: lysosomes; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MTOR: mechanistic target of rapamycin kinase; RBFOX3/NeuN: RNA binding protein, fox-1 homolog (C. elegans) 3; RFP: red fluorescent protein; RPS6KB1: ribosomal protein S6 kinase, polypeptide 1; SDS-PAGE: sodium dodecyl sulfate-polyacrylamide gel electrophoresis; SQSTM1: sequestosome 1; tfLC3: mRFP-eGFP-LC3; TRGL6: Thy1 mRFP eGFP LC3-line 6; PCR: polymerase chain reaction; PD: Parkinson disease

Published
2019
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47. Distinct functions of ATG16L1 isoforms in membrane binding and LC3B lipidation in autophagy-related processes

Author

Lystad, Alf Håkon, Carlsson, Sven R., de la Ballina, Laura R., Kauffman, Karlina J., Nag, Shanta, Yoshimori, Tamotsu, Melia, Thomas J., and Simonsen, Anne

Abstract

Covalent modification of LC3 and GABARAP proteins to phosphatidylethanolamine in the double-membrane phagophore is a key event in the early phase of macroautophagy, but can also occur on single-membrane structures. In both cases this involves transfer of LC3/GABARAP from ATG3 to phosphatidylethanolamine at the target membrane. Here we have purified the full-length human ATG12-5–ATG16L1 complex and show its essential role in LC3B/GABARAP lipidation in vitro. We have identified two functionally distinct membrane-binding regions in ATG16L1. An N-terminal membrane-binding amphipathic helix is required for LC3B lipidation under all conditions tested. By contrast, the C-terminal membrane-binding region is dispensable for canonical autophagy but essential for VPS34-independent LC3B lipidation at perturbed endosomes. We further show that the ATG16L1 C-terminus can compensate for WIPI2 depletion to sustain lipidation during starvation. This C-terminal membrane-binding region is present only in the β-isoform of ATG16L1, showing that ATG16L1 isoforms mechanistically distinguish between different LC3B lipidation mechanisms under different cellular conditions.

Published
2019
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48. Predictive factors of the presence of pulmonary embolism in patients with interstitial lung disease: Observational study

Author

Shimoda, Masafumi, Nunokawa, Hiroki, Tanaka, Yoshiaki, Morimoto, Kozo, Moue, Iori, Yoshimori, Kozo, Saraya, Takeshi, Ohta, Ken, and Ishii, Haruyuki

Abstract

In patients with interstitial lung disease (ILD), the risk of pulmonary embolism (PE) is increased; however, distinguishing between PE and ILD exacerbation can be difficult. Therefore, this study investigated the usefulness of the Wells criteria and revised Geneva score and predictive factors for diagnosing PE in ILD patients with worsening respiratory symptoms. We retrospectively collected the data of 65 patients with ILD who underwent computed tomography pulmonary angiography at Fukujuji Hospital and Kyorin University Faculty of Medicine from January 2018 to March 2023, including 18 patients in the PE group and 47 patients in the non-PE group, and the data were compared between the 2 groups. The Wells score (P = .165) and revised Geneva score (P = .140) were not useful for distinguishing between the PE and non-PE groups. Patients in the PE group showed higher D-dimer, total protein (TP), and globulin levels than those in the non-PE group (D-dimer median 24.5 µg/mL [range 3.0–79.3] vs 9.3 µg/mL [range 0.5–80.8], P = .016; TP median 7.2 g/dL [range 5.1–8.7] vs 6.4 g/dL [range 5.0–8.2], P = .002; globulin median 3.8 g/dL [range 2.6–5.5] vs 3.2 g/dL [range 3.0–5.3], P = .041). Using cutoff values of TP ≥ 7.0 g/dL and D-dimer ≥ 11.8 µg/mL, the odds ratios for predicting PE were 10.5 and 4.90, respectively. This study demonstrates that high TP and D-dimer levels are useful indicators for predicting PE in ILD patients with worsening respiratory symptoms, while the Wells score and revised Geneva score are not reliable in diagnosing PE.

Published
2024
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50. Autophagy-independent function of lipidated LC3 essential for TFEB activation during the lysosomal damage responses

Author

Nakamura, Shuhei, Akayama, Shiori, and Yoshimori, Tamotsu

Abstract

ABSTRACTLysosomes are digestive organelles in cells containing many hydrolases, and also serve as a signaling hub to integrate intracellular and extracellular inputs; therefore, the integrity of lysosomes is critical for cellular homeostasis. Many agents and conditions can damage lysosomal membranes, which lead to leakage of lysosomal acidic contents into the cytosol thus becoming harmful for cells. Accordingly, cells have developed several defense systems to cope with damaged lysosomes, but underlying mechanisms of each system and their cross-talks are unclear. In our recent study, we found that a master transcription factor regulating autophagy and lysosomal biogenesis, TFEB (transcription factor EB) is activated during lysosomal damage, and this activation depends on an autophagy-independent function of lipidated LC3, which localizes on lysosomes. We further showed that this regulatory mechanism is essential to prevent the progression of the crystal nephropathy that accompanies lysosomal damage.

Published
2021
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