EMBO Molecular Medicine

Journal Information
ISSN / EISSN : 1757-4676 / 1757-4684
Current Publisher: EMBO (10.15252)
Former Publisher: Wiley (10.1002)
Total articles ≅ 2,216
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Latest articles in this journal

Burak Bali, David Lopez de la Morena, Artur Mittring, Thomas Mager, , ,
Published: 7 May 2021
by EMBO
EMBO Molecular Medicine; doi:10.15252/emmm.202013391

Abstract:
Optogenetic stimulation of spiral ganglion neurons (SGNs) in the ear provides a future alternative to electrical stimulation used in current cochlear implants. Here, we employed fast and very fast variants of the red‐light‐activated channelrhodopsin (ChR) Chrimson (f‐Chrimson and vf‐Chrimson) to study their utility for optogenetic stimulation of SGNs in mice. The light requirements were higher for vf‐Chrimson than for f‐Chrimson, even when optimizing membrane expression of vf‐Chrimson by adding potassium channel trafficking sequences. Optogenetic time and intensity coding by single putative SGNs were compared with coding of acoustic clicks. vf‐Chrimson enabled putative SGNs to fire at near‐physiological rates with good temporal precision up to 250 Hz of stimulation. The dynamic range of SGN spike rate coding upon optogenetic stimulation was narrower than for acoustic clicks but larger than reported for electrical stimulation. The dynamic range of spike timing, on the other hand, was more comparable for optogenetic and acoustic stimulation. In conclusion, f‐Chrimson and vf‐Chrimson are promising candidates for optogenetic stimulation of SGNs in auditory research and future cochlear implants.
Carla E Cano, María José Sandí, Tewfik Hamidi, Ezequiel L Calvo, Olivier Turrini, Laurent Bartholin, Céline Loncle, Véronique Secq, Stéphane Garcia, Gwen Lomberk, et al.
Published: 7 May 2021
by EMBO
EMBO Molecular Medicine, Volume 13; doi:10.15252/emmm.202114243

Yi‐Hao Chan, Siew‐Wai Fong, Chek‐Meng Poh, Guillaume Carissimo, Nicholas Kim‐Wah Yeo, Siti Naqiah Amrun, Yun Shan Goh, Jackwee Lim, Weili Xu, Rhonda Sin‐Ling Chee, et al.
Published: 7 May 2021
by EMBO
EMBO Molecular Medicine; doi:10.15252/emmm.202114045

Abstract:
The immune responses and mechanisms limiting symptom progression in asymptomatic cases of SARS‐CoV‐2 infection remain unclear. We comprehensively characterized transcriptomic profiles, cytokine responses, neutralization capacity of antibodies and cellular immune phenotypes of asymptomatic patients with acute SARS‐CoV‐2 infection to identify potential protective mechanisms. Compared to symptomatic patients, asymptomatic patients had higher counts of mature neutrophils and lower proportion of CD169+ expressing monocytes in the peripheral blood. Systemic levels of pro‐inflammatory cytokines were also lower in asymptomatic patients, accompanied by milder pro‐inflammatory gene signatures. Mechanistically, a more robust systemic Th2 cell signature with a higher level of virus‐specific Th17 cells and a weaker yet sufficient neutralizing antibody profile against SARS‐CoV‐2 was observed in asymptomatic patients. In addition, asymptomatic COVID‐19 patients had higher systemic levels of growth factors that are associated with cellular repair. Together, the data suggest that asymptomatic patients mount less pro‐inflammatory and more protective immune responses against SARS‐CoV‐2 indicative of disease tolerance. Insights from this study highlight key immune pathways that could serve as therapeutic targets to prevent disease progression in COVID‐19.
Rosanna Mezzapelle, , Chiara Passera, Manuela Leo, Francesca Brambilla, Federica Colombo, Maura Casalgrandi, Alessandro Preti, Samuel Zambrano, Patrizia Castellani, et al.
Published: 6 May 2021
by EMBO
EMBO Molecular Medicine; doi:10.15252/emmm.202012344

Abstract:
Boosting antitumor immunity has emerged as a powerful strategy in cancer treatment. While releasing T‐cell brakes has received most attention, tumor recognition by T cells is a pre‐requisite. Radiotherapy and certain cytotoxic drugs induce the release of damage‐associated molecular patterns, which promote tumor antigen cross‐presentation and T‐cell priming. Antibodies against the “do not eat me” signal CD47 cause macrophage phagocytosis of live tumor cells and drive the emergence of antitumor T cells. Here we show that CXCR4 activation, so far associated only with tumor progression and metastasis, also flags tumor cells to immune recognition. Both CXCL12, the natural CXCR4 ligand, and BoxA, a fragment of HMGB1, promote the release of DAMPs and the internalization of CD47, leading to protective antitumor immunity. We designate as Immunogenic Surrender the process by which CXCR4 turns in tumor cells to macrophages, thereby subjecting a rapidly growing tissue to immunological scrutiny. Importantly, while CXCL12 promotes tumor cell proliferation, BoxA reduces it, and might be exploited for the treatment of malignant mesothelioma and a variety of other tumors.
, Shorena Janelidze, Randall J Bateman, Ruben Smith, Erik Stomrud, Geidy E Serrano, Eric M Reiman, , Jeffrey L Dage, Thomas G Beach, et al.
Published: 5 May 2021
by EMBO
EMBO Molecular Medicine; doi:10.15252/emmm.202114022

Abstract:
Alzheimer’s disease is characterized by β‐amyloid plaques and tau tangles. Plasma levels of phospho‐tau217 (P‐tau217) accurately differentiate Alzheimer’s disease dementia from other dementias, but it is unclear to what degree this reflects β‐amyloid plaque accumulation, tau tangle accumulation, or both. In a cohort with post‐mortem neuropathological data (N = 88), both plaque and tangle density contributed independently to higher P‐tau217, but P‐tau217 was not elevated in patients with non‐Alzheimer’s disease tauopathies (N = 9). Several findings were replicated in a cohort with PET imaging (“BioFINDER‐2”, N = 426), where β‐amyloid and tau PET were independently associated with P‐tau217. P‐tau217 concentrations correlated with β‐amyloid PET (but not tau PET) in early disease stages and with both β‐amyloid and (more strongly) tau PET in late disease stages. Finally, P‐tau217 mediated the association between β‐amyloid and tau in both cohorts, especially for tau outside of the medial temporal lobe. These findings support the hypothesis that plasma P‐tau217 concentration is increased by both β‐amyloid plaques and tau tangles and is congruent with the hypothesis that P‐tau is involved in β‐amyloid‐dependent formation of neocortical tau tangles.
Jonathan Trujillo‐Viera, Rabih El‐Merahbi, Vanessa Schmidt, Till Karwen, Angel Loza‐Valdes, Akim Strohmeyer, Saskia Reuter, Minhee Noh, Magdalena Wit, Izabela Hawro, et al.
Published: 5 May 2021
by EMBO
EMBO Molecular Medicine; doi:10.15252/emmm.202013548

Abstract:
Lipids are the most energy‐dense components of the diet, and their overconsumption promotes obesity and diabetes. Dietary fat content has been linked to the lipid processing activity by the intestine and its overall capacity to absorb triglycerides (TG). However, the signaling cascades driving intestinal lipid absorption in response to elevated dietary fat are largely unknown. Here, we describe an unexpected role of the protein kinase D2 (PKD2) in lipid homeostasis. We demonstrate that PKD2 activity promotes chylomicron‐mediated TG transfer in enterocytes. PKD2 increases chylomicron size to enhance the TG secretion on the basolateral side of the mouse and human enterocytes, which is associated with decreased abundance of APOA4. PKD2 activation in intestine also correlates positively with circulating TG in obese human patients. Importantly, deletion, inactivation, or inhibition of PKD2 ameliorates high‐fat diet‐induced obesity and diabetes and improves gut microbiota profile in mice. Taken together, our findings suggest that PKD2 represents a key signaling node promoting dietary fat absorption and may serve as an attractive target for the treatment of obesity.
Nathan L Price, Leigh Goedeke, ,
Published: 3 May 2021
by EMBO
EMBO Molecular Medicine, Volume 13; doi:10.15252/emmm.202012606

Abstract:
MiRNAs have emerged as critical regulators of nearly all biologic processes and important therapeutic targets for numerous diseases. However, despite the tremendous progress that has been made in this field, many misconceptions remain among much of the broader scientific community about the manner in which miRNAs function. In this review, we focus on miR‐33, one of the most extensively studied miRNAs, as an example, to highlight many of the advances that have been made in the miRNA field and the hurdles that must be cleared to promote the development of miRNA‐based therapies. We discuss how the generation of novel animal models and newly developed experimental techniques helped to elucidate the specialized roles of miR‐33 within different tissues and begin to define the specific mechanisms by which miR‐33 contributes to cardiometabolic diseases including obesity and atherosclerosis. This review will summarize what is known about miR‐33 and highlight common obstacles in the miRNA field and then describe recent advances and approaches that have allowed researchers to provide a more complete picture of the specific functions of this miRNA.
Yujun Lin, Cheng Cui, Min Su, Lawrence K Silbart, Haiyan Liu, Jin Zhao, Lang He, Yuanmao Huang, Dexin Xu, Xiaodan Wei, et al.
Published: 3 May 2021
by EMBO
EMBO Molecular Medicine, Volume 13; doi:10.15252/emmm.202013404

Abstract:
T cell stimulatory and inhibitory molecules are critical for the regulation of immune responses. In this study, we identify a novel T cell co‐inhibitory molecule TAPBPL, whose amino acid sequence shares homology with known B7 family members. TAPBPL protein is expressed on resting and activated T cells, B cells, monocytes, and dendritic cells (DCs), as well as on some tumor tissues. The putative TAPBPL receptor is expressed on activated CD4 and CD8 T cells. A soluble recombinant human TAPBPL‐IgG Fc (hTAPBPL‐Ig) fusion protein inhibits the proliferation, activation, and cytokine production of both mouse and human T cells in vitro. In vivo administration of hTAPBPL‐Ig protein attenuates experimental autoimmune encephalomyelitis (EAE) in mice. Furthermore, an anti‐TAPBPL monoclonal antibody neutralizes the inhibitory activity of hTAPBPL‐Ig on T cells, enhances antitumor immunity, and inhibits tumor growth in animal models. Our results suggest that therapeutic intervention of the TAPBPL inhibitory pathway may represent a new strategy to modulate T cell‐mediated immunity for the treatment of cancer, infections, autoimmune diseases, and transplant rejection.
Kalliopi Sofou, Kolja Meier, Leslie E Sanderson, Debora Kaminski, Laia Montoliu‐Gaya, Emma Samuelsson, Maria Blomqvist, Lotta Agholme, Jutta Gärtner, Chris Mühlhausen, et al.
Published: 3 May 2021
by EMBO
EMBO Molecular Medicine, Volume 13; doi:10.15252/emmm.202013376

Abstract:
Lysosomal storage diseases, including mucopolysaccharidoses, result from genetic defects that impair lysosomal catabolism. Here, we describe two patients from two independent families presenting with progressive psychomotor regression, delayed myelination, brain atrophy, neutropenia, skeletal abnormalities, and mucopolysaccharidosis‐like dysmorphic features. Both patients were homozygous for the same intronic variant in VPS16, a gene encoding a subunit of the HOPS and CORVET complexes. The variant impaired normal mRNA splicing and led to an ~85% reduction in VPS16 protein levels in patient‐derived fibroblasts. Levels of other HOPS/CORVET subunits, including VPS33A, were similarly reduced, but restored upon re‐expression of VPS16. Patient‐derived fibroblasts showed defects in the uptake and endosomal trafficking of transferrin as well as accumulation of autophagosomes and lysosomal compartments. Re‐expression of VPS16 rescued the cellular phenotypes. Zebrafish with disrupted vps16 expression showed impaired development, reduced myelination, and a similar accumulation of lysosomes and autophagosomes in the brain, particularly in glia cells. This disorder resembles previously reported patients with mutations in VPS33A, thus expanding the family of mucopolysaccharidosis‐like diseases that result from mutations in HOPS/CORVET subunits.
Stefanie Weber, Christina M. Ramirez, Barbara Weiser, Harold Burger,
Published: 1 May 2021
by EMBO
EMBO Molecular Medicine; doi:10.15252/emmm.202114062

Abstract:
Scientists and the public were alarmed at the first large viral variant of SARS‐CoV2 reported in December 2020. We have followed the time course of emerging viral mutants and variants during the SARS‐CoV‐2 pandemic in ten countries on four continents. We examined > 383.500 complete SARS‐CoV‐2 nucleotide sequences in GISAID, (Global Initiative of Sharing All Influenza Data) with sampling dates extending until April 05, 2021. These sequences originated from ten different countries: United Kingdom, South Africa, Brazil, USA, India, Russia, France, Spain, Germany, and China. Among the ~180 novel mutations, some previously reported mutations waned and some of them increased in prevalence over time. VUI2012/01 (B.1.1.7) and 501Y.V2 (B.1.351), the so‐called UK and South Africa variants, respectively, and two variants from Brazil, 484K.V2, now called P.1 and P.2, increased in prevalence. Despite lockdowns, worldwide active replication in genetically and socio‐economically diverse populations facilitated selection of new mutations. The data on mutant and variant SARS‐CoV‐2 strains provided here comprise a global resource for easy access to the myriad mutations and variants detected to date globally. Rapidly evolving new variant and mutant strains might give rise to escape variants, capable of limiting the efficacy of vaccines, therapies, and diagnostic tests.
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