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Cell Reports Medicine
All content is freely available to readers and supported through open access

Sep 20, 2022

Volume 3Issue 9
Open Access
On the cover: The China Cardiometabolic Disease and Cancer Cohort (4C) Study shows changes in systematic amino acids and microbiota-related metabolites before T2DM onset. The cover art depicts a seesaw as a metaphor for the balance of glucose metabolism. Circulating amino acids and microbiota-related metabolites push the sugar cube up and cause elevated glucose levels. Cover art by Shuowen Xu....
On the cover: The China Cardiometabolic Disease and Cancer Cohort (4C) Study shows changes in systematic amino acids and microbiota-related metabolites before T2DM onset. The cover art depicts a seesaw as a metaphor for the balance of glucose metabolism. Circulating amino acids and microbiota-related metabolites push the sugar cube up and cause elevated glucose levels. Cover art by Shuowen Xu.

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Spotlights

Report

  • A genetically modified minipig model for Alzheimer’s disease with SORL1 haploinsufficiency

    • Olav M. Andersen,
    • Nikolaj Bøgh,
    • Anne M. Landau,
    • Gro G. Pløen,
    • Anne Mette G. Jensen,
    • Giulia Monti,
    • Benedicte P. Ulhøi,
    • Jens R. Nyengaard,
    • Kirsten R. Jacobsen,
    • Margarita M. Jørgensen,
    • Ida E. Holm,
    • Marianne L. Kristensen,
    • Aage Kristian O. Alstrup,
    • Esben S.S. Hansen,
    • Charlotte E. Teunissen,
    • Laura Breidenbach,
    • Mathias Droescher,
    • Ying Liu,
    • Hanne S. Pedersen,
    • Henrik Callesen,
    • Yonglun Luo,
    • Lars Bolund,
    • David J. Brooks,
    • Christoffer Laustsen,
    • Scott A. Small,
    • Lars F. Mikkelsen,
    • Charlotte B. Sørensen
    Andersen et al. develop a Göttingen minipig model for Alzheimer’s Disease (AD) with SORL1 haploinsufficiency and demonstrate that their young (<3 years) minipigs have enlarged endosomes and elevated Aβ peptide and tau CSF levels but are unaffected by AD brain pathologies and neurodegeneration, as assessed by PET and MRI scanning methods.

Articles

  • Amino acids, microbiota-related metabolites, and the risk of incident diabetes among normoglycemic Chinese adults: Findings from the 4C study

    • Shuangyuan Wang,
    • Mian Li,
    • Hong Lin,
    • Guixia Wang,
    • Yu Xu,
    • Xinjie Zhao,
    • Chunyan Hu,
    • Yi Zhang,
    • Ruizhi Zheng,
    • Ruying Hu,
    • Lixin Shi,
    • Rui Du,
    • Qing Su,
    • Jiqiu Wang,
    • Yuhong Chen,
    • Xuefeng Yu,
    • Li Yan,
    • Tiange Wang,
    • Zhiyun Zhao,
    • Ruixin Liu,
    • Xiaolin Wang,
    • Qi Li,
    • Guijun Qin,
    • Qin Wan,
    • Gang Chen,
    • Min Xu,
    • Meng Dai,
    • Di Zhang,
    • Xulei Tang,
    • Zhengnan Gao,
    • Feixia Shen,
    • Zuojie Luo,
    • Yingfen Qin,
    • Li Chen,
    • Yanan Huo,
    • Qiang Li,
    • Zhen Ye,
    • Yinfei Zhang,
    • Chao Liu,
    • Youmin Wang,
    • Shengli Wu,
    • Tao Yang,
    • Huacong Deng,
    • Jiajun Zhao,
    • Shenghan Lai,
    • Yiming Mu,
    • Lulu Chen,
    • Donghui Li,
    • Guowang Xu,
    • Guang Ning,
    • Weiqing Wang,
    • Yufang Bi,
    • Jieli Lu
    • for the 4C Study Group
    Wang et al. report a systematic amino acids and microbiota-related metabolites change profile before T2DM onset. Causal mediation analyses indicate significant mediation linkages through obesity and lipids. Variances explained in serum metabolites are modestly limited in the comprehensive catalog of risk factor–metabolite–diabetes associations.
  • Source of human milk (mother or donor) is more important than fortifier type (human or bovine) in shaping the preterm infant microbiome

    • Shreyas V. Kumbhare,
    • William-Diehl Jones,
    • Sharla Fast,
    • Christine Bonner,
    • Geert ‘t Jong,
    • Gary Van Domselaar,
    • Morag Graham,
    • Michael Narvey,
    • Meghan B. Azad
    Kumbhare et al. demonstrate that the type of milk fortifier (bovine versus human) has no major impact on the gut microbiome of very low birth weight (VLBW) infants, whereas the source of human milk (mother versus donor) is strongly associated with the gut microbiome, healthier weight gain, and reduced gut inflammation.
  • Multiple BCG vaccinations for the prevention of COVID-19 and other infectious diseases in type 1 diabetes

    • Denise L. Faustman,
    • Amanda Lee,
    • Emma R. Hostetter,
    • Anna Aristarkhova,
    • Nathan C. Ng,
    • Gabriella F. Shpilsky,
    • Lisa Tran,
    • Grace Wolfe,
    • Hiroyuki Takahashi,
    • Hans F. Dias,
    • Joan Braley,
    • Hui Zheng,
    • David A. Schoenfeld,
    • Willem M. Kühtreiber
    In a randomized, double-blinded, placebo-controlled phase 2/3 trial, Faustman et al. investigate the safety and efficacy of multiple doses of the more than 100-year-old Bacillus Calmette-Guérin (BCG) vaccine against COVID-19. They also determine vaccine efficacy against other infectious diseases, which, if present, would suggest platform protection against new SARS-CoV-2 variants.
  • Virological features and pathogenicity of SARS-CoV-2 Omicron BA.2

    • Jasper Fuk-Woo Chan,
    • Bingjie Hu,
    • Yue Chai,
    • Huiping Shuai,
    • Huan Liu,
    • Jialu Shi,
    • Yuanchen Liu,
    • Chaemin Yoon,
    • Jinjin Zhang,
    • Jing-Chu Hu,
    • Yuxin Hou,
    • Xiner Huang,
    • Terrence Tsz-Tai Yuen,
    • Tianrenzheng Zhu,
    • Wenjun Li,
    • Jian-Piao Cai,
    • Cuiting Luo,
    • Cyril Chik-Yan Yip,
    • Anna Jinxia Zhang,
    • Jie Zhou,
    • Shuofeng Yuan,
    • Bao-Zhong Zhang,
    • Jian-Dong Huang,
    • Kelvin Kai-Wang To,
    • Kwok-Yung Yuen,
    • Hin Chu
    Chan et al. investigate the virological features and pathogenicity of BA.2. They find that BA.2 is less efficient regarding plasma membrane entry compared with BA.1. In K18-hACE2 mice, BA.2 replicates more efficiently in the nasal turbinates but less efficiently in the lungs compared with BA.1.
  • Remdesivir-induced emergence of SARS-CoV2 variants in patients with prolonged infection

    • Andreas Heyer,
    • Thomas Günther,
    • Alexis Robitaille,
    • Marc Lütgehetmann,
    • Marylyn M. Addo,
    • Dominik Jarczak,
    • Stefan Kluge,
    • Martin Aepfelbacher,
    • Julian Schulze zur Wiesch,
    • Nicole Fischer,
    • Adam Grundhoff
    Heyer et al. investigate SARS-CoV2 intra-host genomic diversity in longitudinal samples from 14 patients suffering from prolonged infection. Whereas viral populations are surprisingly stable overall, novel variant species can rapidly emerge in remdesivir-treated patients, suggesting that antiviral treatment can create evolutionary bottlenecks, which promote emergence of SARS-CoV2 variants.
  • Vaccine subtype and dose interval determine immunogenicity of primary series COVID-19 vaccines in older people

    • Helen Parry,
    • Rachel Bruton,
    • Reni Ayodele,
    • Penny Sylla,
    • Graham McIlroy,
    • Nicola Logan,
    • Sam Scott,
    • Sam Nicol,
    • Kriti Verma,
    • Christine Stephens,
    • Brian Willett,
    • Jianmin Zuo,
    • Paul Moss
    Dual “primary series” SARS-CoV-2 vaccination is the core of global vaccine protection. Parry et al. determine an 8-month profile of antibody and cellular immunity in people aged >80 years following mRNA or adenovirus vaccination. Both are immunogenic, but subtype and dose interval elicit differential immune platforms for booster vaccines.
  • High-fructose feeding suppresses cold-stimulated brown adipose tissue glucose uptake independently of changes in thermogenesis and the gut microbiome

    • Gabriel Richard,
    • Denis P. Blondin,
    • Saad A. Syed,
    • Laura Rossi,
    • Michelle E. Fontes,
    • Mélanie Fortin,
    • Serge Phoenix,
    • Frédérique Frisch,
    • Stéphanie Dubreuil,
    • Brigitte Guérin,
    • Éric E. Turcotte,
    • Martin Lepage,
    • Michael G. Surette,
    • Jonathan D. Schertzer,
    • Gregory R. Steinberg,
    • Katherine M. Morrison,
    • André C. Carpentier
    Richard et al. show that after 2 weeks of fructose overfeeding, brown adipose tissue (BAT) glucose consumption decreases independently of changes in thermogenesis and gut microbiome. This impairment of BAT function does not occur with glucose overfeeding and is a very early sign of fructose-induced dysmetabolism.
  • Design principles to assemble drug combinations for effective tuberculosis therapy using interpretable pairwise drug response measurements

    • Jonah Larkins-Ford,
    • Yonatan N. Degefu,
    • Nhi Van,
    • Artem Sokolov,
    • Bree B. Aldridge
    Larkins-Ford et al. describe an efficient and interpretable method to evaluate drug combinations early in drug regimen design for tuberculosis. Using units of pairwise drug combination measurements in vitro, they predict multidrug treatment outcomes in vivo and describe what properties of pairwise building blocks are required for effective multidrug therapies.
  • Balance between immunoregulatory B cells and plasma cells drives pancreatic tumor immunity

    • Bhalchandra Mirlekar,
    • Yan Wang,
    • Sirui Li,
    • Mi Zhou,
    • Sarah Entwistle,
    • Tristan De Buysscher,
    • Ashley Morrison,
    • Gabriela Herrera,
    • Cameron Harris,
    • Benjamin G. Vincent,
    • Jenny P.- Y. Ting,
    • Naim Rashid,
    • William Y. Kim,
    • Jen Jen Yeh,
    • Yuliya Pylayeva-Gupta
    Mirlekar et al. report that IL-35-driven transcriptional reprogramming of naive B cells in pancreatic cancer shifts B cell development away from effector plasma cell responses toward an immunoregulatory phenotype. Inhibition of IL-35 or BCL6 in naive B cells limits tumor growth by potentiating anti-tumor plasma and T cell responses.
  • Targeting of c-MET and AXL by cabozantinib is a potential therapeutic strategy for patients with head and neck cell carcinoma

    • Anais Hagege,
    • Esma Saada-Bouzid,
    • Damien Ambrosetti,
    • Olivia Rastoin,
    • Julien Boyer,
    • Xingkang He,
    • Julie Rousset,
    • Christopher Montemagno,
    • Jérome Doyen,
    • Florence Pedeutour,
    • Julien Parola,
    • Isabelle Bourget,
    • Frederic Luciano,
    • Alexandre Bozec,
    • Yihai Cao,
    • Gilles Pagès,
    • Maeva Dufies
    Hagege et al. describe that AXL and c-MET are overexpressed in radio- and/or cisplatin HNSCC cells and patients and represent new potential therapeutic targets. Their inhibitor, cabozantinib, shows its efficacy in resistant in vitro and in vivo models, in 3D sections of HNSCC biopsies, and in one resistant patient.
  • PSMG2-controlled proteasome-autophagy balance mediates the tolerance for MEK-targeted therapy in triple-negative breast cancer

    • Xueyan Wang,
    • Jing Yu,
    • Xiaowei Liu,
    • Dan Luo,
    • Yanchu Li,
    • Linlin Song,
    • Xian Jiang,
    • Xiaomeng Yin,
    • Yan Wang,
    • Li Chai,
    • Ting Luo,
    • Jing Jing,
    • Hubing Shi
    By means of high-throughput screening, Wang et al. show that a proteasome blockade sensitizes TNBCs to MEK-targeted therapy through autophagy-mediated degradation of PDPK1. The combination of MEK and proteasome inhibitors synergistically suppresses tumor proliferation in vitro and in vivo.
  • Proteomic and functional characterization of intra-tumor heterogeneity in human endometrial cancer

    • M. Fairuz B. Jamaluddin,
    • Yi-An Ko,
    • Arnab Ghosh,
    • Shafiq M. Syed,
    • Yvette Ius,
    • Rachel O’Sullivan,
    • Jacob K. Netherton,
    • Mark A. Baker,
    • Pravin Nahar,
    • Kenneth Jaaback,
    • Pradeep S. Tanwar
    Despite significant investment in the molecular analysis of solid tumors, few preclinical findings translate to patients. Tumor heterogeneity is suspected as one primary reason for the targeted therapy failure. Here, Jamaluddin et al. describe endometrial cancer intra-tumor heterogeneity using quantitative proteomics and patient-derived organoids.
  • Gene-environment interactions explain a substantial portion of variability of common neuropsychiatric disorders

    • Hanxin Zhang,
    • Atif Khan,
    • Andrey Rzhetsky
    Zhang et al. show that gene-environment interactions account for a significant portion of the phenotypic variance of common neuropsychiatric disorders: over 20% for ADHD, migraine, and anxiety/phobic disorder and close to 30% for recurrent headaches, sleep disorders, and post-traumatic stress disorder.
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