Science
28 Oct 2022
Volume 378 | Issue 6618
Research
Research Articles
1.Spermidine activates mitochondrial trifunctional protein and improves antitumor immunity in mice
下载原文
First Author:
Huna AI-Habsi①
Corresponding Author:
Sidonia Fagarasan②
Affiliations:
Division of Immunology and Genomic Medicine, Center for Cancer Immunotherapy and Immunobiology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.①
National Genetic Center, Ministry of Health, Muscat, Oman.①
Division of Integrated High-Order Regulatory Systems, Center for Cancer Immunotherapy and Immunobiology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.①②
Laboratory for Mucosal Immunity, Center for Integrative Medical Sciences, RIKEN Yokohama Institute, Yokohama, Japan.②
Abstract:
Spermidine (SPD) delays age-related pathologies in various organisms. SPD supplementation overcame the impaired immunotherapy against tumors in aged mice by increasing mitochondrial function and activating CD8+ T cells. Treatment of naïve CD8+ T cells with SPD acutely enhanced fatty acid oxidation. SPD conjugated to beads bound to the mitochondrial trifunctional protein (MTP). In the MTP complex, synthesized and purified from Escherichia coli, SPD bound to the α and β subunits of MTP with strong affinity and allosterically enhanced their enzymatic activities. T cell–specific deletion of the MTP α subunit abolished enhancement of programmed cell death protein 1 (PD-1) blockade immunotherapy by SPD, indicating that MTP is required for SPD-dependent T cell activation.
2. Commensal microbiota from patients with inflammatory bowel disease produce genotoxic metabolites下载原文
First Author:
Yiyun Cao①
Corresponding Author:
Noah W. Palm②
Affiliations:
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06519, USA.①②
Abstract:
Microbiota-derived metabolites that elicit DNA damage can contribute to colorectal cancer (CRC). However, the full spectrum of genotoxic chemicals produced by indigenous gut microbes remains to be defined. We established a pipeline to systematically evaluate the genotoxicity of an extensive collection of gut commensals from inflammatory bowel disease patients. We identified isolates from divergent phylogenies whose metabolites caused DNA damage and discovered a distinctive family of genotoxins—termed the indolimines—produced by the CRC-associated species Morganella morganii. A non–indolimine-producing M. morganii mutant lacked genotoxicity and failed to exacerbate colon tumorigenesis in mice. These studies reveal the existence of a previously unexplored universe of genotoxic small molecules from the microbiome that may affect host biology in homeostasis and disease.
3. Plastic deformation in silicon nitride ceramics via bond switching at coherent interfaces下载原文
First Author:
Jie Zhang①
Corresponding Author:
Kexin Chen②
Affiliations:
State Key Laboratory of New Ceramics and Fine Processing, School of Materials Science and Engineering, Tsinghua University, Beijing 100084, P.R. China.①
Department of Engineering and Material Sciences, National Natural Science Foundation of China (NSFC), Beijing 100085, P.R. China.②
Abstract:
Covalently bonded ceramics exhibit preeminent properties—including hardness, strength, chemical inertness, and resistance against heat and corrosion—yet their wider application is challenging because of their room-temperature brittleness. In contrast to the atoms in metals that can slide along slip planes to accommodate strains, the atoms in covalently bonded ceramics require bond breaking because of the strong and directional characteristics of covalent bonds. This eventually leads to catastrophic failure on loading. We present an approach for designing deformable covalently bonded silicon nitride (Si3N4) ceramics that feature a dual-phase structure with coherent interfaces. Successive bond switching is realized at the coherent interfaces, which facilitates a stress-induced phase transformation and, eventually, generates plastic deformability.
4. Attenuated evolution of mammals through the Cenozoic下载原文
First/ Corresponding Author:
Anjali Goswami
Affiliations:
Department of Life Sciences, Natural History Museum, London, UK.
Department of Genetics, Evolution, and Environment, University College London, London, UK.
Abstract:
The Cenozoic diversification of placental mammals is the archetypal adaptive radiation. Yet, discrepancies between molecular divergence estimates and the fossil record fuel ongoing debate around the timing, tempo, and drivers of this radiation. Analysis of a three-dimensional skull dataset for living and extinct placental mammals demonstrates that evolutionary rates peak early and attenuate quickly. This long-term decline in tempo is punctuated by bursts of innovation that decreased in amplitude over the past 66 million years. Social, precocial, aquatic, and herbivorous species evolve fastest, especially whales, elephants, sirenians, and extinct ungulates. Slow rates in rodents and bats indicate dissociation of taxonomic and morphological diversification. Frustratingly, highly similar ancestral shape estimates for placental mammal superorders suggest that their earliest representatives may continue to elude unequivocal identification.
5. Stereochemical editing logic powered by the epimerization of unactivated tertiary stereocenters下载原文
First Author:
Yu-An Zhang①
Corresponding Author:
Alison E. Wendlandt②
Affiliations:
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.①②
Abstract:
The stereoselective synthesis of complex targets requires the precise orchestration of chemical transformations that simultaneously establish the connectivity and spatial orientation of desired bonds. In this work, we describe a complementary paradigm for the synthesis of chiral molecules and their isomers, which tunes the three-dimensional structure of a molecule at a late stage. Key to the success of this strategy is the development of a mild and highly general photocatalytic method composed of decatungstate polyanion and disulfide cocatalysts, which enable the interconversion of unactivated tertiary stereogenic centers that were previously configurationally fixed. We showcase the versatility of this method—and the implementation of stereoediting logic—by the rapid construction of chiral scaffolds that would be challenging to access using existing tools and by the late-stage stereoediting of complex targets.
6. Design of fast-onset antidepressant by dissociating SERT from nNOS in the DRN下载原文
First Author:
Nan Sun①
Corresponding Author:
Ting-You Li②
Affiliations:
State Key Laboratory of Reproductive Medicine, Department of Clinic Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China.①
Jiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application, NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, Xuzhou 221004, China.①
Department of Pharmacochemistry, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China.②
Abstract:
Major depressive disorder (MDD) is one of the most common mental disorders. We designed a fast-onset antidepressant that works by disrupting the interaction between the serotonin transporter (SERT) and neuronal nitric oxide synthase (nNOS) in the dorsal raphe nucleus (DRN). Chronic unpredictable mild stress (CMS) selectively increased the SERT-nNOS complex in the DRN in mice. Augmentation of SERT-nNOS interactions in the DRN caused a depression-like phenotype and accounted for the CMS-induced depressive behaviors. Disrupting the SERT-nNOS interaction produced a fast-onset antidepressant effect by enhancing serotonin signaling in forebrain circuits. We discovered a small-molecule compound, ZZL-7, that elicited an antidepressant effect 2 hours after treatment without undesirable side effects. This compound, or analogous reagents, may serve as a new, rapidly acting treatment for MDD.
7. Closed-loop optimization of general reaction conditions for heteroaryl Suzuki-Miyaura coupling下载原文
First Author:
Nicholas H.Angello①
Corresponding Author:
Bartosz A. Grzybowski②
Affiliations:
Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL, USA.①
Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL, USA.①
Allchemy, Inc., Highland, IN, USA.②
Institute of Organic Chemistry, Polish Academy of Sciences, Warsaw, Poland.②
Center for Soft and Living Matter, Institute for Basic Science, Ulsan, Republic of Korea.②
Department of Chemistry, Ulsan Institute of Science and Technology, Ulsan, Republic of Korea.②
Abstract:
General conditions for organic reactions are important but rare, and efforts to identify them usually consider only narrow regions of chemical space. Discovering more general reaction conditions requires considering vast regions of chemical space derived from a large matrix of substrates crossed with a high-dimensional matrix of reaction conditions, rendering exhaustive experimentation impractical. Here, we report a simple closed-loop workflow that leverages data-guided matrix down-selection, uncertainty-minimizing machine learning, and robotic experimentation to discover general reaction conditions. Application to the challenging and consequential problem of heteroaryl Suzuki-Miyaura cross-coupling identified conditions that double the average yield relative to a widely used benchmark that was previously developed using traditional approaches. This study provides a practical road map for solving multidimensional chemical optimization problems with large search spaces.
8. Mirror-image T7 transcription of chirally inverted ribosomal and functional RNAs下载原文
First Author:
Yuan Xu①
Corresponding Author:
Ting F. Zhu②
Affiliations:
School of Life Sciences, Tsinghua-Peking Center for Life Sciences, Beijing Frontier Research Center for Biological Structure, Tsinghua University, Beijing, China.①②
School of Life Sciences, Research Center for Industries of the Future, Westlake University, Hangzhou, Zhejiang, China.①
Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China.①②
Abstract:
To synthesize a chirally inverted ribosome with the goal of building mirror-image biology systems requires the preparation of kilobase-long mirror-image ribosomal RNAs that make up the structural and catalytic core and about two-thirds of the molecular mass of the mirror-image ribosome. Here, we chemically synthesized a 100-kilodalton mirror-image T7 RNA polymerase, which enabled efficient and faithful transcription of the full-length mirror-image 5S, 16S, and 23S ribosomal RNAs from enzymatically assembled long mirror-image genes. We further exploited the versatile mirror-image T7 transcription system for practical applications such as biostable mirror-image riboswitch sensor, long-term storage of unprotected kilobase-long l-RNA in water, and l-ribozyme–catalyzed l-RNA polymerization to serve as a model system for basic RNA research.