Showing papers by "Osaka University published in 2019"

MAFFT online service: Multiple sequence alignment, interactive sequence choice and visualization

Abstract: This article describes several features in the MAFFT online service for multiple sequence alignment (MSA). As a result of recent advances in sequencing technologies, huge numbers of biological sequences are available and the need for MSAs with large numbers of sequences is increasing. To extract biologically relevant information from such data, sophistication of algorithms is necessary but not sufficient. Intuitive and interactive tools for experimental biologists to semiautomatically handle large data are becoming important. We are working on development of MAFFT toward these two directions. Here, we explain (i) the Web interface for recently developed options for large data and (ii) interactive usage to refine sequence data sets and MSAs.

Avelumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma

Abstract: Background In a single-group, phase 1b trial, avelumab plus axitinib resulted in objective responses in patients with advanced renal-cell carcinoma. This phase 3 trial involving previously...

Clinical use of current polygenic risk scores may exacerbate health disparities.

Abstract: Polygenic risk scores (PRS) are poised to improve biomedical outcomes via precision medicine. However, the major ethical and scientific challenge surrounding clinical implementation of PRS is that those available today are several times more accurate in individuals of European ancestry than other ancestries. This disparity is an inescapable consequence of Eurocentric biases in genome-wide association studies, thus highlighting that-unlike clinical biomarkers and prescription drugs, which may individually work better in some populations but do not ubiquitously perform far better in European populations-clinical uses of PRS today would systematically afford greater improvement for European-descent populations. Early diversifying efforts show promise in leveling this vast imbalance, even when non-European sample sizes are considerably smaller than the largest studies to date. To realize the full and equitable potential of PRS, greater diversity must be prioritized in genetic studies, and summary statistics must be publically disseminated to ensure that health disparities are not increased for those individuals already most underserved.

The Japanese Society of Hypertension Guidelines for the Management of Hypertension (JSH 2019)

Abstract: Satoshi Umemura ● Hisatomi Arima ● Shuji Arima ● Kei Asayama ● Yasuaki Dohi ● Yoshitaka Hirooka ● Takeshi Horio ● Satoshi Hoshide ● Shunya Ikeda ● Toshihiko Ishimitsu ● Masaaki Ito ● Sadayoshi Ito ● Yoshio Iwashima ● Hisashi Kai ● Kei Kamide ● Yoshihiko Kanno ● Naoki Kashihara ● Yuhei Kawano ● Toru Kikuchi ● Kazuo Kitamura ● Takanari Kitazono ● Katsuhiko Kohara ● Masataka Kudo ● Hiroo Kumagai ● Kiyoshi Matsumura ● Hideo Matsuura ● Katsuyuki Miura ● Masashi Mukoyama ● Satoko Nakamura ● Takayoshi Ohkubo ● Yusuke Ohya ● Takafumi Okura ● Hiromi Rakugi ● Shigeyuki Saitoh ● Hirotaka Shibata ● Tatsuo Shimosawa ● Hiromichi Suzuki ● Shori Takahashi ● Kouichi Tamura ● Hirofumi Tomiyama ● Takuya Tsuchihashi ● Shinichiro Ueda ● Yoshinari Uehara ● Hidenori Urata ● Nobuhito Hirawa

Guidelines for the use of flow cytometry and cell sorting in immunological studies (second edition)

Abstract: These guidelines are a consensus work of a considerable number of members of the immunology and flow cytometry community. They provide the theory and key practical aspects of flow cytometry enabling immunologists to avoid the common errors that often undermine immunological data. Notably, there are comprehensive sections of all major immune cell types with helpful Tables detailing phenotypes in murine and human cells. The latest flow cytometry techniques and applications are also described, featuring examples of the data that can be generated and, importantly, how the data can be analysed. Furthermore, there are sections detailing tips, tricks and pitfalls to avoid, all written and peer-reviewed by leading experts in the field, making this an essential research companion.

Meta-analysis of fecal metagenomes reveals global microbial signatures that are specific for colorectal cancer

Abstract: Association studies have linked microbiome alterations with many human diseases. However, they have not always reported consistent results, thereby necessitating cross-study comparisons. Here, a meta-analysis of eight geographically and technically diverse fecal shotgun metagenomic studies of colorectal cancer (CRC, n = 768), which was controlled for several confounders, identified a core set of 29 species significantly enriched in CRC metagenomes (false discovery rate (FDR) < 1 × 10−5). CRC signatures derived from single studies maintained their accuracy in other studies. By training on multiple studies, we improved detection accuracy and disease specificity for CRC. Functional analysis of CRC metagenomes revealed enriched protein and mucin catabolism genes and depleted carbohydrate degradation genes. Moreover, we inferred elevated production of secondary bile acids from CRC metagenomes, suggesting a metabolic link between cancer-associated gut microbes and a fat- and meat-rich diet. Through extensive validations, this meta-analysis firmly establishes globally generalizable, predictive taxonomic and functional microbiome CRC signatures as a basis for future diagnostics. Cross-study analysis defines fecal microbial species associated with colorectal cancer.

Metagenomic and metabolomic analyses reveal distinct stage-specific phenotypes of the gut microbiota in colorectal cancer

Abstract: In most cases of sporadic colorectal cancers, tumorigenesis is a multistep process, involving genomic alterations in parallel with morphologic changes. In addition, accumulating evidence suggests that the human gut microbiome is linked to the development of colorectal cancer. Here we performed fecal metagenomic and metabolomic studies on samples from a large cohort of 616 participants who underwent colonoscopy to assess taxonomic and functional characteristics of gut microbiota and metabolites. Microbiome and metabolome shifts were apparent in cases of multiple polypoid adenomas and intramucosal carcinomas, in addition to more advanced lesions. We found two distinct patterns of microbiome elevations. First, the relative abundance of Fusobacterium nucleatum spp. was significantly (P < 0.005) elevated continuously from intramucosal carcinoma to more advanced stages. Second, Atopobium parvulum and Actinomyces odontolyticus, which co-occurred in intramucosal carcinomas, were significantly (P < 0.005) increased only in multiple polypoid adenomas and/or intramucosal carcinomas. Metabolome analyses showed that branched-chain amino acids and phenylalanine were significantly (P < 0.005) increased in intramucosal carcinomas and bile acids, including deoxycholate, were significantly (P < 0.005) elevated in multiple polypoid adenomas and/or intramucosal carcinomas. We identified metagenomic and metabolomic markers to discriminate cases of intramucosal carcinoma from the healthy controls. Our large-cohort multi-omics data indicate that shifts in the microbiome and metabolome occur from the very early stages of the development of colorectal cancer, which is of possible etiological and diagnostic importance. Colorectal cancer stages are associated with distinct microbial and metabolomic profiles that could shed light on cancer progression.

Petawatt and exawatt class lasers worldwide

Abstract: In the 2015 review paper 'Petawatt Class Lasers Worldwide' a comprehensive overview of the current status of highpower facilities of >200 TW was presented. This was largely based on facility specifications, with some description of their uses, for instance in fundamental ultra-high-intensity interactions, secondary source generation, and inertial confinement fusion (ICF). With the 2018 Nobel Prize in Physics being awarded to Professors Donna Strickland and Gerard Mourou for the development of the technique of chirped pulse amplification (CPA), which made these lasers possible, we celebrate by providing a comprehensive update of the current status of ultra-high-power lasers and demonstrate how the technology has developed. We are now in the era of multi-petawatt facilities coming online, with 100 PW lasers being proposed and even under construction. In addition to this there is a pull towards development of industrial and multidisciplinary applications, which demands much higher repetition rates, delivering high-average powers with higher efficiencies and the use of alternative wavelengths: mid-IR facilities. So apart from a comprehensive update of the current global status, we want to look at what technologies are to be deployed to get to these new regimes, and some of the critical issues facing their development.

PD-1+ regulatory T cells amplified by PD-1 blockade promote hyperprogression of cancer

Abstract: PD-1 blockade is a cancer immunotherapy effective in various types of cancer. In a fraction of treated patients, however, it causes rapid cancer progression called hyperprogressive disease (HPD). With our observation of HPD in ∼10% of anti–PD-1 monoclonal antibody (mAb)-treated advanced gastric cancer (GC) patients, we explored how anti–PD-1 mAb caused HPD in these patients and how HPD could be treated and prevented. In the majority of GC patients, tumor-infiltrating FoxP3highCD45RA−CD4+ T cells [effector Treg (eTreg) cells], which were abundant and highly suppressive in tumors, expressed PD-1 at equivalent levels as tumor-infiltrating CD4+ or CD8+ effector/memory T cells and at much higher levels than circulating eTreg cells. Comparison of GC tissue samples before and after anti–PD-1 mAb therapy revealed that the treatment markedly increased tumor-infiltrating proliferative (Ki67+) eTreg cells in HPD patients, contrasting with their reduction in non-HPD patients. Functionally, circulating and tumor-infiltrating PD-1+ eTreg cells were highly activated, showing higher expression of CTLA-4 than PD-1− eTreg cells. PD-1 blockade significantly enhanced in vitro Treg cell suppressive activity. Similarly, in mice, genetic ablation or antibody-mediated blockade of PD-1 in Treg cells increased their proliferation and suppression of antitumor immune responses. Taken together, PD-1 blockade may facilitate the proliferation of highly suppressive PD-1+ eTreg cells in HPDs, resulting in inhibition of antitumor immunity. The presence of actively proliferating PD-1+ eTreg cells in tumors is therefore a reliable marker for HPD. Depletion of eTreg cells in tumor tissues would be effective in treating and preventing HPD in PD-1 blockade cancer immunotherapy.

Nivolumab versus chemotherapy in patients with advanced oesophageal squamous cell carcinoma refractory or intolerant to previous chemotherapy (ATTRACTION-3): a multicentre, randomised, open-label, phase 3 trial

Abstract: Summary Background Chemotherapy for patients with advanced oesophageal squamous cell carcinoma offers poor long-term survival prospects. We report the final analysis from our study of the immune checkpoint PD-1 inhibitor nivolumab versus chemotherapy in patients with previously treated advanced oesophageal squamous cell carcinoma. Methods We did a multicentre, randomised, open-label, phase 3 trial (ATTRACTION-3) at 90 hospitals and cancer centres in Denmark, Germany, Italy, Japan, South Korea, Taiwan, the UK, and the USA. We enrolled patients aged 20 years and older with unresectable advanced or recurrent oesophageal squamous cell carcinoma (regardless of PD-L1 expression), at least one measurable or non-measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, a baseline Eastern Cooperative Oncology Group performance status of 0–1, and who were refractory or intolerant to one previous fluoropyrimidine-based and platinum-based chemotherapy and had a life expectancy of at least 3 months. Patients were randomly assigned (1:1) to either nivolumab (240 mg for 30 min every 2 weeks) or investigator's choice of chemotherapy (paclitaxel 100 mg/m2 for at least 60 min once per week for 6 weeks then 1 week off; or docetaxel 75 mg/m2 for at least 60 min every 3 weeks), all given intravenously. Treatment continued until disease progression assessed by the investigator per RECIST version 1.1 or unacceptable toxicity. Randomisation was done using an interactive web response system with a block size of four and stratified according to geographical region (Japan vs rest of the world), number of organs with metastases, and PD-L1 expression. Patients and investigators were not masked to treatment allocation. The primary endpoint was overall survival, defined as the time from randomisation until death from any cause, in the intention-to-treat population that included all randomly assigned patients. Safety was assessed in all patients who received at least one dose of the assigned treatment. This trial is registered with ClinicalTrials.gov , number NCT02569242 , and follow-up for long-term outcomes is ongoing. Findings Between Jan 7, 2016, and May 25, 2017, we assigned 419 patients to treatment: 210 to nivolumab and 209 to chemotherapy. At the time of data cutoff on Nov 12, 2018, median follow-up for overall survival was 10·5 months (IQR 4·5–19·0) in the nivolumab group and 8·0 months (4·6–15·2) in the chemotherapy group. At a minimum follow-up time (ie, time from random assignment of the last patient to data cutoff) of 17·6 months, overall survival was significantly improved in the nivolumab group compared with the chemotherapy group (median 10·9 months, 95% CI 9·2–13·3 vs 8·4 months, 7·2–9·9; hazard ratio for death 0·77, 95% CI 0·62–0·96; p=0·019). 38 (18%) of 209 patients in the nivolumab group had grade 3 or 4 treatment-related adverse events compared with 131 (63%) of 208 patients in the chemotherapy group. The most frequent grade 3 or 4 treatment-related adverse events were anaemia (four [2%]) in the nivolumab group and decreased neutrophil count (59 [28%]) in the chemotherapy group. Five deaths were deemed treatment-related: two in the nivolumab group (one each of interstitial lung disease and pneumonitis) and three in the chemotherapy group (one each of pneumonia, spinal cord abscess, and interstitial lung disease). Interpretation Nivolumab was associated with a significant improvement in overall survivaland a favourable safety profile compared with chemotherapy in previously treated patients with advanced oesophageal squamous cell carcinoma, and might represent a new standard second-line treatment option for these patients. Funding ONO Pharmaceutical and Bristol-Myers Squibb.

Metagenomic analysis of colorectal cancer datasets identifies cross-cohort microbial diagnostic signatures and a link with choline degradation

Abstract: Several studies have investigated links between the gut microbiome and colorectal cancer (CRC), but questions remain about the replicability of biomarkers across cohorts and populations. We performed a meta-analysis of five publicly available datasets and two new cohorts and validated the findings on two additional cohorts, considering in total 969 fecal metagenomes. Unlike microbiome shifts associated with gastrointestinal syndromes, the gut microbiome in CRC showed reproducibly higher richness than controls (P < 0.01), partially due to expansions of species typically derived from the oral cavity. Meta-analysis of the microbiome functional potential identified gluconeogenesis and the putrefaction and fermentation pathways as being associated with CRC, whereas the stachyose and starch degradation pathways were associated with controls. Predictive microbiome signatures for CRC trained on multiple datasets showed consistently high accuracy in datasets not considered for model training and independent validation cohorts (average area under the curve, 0.84). Pooled analysis of raw metagenomes showed that the choline trimethylamine-lyase gene was overabundant in CRC (P = 0.001), identifying a relationship between microbiome choline metabolism and CRC. The combined analysis of heterogeneous CRC cohorts thus identified reproducible microbiome biomarkers and accurate disease-predictive models that can form the basis for clinical prognostic tests and hypothesis-driven mechanistic studies. Multicohort analysis identifies microbial signatures of colorectal cancer in fecal microbiomes.

Microlensing constraints on primordial black holes with Subaru/HSC Andromeda observations

Abstract: Primordial black holes (PBHs) have long been suggested as a viable candidate for the elusive dark matter. The abundance of such PBHs has been constrained using a number of astrophysical observations, except for a hitherto unexplored mass window of MPBH = [10−14, 10−9] solar masses. Here we carry out a dense-cadence, 7-hour-long observation of M31 with the Subaru Hyper Suprime-Cam (HSC) to search for microlensing of stars in M31 by PBHs lying in the halo regions of the Milky Way and M31. Given our simultaneous monitoring of tens of millions of stars in M31, if such light PBHs make up a significant fraction of dark matter, we expect to find many microlensing events. However, we identify only a single candidate event, which translates into stringent upper bounds on the abundance of PBHs in the mass range MPBH ≃ [10−11, 10−6] solar masses. The abundance of primordial black holes in the Galactic halo is constrained through their microlensing of stars in M31. Despite monitoring tens of millions of stars, only a single candidate event is found, providing stringent upper bounds on their abundance.

JCS 2017/JHFS 2017 Guideline on Diagnosis and Treatment of Acute and Chronic Heart Failure ― Digest Version ―

Abstract: J-STAGE Advance Publication released online September 10, 2019 Mailing address: Scientific Committee of the Japanese Circulation Society, 18F Imperial Hotel Tower, 1-1-1 Uchisaiwai-cho, Chiyoda-ku, Tokyo 100-0011, Japan. E-mail: meeting@j-circ.or.jp This English language document is a revised digest version of Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure (JCS 2017/JHFS 2017) reported at the Japanese Circulation Society Joint Working Groups performed in 2017 (Website: http://www.j-circ.or.jp/guideline/pdf/JCS2017_tsutsui_d.pdf). Joint Working Groups: The Japanese Circulation Society; the Japanese Heart Failure Society; the Japanese Association for Thoracic Surgery; the Japanese Society of Hypertension; the Japanese Society of Echocardiography; the Japanese Society for Cardiovascular Surgery; the Japanese College of Cardiology; the Japanese Association of Cardiac Rehabilitation; the Japan Society of Ultrasonics in Medicine; the Japan Diabetes Society; the Japanese Heart Rhythm Society; “the Study Group on Idiopathic Cardiomyopathy” supported by the Health and Labor Sciences Research Grant on Intractable Diseases; and “the Study Group on the Multi-center Observational Study of Dilatedphase Hypertrophic Cardiomyopathy”, supported by the “Practical Research Project for Rare/ intractable Diseases by the Japan Agency for Medical Research and Development”. ISSN-1346-9843 All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: cj@j-circ.or.jp JCS 2017/JHFS 2017 Guideline on Diagnosis and Treatment of Acute and Chronic Heart Failure ― Digest Version ―

Esophageal cancer practice guidelines 2017 edited by the Japan Esophageal Society: part 1.

Abstract: Purpose of the guidelines The primary objective of these guidelines is to provide general clinicians with information that would guide them to make informed choices of the available diagnosis/treatment strategies for esophageal cancer (intended for malignant esophageal tumors of epithelial origin, not for any other non-epithelial malignant tumors of the esophagus or metastatic esophageal malignant tumors). Furthermore, these guidelines are also intended as an aid for healthcare professionals other than the physicians, patients, and patients’ family members, to obtain an understanding of the fundamental principles of the diagnosis and treatment of esophageal cancer. These guidelines are intended to allow physicians to undertake diagnosis and treatment of esophageal cancer by sharing the information contained in the guidelines and promote mutual understanding among the healthcare professionals, patients, and their family members.

MAFFT-DASH: integrated protein sequence and structural alignment.

Abstract: Here, we describe a web server that integrates structural alignments with the MAFFT multiple sequence alignment (MSA) tool. For this purpose, we have prepared a web-based Database of Aligned Structural Homologs (DASH), which provides structural alignments at the domain and chain levels for all proteins in the Protein Data Bank (PDB), and can be queried interactively or by a simple REST-like API. MAFFT-DASH integration can be invoked with a single flag on either the web (https://mafft.cbrc.jp/alignment/server/) or command-line versions of MAFFT. In our benchmarks using 878 cases from the BAliBase, HomFam, OXFam, Mattbench and SISYPHUS datasets, MAFFT-DASH showed 10-20% improvement over standard MAFFT for MSA problems with weak similarity, in terms of Sum-of-Pairs (SP), a measure of how well a program succeeds at aligning input sequences in comparison to a reference alignment. When MAFFT alignments were supplemented with homologous sequences, further improvement was observed. Potential applications of DASH beyond MSA enrichment include functional annotation through detection of remote homology and assembly of template libraries for homology modeling.

The geomorphology, color, and thermal properties of Ryugu: Implications for parent-body processes

Abstract: Additional co-authors: N Namiki, S Tanaka, Y Iijima, K Yoshioka, M Hayakawa, Y Cho, M Matsuoka, N Hirata, N Hirata, H Miyamoto, D Domingue, M Hirabayashi, T Nakamura, T Hiroi, T Michikami, P Michel, R-L Ballouz, O S Barnouin, C M Ernst, S E Schroder, H Kikuchi, R Hemmi, G Komatsu, T Fukuhara, M Taguchi, T Arai, H Senshu, H Demura, Y Ogawa, Y Shimaki, T Sekiguchi, T G Muller, T Mizuno, H Noda, K Matsumoto, R Yamada, Y Ishihara, H Ikeda, H Araki, K Yamamoto, S Abe, F Yoshida, A Higuchi, S Sasaki, S Oshigami, S Tsuruta, K Asari, S Tazawa, M Shizugami, J Kimura, T Otsubo, H Yabuta, S Hasegawa, M Ishiguro, S Tachibana, E Palmer, R Gaskell, L Le Corre, R Jaumann, K Otto, N Schmitz, P A Abell, M A Barucci, M E Zolensky, F Vilas, F Thuillet, C Sugimoto, N Takaki, Y Suzuki, H Kamiyoshihara, M Okada, K Nagata, M Fujimoto, M Yoshikawa, Y Yamamoto, K Shirai, R Noguchi, N Ogawa, F Terui, S Kikuchi, T Yamaguchi, Y Oki, Y Takao, H Takeuchi, G Ono, Y Mimasu, K Yoshikawa, T Takahashi, Y Takei, A Fujii, C Hirose, S Nakazawa, S Hosoda, O Mori, T Shimada, S Soldini, T Iwata, M Abe, H Yano, R Tsukizaki, M Ozaki, K Nishiyama, T Saiki, S Watanabe, Y Tsuda

Resorcinol-formaldehyde resins as metal-free semiconductor photocatalysts for solar-to-hydrogen peroxide energy conversion.

Abstract: Artificial photosynthesis is a critical challenge in moving towards a sustainable energy future. Photocatalytic generation of hydrogen peroxide from water and dioxygen (H2O + $$\frac{1}{2}$$ O2 → H2O2, ΔG° = 117 kJ mol–1) by sunlight is a promising strategy for artificial photosynthesis because H2O2 is a storable and transportable fuel that can be used directly for electricity generation. All previously reported powder photocatalysts, however, have suffered from low efficiency in H2O2 generation. Here we report that resorcinol–formaldehyde resins, widely used inexpensive polymers, act as efficient semiconductor photocatalysts to provide a new basis for H2O2 generation. Simple high-temperature hydrothermal synthesis (~523 K) produces low-bandgap resorcinol–formaldehyde resins comprising π-conjugated and π-stacked benzenoid–quinoid donor–acceptor resorcinol couples. The resins absorb broad-wavelength light up to 700 nm and catalyse water oxidation and O2 reduction by the photogenerated charges. Simulated sunlight irradiation of the resins stably generates H2O2 with more than 0.5% solar-to-chemical conversion efficiency. Therefore, this metal-free system shows significant potential as a new artificial photosynthesis system. Generation of hydrogen peroxide from water and dioxygen is promising for artificial photosynthesis but photocatalysts suffer from low efficiency. Resorcinol–formaldehyde resins exhibit stable H2O2 generation with more than 0.5% solar-to-chemical conversion efficiency.

Esophageal cancer practice guidelines 2017 edited by the Japan esophageal society: part 2

Abstract: Endoscopic resection (ER) includes endoscopic mucosal resection (EMR), wherein the affected mucosal lesion is held or aspirated and resected with a snare, and endoscopic submucosal dissection (ESD), which refers to en bloc resection of an extensive lesion using an IT knife or hook knife [1–4]. Other endoscopic treatments available include photodynamic therapy (PDT), argon plasma coagulation (APC), and electromagnetic coagulation therapy. General remarks

KAGRA: 2.5 Generation Interferometric Gravitational Wave Detector

Abstract: The recent detections of gravitational waves (GWs) reported by the LIGO and Virgo collaborations have made a significant impact on physics and astronomy. A global network of GW detectors will play a key role in uncovering the unknown nature of the sources in coordinated observations with astronomical telescopes and detectors. Here we introduce KAGRA, a new GW detector with two 3 km baseline arms arranged in an ‘L’ shape. KAGRA’s design is similar to the second generations of Advanced LIGO and Advanced Virgo, but it will be operating at cryogenic temperatures with sapphire mirrors. This low-temperature feature is advantageous for improving the sensitivity around 100 Hz and is considered to be an important feature for the third-generation GW detector concept (for example, the Einstein Telescope of Europe or the Cosmic Explorer of the United States). Hence, KAGRA is often called a 2.5-generation GW detector based on laser interferometry. KAGRA’s first observation run is scheduled in late 2019, aiming to join the third observation run of the advanced LIGO–Virgo network. When operating along with the existing GW detectors, KAGRA will be helpful in locating GW sources more accurately and determining the source parameters with higher precision, providing information for follow-up observations of GW trigger candidates.

Long-read sequencing identifies GGC repeat expansions in NOTCH2NLC associated with neuronal intranuclear inclusion disease.

Abstract: Neuronal intranuclear inclusion disease (NIID) is a progressive neurodegenerative disease that is characterized by eosinophilic hyaline intranuclear inclusions in neuronal and somatic cells. The wide range of clinical manifestations in NIID makes ante-mortem diagnosis difficult1–8, but skin biopsy enables its ante-mortem diagnosis9–12. The average onset age is 59.7 years among approximately 140 NIID cases consisting of mostly sporadic and several familial cases. By linkage mapping of a large NIID family with several affected members (Family 1), we identified a 58.1 Mb linked region at 1p22.1–q21.3 with a maximum logarithm of the odds score of 4.21. By long-read sequencing, we identified a GGC repeat expansion in the 5′ region of NOTCH2NLC (Notch 2 N-terminal like C) in all affected family members. Furthermore, we found similar expansions in 8 unrelated families with NIID and 40 sporadic NIID cases. We observed abnormal anti-sense transcripts in fibroblasts specifically from patients but not unaffected individuals. This work shows that repeat expansion in human-specific NOTCH2NLC, a gene that evolved by segmental duplication, causes a human disease. Long-read sequencing identifies a GGC repeat expansion in NOTCH2NLC that is associated with neuronal intranuclear inclusion disease, a progressive neurodegenerative disorder. The expansion results in abnormal anti-sense transcripts that could contribute to disease pathogenesis.

Current knowledge on enzymatic PET degradation and its possible application to waste stream management and other fields

Abstract: Enzymatic hydrolysis of polyethylene terephthalate (PET) has been the subject of extensive previous research that can be grouped into two categories, viz. enzymatic surface modification of polyester fibers and management of PET waste by enzymatic hydrolysis. Different enzymes with rather specific properties are required for these two processes. Enzymatic surface modification is possible with several hydrolases, such as lipases, carboxylesterases, cutinases, and proteases. These enzymes should be designated as PET surface-modifying enzymes and should not degrade the building blocks of PET but should hydrolyze the surface polymer chain so that the intensity of PET is not weakened. Conversely, management of PET waste requires substantial degradation of the building blocks of PET; therefore, only a limited number of cutinases have been recognized as PET hydrolases since the first PET hydrolase was discovered by Muller et al. (Macromol Rapid Commun 26:1400-1405, 2005). Here, we introduce current knowledge on enzymatic degradation of PET with a focus on the key class of enzymes, PET hydrolases, pertaining to the definition of enzymatic requirements for PET hydrolysis, structural analyses of PET hydrolases, and the reaction mechanisms. This review gives a deep insight into the structural basis and dynamics of PET hydrolases based on the recent progress in X-ray crystallography. Based on the knowledge accumulated to date, we discuss the potential for PET hydrolysis applications, such as in designing waste stream management.

Metabolism of Dietary and Microbial Vitamin B Family in the Regulation of Host Immunity

Abstract: Vitamins are micronutrients that have physiological effects on various biological responses, including host immunity. Therefore, vitamin deficiency leads to increased risk of developing infectious, allergic, and inflammatory diseases. Since B vitamins are synthesized by plants, yeasts, and bacteria, but not by mammals, mammals must acquire B vitamins from dietary or microbial sources, such as the intestinal microbiota. Similarly, some intestinal bacteria are unable to synthesize B vitamins and must acquire them from the host diet or from other intestinal bacteria for their growth and survival. This suggests that the composition and function of the intestinal microbiota may affect host B vitamin usage and, by extension, host immunity. Here, we review the immunological functions of B vitamins and their metabolism by intestinal bacteria with respect to the control of host immunity.

LiteBIRD: A Satellite for the Studies of B-Mode Polarization and Inflation from Cosmic Background Radiation Detection

Abstract: LiteBIRD is a candidate satellite for a strategic large mission of JAXA. With its expected launch in the middle of the 2020s with a H3 rocket, LiteBIRD plans to map the polarization of the cosmic microwave background radiation over the full sky with unprecedented precision. The full success of LiteBIRD is to achieve $\delta r < 0.001$ , where $\delta r$ is the total error on the tensor-to-scalar ratio r. The required angular coverage corresponds to $2 \le \ell \le 200$ , where $\ell $ is the multipole moment. This allows us to test well-motivated cosmic inflation models. Full-sky surveys for 3 years at a Lagrangian point L2 will be carried out for 15 frequency bands between 34 and 448 GHz with two telescopes to achieve the total sensitivity of 2.5 $\upmu $ K arcmin with a typical angular resolution of 0.5$^\circ $ at 150 GHz. Each telescope is equipped with a half-wave plate system for polarization signal modulation and a focal plane filled with polarization-sensitive TES bolometers. A cryogenic system provides a 100 mK base temperature for the focal planes and 2 K and 5 K stages for optical components.

Rhodium-Catalyzed C(sp 2 )- or C(sp 3 )-H Bond Functionalization Assisted by Removable Directing Groups

Abstract: In recent years, transition-metal-catalyzed C-H activation has become a key strategy in the field of organic synthesis. Rhodium complexes are widely used as catalysts in a variety of C-H functionalization reactions because of their high reactivity and selectivity. The availability of a number of rhodium complexes in various oxidation states enables diverse reaction patterns to be obtained. Regioselectivity, an important issue in C-H activation chemistry, can be accomplished by using a directing group to assist the reaction. However, to obtain the target functionalized compounds, it is also necessary to use a directing group that can be easily removed. A wide range of directed C-H functionalization reactions catalyzed by rhodium complexes have been reported to date. In this Review, we discuss Rh-catalyzed C-H functionalization reactions that are aided by the use of a removable directing group such as phenol, amine, aldehyde, ketones, ester, acid, sulfonic acid, and N-heteroaromatic derivatives.

Constraints on Earth-mass primordial black holes from OGLE 5-year microlensing events

Abstract: We constrain the abundance of primordial black holes (PBH) using 2622 microlensing events obtained from 5-years observations of stars in the Galactic bulge by the Optical Gravitational Lensing Experiment (OGLE). The majority of microlensing events display a single or at least continuous population that has a peak around the light curve timescale ${t}_{\mathrm{E}}\ensuremath{\simeq}20\text{ }\text{ }\mathrm{days}$ and a wide distribution over the range ${t}_{\mathrm{E}}\ensuremath{\simeq}[1,300]\text{ }\text{ }\mathrm{days}$, while the data also indicates a second population of 6 ultrashort-timescale events in ${t}_{\mathrm{E}}\ensuremath{\simeq}[0.1,0.3]\text{ }\text{ }\mathrm{days}$, which are advocated to be due to free-floating planets. We confirm that the main population of OGLE events can be well modeled by microlensing due to brown dwarfs, main sequence stars and stellar remnants (white dwarfs and neutron stars) in the standard Galactic bulge and disk models for their spatial and velocity distributions. Using the dark matter (DM) model for the Milky Way (MW) halo relative to the Galactic bulge/disk models, we obtain the tightest upper bound on the PBH abundance in the mass range ${M}_{\mathrm{PBH}}\ensuremath{\simeq}[{10}^{\ensuremath{-}6},{10}^{\ensuremath{-}3}]\text{ }\text{ }{M}_{\ensuremath{\bigodot}}$ (Earth-Jupiter mass range), if we employ the ``null hypothesis'' that the OGLE data does not contain any PBH microlensing event. More interestingly, we also show that Earth-mass PBHs can well reproduce the 6 ultrashort-timescale events, without the need of free-floating planets, if the mass fraction of PBH to DM is at a per cent level, which is consistent with other constraints such as the microlensing search for Andromeda galaxy (M31) and the longer timescale OGLE events. Our result gives a hint of PBH existence, and can be confirmed or falsified by microlensing search for stars in M31, because M31 is towards the MW halo direction and should therefore contain a much less number of free-floating planets, even if exist, than the direction to the MW center.