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  • Post-translational Mechanisms of Host Subversion by Bacterial Effectors
    Trends Mol. Med. (IF 10.732) Pub Date : 2017-11-14
    Nichollas E. Scott, Elizabeth L. Hartland

    Bacterial effector proteins are a specialized class of secreted proteins that are translocated directly into the host cytoplasm by bacterial pathogens. Effector proteins have diverse activities and targets, and many mediate post-translational modifications of host proteins. Effector proteins offer potential in novel biotechnological and medical applications as enzymes that may modify human proteins. Here, we discuss the mechanisms used by effectors to subvert the human host through blocking, blunting, or subverting immune mechanisms. This capacity allows bacteria to control host cell function to support pathogen survival, replication and dissemination to other hosts. In addition, we highlight that knowledge of effector protein activity may be used to develop chemical inhibitors as a new approach to treat bacterial infections.

  • CD4+ T Cell Differentiation in Chronic Viral Infections: The Tfh Perspective
    Trends Mol. Med. (IF 10.732) Pub Date : 2017-11-12
    Laura A. Vella, Ramin S. Herati, E. John Wherry

    CD4+ T cells play a critical role in the response to chronic viral infections during the acute phase and in the partial containment of infections once chronic infection is established. As infection persists, the virus-specific CD4+ T cell response begins to shift in phenotype. The predominant change described in both mouse and human studies of chronic viral infection is a decrease in detectable T helper type (Th)1 responses. Some Th1 loss is due to decreased proliferative potential and decreased cytokine production in the setting of chronic antigen exposure. However, recent data suggest that Th1 dysfunction is accompanied by a shift in the differentiation pathway of virus-specific CD4+ T cells, with enrichment for cells with a T follicular helper cell (Tfh) phenotype. A Tfh-like program during chronic infection has now been identified in virus-specific CD8+ T cells as well. In this review, we discuss what is known about CD4+ T cell differentiation in chronic viral infections, with a focus on the emergence of the Tfh program and the implications of this shift with respect to Tfh function and the host–pathogen interaction.

  • Characterization, Detection, and Treatment Approaches for Homologous Recombination Deficiency in Cancer
    Trends Mol. Med. (IF 10.732) Pub Date : 2017-11-10
    Grainne M. O’Kane, Ashton A. Connor, Steven Gallinger

    Investigations of carcinogenesis have evolved from the identification of clonal driver mutations in candidate genes to the integration of large volumes of genomic and transcriptomic data revealing recurrently altered pathways and signatures of mutational processes. Inactivation of BRCA1, BRCA2, or PALB2 impairs efficient double-strand break repair (DSBR), giving rise to a spectrum of homologous recombination deficiency (HRD) cancer phenotypes. Harnessing HRD therapeutically has been promising in a number of tumors; these approaches include leveraging synthetic lethality by targeting alternative repair pathways via PARP inhibition, inducing HRD to modulate potential tumor vulnerabilities, and preventing mechanisms of drug resistance. It is therefore crucial to develop assays for accurate HRD detection and to broaden the patient population who can avail of novel treatment options.

  • Boosting Natural Killer Cell-Based Immunotherapy with Anticancer Drugs: a Perspective
    Trends Mol. Med. (IF 10.732) Pub Date : 2017-11-10
    Loredana Cifaldi, Franco Locatelli, Emiliano Marasco, Lorenzo Moretta, Vito Pistoia

    Natural killer (NK) cells efficiently recognize and kill tumor cells through several mechanisms including the expression of ligands for NK cell-activating receptors on target cells. Different clinical trials indicate that NK cell-based immunotherapy represents a promising antitumor treatment. However, tumors develop immune-evasion strategies, including downregulation of ligands for NK cell-activating receptors, that can negatively affect antitumor activity of NK cells, which either reside endogenously, or are adoptively transferred. Thus, restoration of the expression of NK cell-activating ligands on tumor cells represents a strategic therapeutic goal. As discussed here, various anticancer drugs can fulfill this task via different mechanisms. We envision that the combination of selected chemotherapeutic agents with NK cell adoptive transfer may represent a novel strategy for cancer immunotherapy.

  • Sensing the Breaks: Cytosolic Chromatin in Senescence and Cancer
    Trends Mol. Med. (IF 10.732) Pub Date : 2017-11-10
    Raffaella Di Micco

    Cellular senescence constitutes a stable growth arrest characterized by DNA damage response (DDR) activation and by the senescence-associated secretory phenotype (SASP). SASP, through its paracrine effects, stimulates the immune system for senescence eradication. Similarly, chemotherapy-treated cancers activate an interferon-mediated response to induce anti-tumor immunity. Recent studies now uncover a new role for the innate DNA sensing pathway in the recognition of cytosolic chromatin in senescence and cancer.

  • Checkpoint Blockade Plus Oncolytic Virus: A Hot Therapeutic Cancer Strategy
    Trends Mol. Med. (IF 10.732) Pub Date : 2017-11-11
    Caroline Robert

    How can we transform an immune desert into a ‘hot tumor’ that is prone to respond to anti-programmed death (PD)-1 immunotherapy? This might be possible by injecting an oncolytic virus, engineered to induce local immune stimulation, prior to anti-PD-1 therapy. A recent study demonstrated that this combination – evaluated in a Phase Ib metastatic melanoma clinical study – yields promising results.

  • Biomarker Potential of Extracellular miRNAs in Duchenne Muscular Dystrophy
    Trends Mol. Med. (IF 10.732) Pub Date : 2017-10-05
    Anna M.L. Coenen-Stass, Matthew J.A. Wood, Thomas C. Roberts

    miRNAs are small, noncoding RNAs that not only regulate gene expression within cells, but might also constitute promising extracellular biomarkers for a variety of pathologies, including the progressive muscle-wasting disorder Duchenne Muscular Dystrophy (DMD). A set of muscle-enriched miRNAs, the myomiRs (miR-1, miR-133, and miR-206) are highly elevated in the serum of patients with DMD and in dystrophin-deficient animal models. Furthermore, circulating myomiRs might be used as pharmacodynamic biomarkers, given that their levels can be restored towards wild-type levels following exon skipping therapy in dystrophic mice. The relationship between muscle pathology and extracellular myomiR release is complex, and incompletely understood. Here, we discuss current progress leading towards the clinical utility of extracellular miRNAs as putative DMD biomarkers, and their possible contribution to muscle physiology.

  • TRPV1: A Potential Therapeutic Target in Type 2 Diabetes and Comorbidities?
    Trends Mol. Med. (IF 10.732) Pub Date : 2017-11-11
    Dorte X. Gram, Jens J. Holst, Arpad Szallasi

    With an estimated 422 million affected patients worldwide in 2016, type 2 diabetes (T2D) has reached pandemic proportions and represents a major unmet medical need. T2D is a polygenic disease with a chronic, low-grade inflammatory component. Second-generation transient receptor potential vanilloid-1 (TRPV1) antagonists are potent anti-inflammatory agents with proven clinical safety. In rodent models of T2D, TRPV1 blockade was shown to halt disease progression and improve glucose metabolism. Thus, we propose that TRPV1 antagonists merit further study as novel therapeutic approaches to potentially treat T2D and its comorbidities.

  • Oxygen, Metabolism, and Regeneration: Lessons from Mice
    Trends Mol. Med. (IF 10.732) Pub Date : 2017-10-05
    Ellen Heber-Katz

    The discovery that the Murphy Roths Large (MRL) mouse strain is a fully competent, epimorphic tissue regenerator, proved that the machinery of regeneration was preserved through evolution from hydra, to salamanders, to mammals. Such concepts have allowed translation of the biology of amphibians, and their ability to regenerate, to a mammalian context. We identified the ancient hypoxia-inducible factor (HIF)-1α pathway, operating through prolyl hydroxylase domain proteins (PHDs), as a central player in mouse regeneration. Thus, the possibility of targeting PHDs or other HIF-1α modifiers to effectively recreate the amphibian regenerative state has emerged. We posit that these regenerative pathways are critical in mammals. Moreover, the current approved use of PHD inhibitors in the clinic should allow fast-track translation from mouse studies to drug-based regenerative therapy in humans.

  • Targeting Obesity and Cachexia: Identification of the GFRAL Receptor–MIC-1/GDF15 Pathway
    Trends Mol. Med. (IF 10.732) Pub Date : 2017-11-09
    Samuel N. Breit, Vicky Wang-Wei Tsai, David A. Brown

    Macrophage inhibitory cytokine-1/growth differentiation factor 15 (MIC-1/GDF15) is a divergent transforming growth factor (TGFβ) superfamily cytokine implicated in biological and disease processes including metabolism, cancer, and chronic inflammation, but whose receptor has remained elusive. Four laboratories have recently identified GFRAL, an orphan receptor of the glial-derived neurotrophic factor (GDNF) receptor α family, as the receptor for MIC-1/GDF15, signaling though the coreceptor Ret. These data identify a new systemic to central nervous system (CNS) circuit that regulates metabolism in response to stress and which could be targeted to treat both severe obesity and anorexia/cachexia syndrome.

  • NEMO Links Nuclear Factor-κB to Human Diseases
    Trends Mol. Med. (IF 10.732) Pub Date : 2017-11-08
    Gunter Maubach, Michael Naumann

    The nuclear factor (NF)-κB essential modulator (NEMO) is a key regulator in NF-κB-mediated signaling. By transmitting extracellular or intracellular signals, NEMO can control NF-κB-regulated genes. NEMO dysfunction is associated with inherited diseases such as incontinentia pigmenti (IP), ectodermal dysplasia, anhidrotic, with immunodeficiency (EDA-ID), and some cancers. We focus on molecular studies, human case reports, and mouse models emphasizing the significance of NEMO molecular interactions and modifications in health and diseases. This knowledge opens new opportunities to engineer suitable drugs that may putatively target precise NEMO functions attributable to various diseases, while leaving other functions intact, and eliminating cytotoxicity. Indeed, with the advent of novel gene editing tools such as clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein (Cas)9, treating some inherited diseases may in the long run, become a reality.

  • Inflammation and Autism: From Maternal Gut to Fetal Brain
    Trends Mol. Med. (IF 10.732) Pub Date : 2017-11-06
    Ivan Osokine, Adrian Erlebacher

    Maternal immune activation (MIA) during pregnancy is associated with an increased risk of behavioral disorders in the offspring of affected mothers. Two recent studies highlight how maternal inflammation disrupts inhibitory interneuron networks and suggest that the maternal gut microbiome may be a contributing risk factor for MIA-induced behavioral abnormalities.

  • TNFR2: A Novel Target for Cancer Immunotherapy
    Trends Mol. Med. (IF 10.732) Pub Date : 2017-10-12
    Éva S. Vanamee, Denise L. Faustman

    Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy but exhibit variable efficacy and relapse and can induce autoimmunity. Tumor necrosis factor (TNF) receptor 2 (TNFR2) is a signaling molecule found on the surface of a subset of potent regulatory T cells (Tregs) that can activate the proliferation of these cells through nuclear factor kappa B (NF-κB). TNFR2 is also abundantly expressed on the surface of many human tumors. We propose that blocking TNFR2 might target abundant TNFR2+ tumor-infiltrating Tregs and directly kill TNFR2-expressing tumors. We also posit that TNFR2 inhibitors might potentially constitute safer and more targeted alternatives to ICI cancer treatment because the expression of TNFR2 on immune cells, concentrated in the tumor microenvironment of various cancers, appears to be more selective than that of checkpoint molecules.

  • Promoting In Vitro Gametogenesis Research with a Social Understanding
    Trends Mol. Med. (IF 10.732) Pub Date : 2017-10-12
    Tetsuya Ishii, Mitinori Saitou

    Recent advances in in vitro gametogenesis (IVG), including in humans, have raised ethical concerns regarding the potential misuse and manipulation of ‘artificial embryos’. However, basic research on IVG is expected to be of immense scientific and social value provided that the ethical, legal, and social issues are carefully considered.

  • Targeting ATP-Citrate Lyase in Hyperlipidemia and Metabolic Disorders
    Trends Mol. Med. (IF 10.732) Pub Date : 2017-10-06
    Stephen L. Pinkosky, Pieter H.E. Groot, Narendra D. Lalwani, Gregory R. Steinberg

    Chronic overnutrition and a sedentary lifestyle promote imbalances in metabolism, often manifesting as risk factors for life-threating diseases such as atherosclerotic cardiovascular disease (ASCVD) and nonalcoholic fatty liver disease (NAFLD). Nucleocytosolic acetyl-coenzyme A (CoA) has emerged as a central signaling node used to coordinate metabolic adaptations in response to a changing nutritional status. ATP-citrate lyase (ACL) is the enzyme primarily responsible for the production of extramitochondrial acetyl-CoA and is thus strategically positioned at the intersection of nutrient catabolism and lipid biosynthesis. Here, we discuss recent findings from preclinical studies, as well as Mendelian and clinical randomized trials, demonstrating the importance of ACL activity in metabolism, and supporting its inhibition as a potential therapeutic approach to treating ASCVD, NAFLD, and other metabolic disorders.

  • A Maternal Functional Module in the Mammalian Oocyte-To-Embryo Transition
    Trends Mol. Med. (IF 10.732) Pub Date : 2017-10-06
    Xukun Lu, Zheng Gao, Dandan Qin, Lei Li

    Prior to zygotic genome activation, early mammalian development relies on maternal-effect genes to orchestrate the oocyte-to-embryo transition. Recently, a subcortical maternal complex (SCMC) was identified to be essential for mouse preimplantation development. The SCMC integrates multiple proteins encoded by maternal-effect genes and appears to be functionally conserved across mammalian species. In addition, mutations in human SCMC genes are associated with certain human reproductive disorders. Here, we highlight recent advances in the biology of the SCMC and propose that this complex may be a representative example of maternal functional modules in mammalian oocyte-to-embryo transition. These findings may provide further insights into the molecular regulation of mammalian early embryogenesis, with possible implications for human early embryonic development and reproduction medicine.

  • Partners in Crime: Phenolic Glycolipids and Macrophages
    Trends Mol. Med. (IF 10.732) Pub Date : 2017-09-29
    Alok Kumar Singh, William R. Bishai

    Two recent articles advance our understanding of mycobacterial pathogenesis, revealing key roles for bacterially derived phenolic glycolipids (PGLs). In leprosy, Mycobacterium leprae PGL-1 uniquely subverts local macrophages to produce neurotoxic nitric oxide (NO), leading to nerve demyelination. In a related model, Mycobacterium marinum PGL stimulates the recruitment of growth-conducive monocytes to sites of initial infection as an early immune evasion strategy.

  • NAD+ in Aging: Molecular Mechanisms and Translational Implications
    Trends Mol. Med. (IF 10.732) Pub Date : 2017-09-09
    Evandro F. Fang, Sofie Lautrup, Yujun Hou, Tyler G. Demarest, Deborah L. Croteau, Mark P. Mattson, Vilhelm A. Bohr

    The coenzyme NAD+ is critical in cellular bioenergetics and adaptive stress responses. Its depletion has emerged as a fundamental feature of aging that may predispose to a wide range of chronic diseases. Maintenance of NAD+ levels is important for cells with high energy demands and for proficient neuronal function. NAD+ depletion is detected in major neurodegenerative diseases, such as Alzheimer’s and Parkinson’s diseases, cardiovascular disease and muscle atrophy. Emerging evidence suggests that NAD+ decrements occur in various tissues during aging, and that physiological and pharmacological interventions bolstering cellular NAD+ levels might retard aspects of aging and forestall some age-related diseases. Here, we discuss aspects of NAD+ biosynthesis, together with putative mechanisms of NAD+ action against aging, including recent preclinical and clinical trials.

  • On the Whereabouts of HIV-1 Cellular Entry and Its Fusion Ports
    Trends Mol. Med. (IF 10.732) Pub Date : 2017-09-09
    G. Maria Jakobsdottir, Maro Iliopoulou, Rory Nolan, Luis Alvarez, Alex A. Compton, Sergi Padilla-Parra

    HIV-1 disseminates to diverse tissues through different cell types and establishes long-lived reservoirs. The exact cellular compartment where fusion occurs differs depending on the cell type and mode of viral transmission. This implies that HIV-1 may modulate a number of common host cell factors in different cell types. In this review, we evaluate recent advances on the host cell factors that play an important role in HIV-1 entry and fusion. New insights from restriction factors inhibiting virus–cell fusion in vitro may contribute to the development of future therapeutic interventions. Collectively, novel findings underline the need for potent, host-directed therapies that disrupt the earliest stages of the virus life cycle and preclude the emergence of resistant viral variants.

  • Targeted Immune Interventions for an HIV-1 Cure
    Trends Mol. Med. (IF 10.732) Pub Date : 2017-09-07
    Matthieu Perreau, Riddhima Banga, Giuseppe Pantaleo

    Combination antiretroviral therapy (cART) induces durable suppression of virus replication but is unable to eradicate HIV. Invariably, virus rebound follows treatment interruption and life-long cART is thus required. Advances have been made in our understanding of HIV latency, identification of HIV cell reservoirs, regulation of HIV-specific immune responses, as well as in the development of broad neutralizing antibodies and putative therapeutic vaccines. These have provided a scientific basis to explore alternative strategies that achieve durable suppression of viremia in the absence of cART, the so-called functional cure. Single intervention strategies have shown promise, albeit with limited efficacy. Consequently, a combination of interventions aiming to stimulate the immune response and prevent new rounds of viral infection and spreading may render the HIV functional cure a feasible goal.

  • Modifiers of GRN-Associated Frontotemporal Lobar Degeneration
    Trends Mol. Med. (IF 10.732) Pub Date : 2017-09-07
    Eline Wauters, Sara Van Mossevelde, Julie Van der Zee, Marc Cruts, Christine Van Broeckhoven

    Heterozygous loss-of-function (LOF) mutations in the human progranulin gene (GRN) cause frontotemporal lobar degeneration (FTLD) by a mechanism of haploinsufficiency. Patients present most frequently with frontotemporal dementia, which is the second most common neurodegenerative dementia at young age. Currently, no disease-modifying therapies are available for these patients. Stimulating GRN protein expression or inhibiting its breakdown is an obvious therapeutic strategy, and is indeed the focus of current preclinical research and clinical trials. Multiple studies have demonstrated the heterogeneity in clinical presentation and wide variability in age of onset in patients carrying a GRN LOF mutation. Recently, this heterogeneity became an opportunity to identify disease modifiers, considering that these might constitute suitable targets for developing disease-modifying or disease-delaying therapies.

  • Precision Oncology: The Road Ahead
    Trends Mol. Med. (IF 10.732) Pub Date : 2017-09-05
    Daniela Senft, Mark D.M. Leiserson, Eytan Ruppin, Ze’ev A. Ronai

    Current efforts in precision oncology largely focus on the benefit of genomics-guided therapy. Yet, advances in sequencing techniques provide an unprecedented view of the complex genetic and nongenetic heterogeneity within individual tumors. Herein, we outline the benefits of integrating genomic and transcriptomic analyses for advanced precision oncology. We summarize relevant computational approaches to detect novel drivers and genetic vulnerabilities, suitable for therapeutic exploration. Clinically relevant platforms to functionally test predicted drugs/drug combinations for individual patients are reviewed. Finally, we highlight the technological advances in single cell analysis of tumor specimens. These may ultimately lead to the development of next-generation cancer drugs, capable of tackling the hurdles imposed by genetic and phenotypic heterogeneity on current anticancer therapies.

  • Genome Engineering for Personalized Arthritis Therapeutics
    Trends Mol. Med. (IF 10.732) Pub Date : 2017-09-05
    Shaunak S. Adkar, Jonathan M. Brunger, Vincent P. Willard, Chia-Lung Wu, Charles A. Gersbach, Farshid Guilak

    Arthritis represents a family of complex joint pathologies responsible for the majority of musculoskeletal conditions. Nearly all diseases within this family, including osteoarthritis, rheumatoid arthritis, and juvenile idiopathic arthritis, are chronic conditions with few or no disease-modifying therapeutics available. Advances in genome engineering technology, most recently with CRISPR-Cas9, have revolutionized our ability to interrogate and validate genetic and epigenetic elements associated with chronic diseases such as arthritis. These technologies, together with cell reprogramming methods, including the use of induced pluripotent stem cells, provide a platform for human disease modeling. We summarize new evidence from genome-wide association studies and genomics that substantiates a genetic basis for arthritis pathogenesis. We also review the potential contributions of genome engineering in the development of new arthritis therapeutics.

  • T Cell Exhaustion: An Epigenetically Imprinted Phenotypic and Functional Makeover
    Trends Mol. Med. (IF 10.732) Pub Date : 2017-08-07
    Francesca Alfei, Dietmar Zehn

    A recent article in Cell demonstrates that the absence of a single DNA methyltransferase, Dnmt3a, prevents cytotoxic T cells from acquiring the hypofunctional or exhausted phenotype typically seen in chronic viral infections and tumors. Upon establishing a causal relationship between exhaustion-associated epigenetic changes and reduced CD8+ T cell function, the authors provided mechanistic evidence that exhaustion constitutes a specific differentiation program.

  • A Topical Solution to the Sunless Tanning Problem
    Trends Mol. Med. (IF 10.732) Pub Date : 2017-08-05
    Helen T. Michael, Glenn Merlino

    Skin cancer is the most commonly diagnosed type of cancer and is strongly associated with UV exposure and skin pigmentation. Recent advances in pharmacologic non-UV tanning methods open the possibility of preventing melanoma and non-melanoma skin cancer, especially in people who do not tan in the sun.

  • Putting Glioblastoma in Its Place: IRF3 Inhibits Invasion
    Trends Mol. Med. (IF 10.732) Pub Date : 2017-07-31
    Siobhan S. Pattwell, Eric C. Holland

    With an unsurpassed capacity for invasion into normal brain tissue, glioblastoma multiforme is the most lethal primary brain tumor. New research suggests that altering a subset of extracellular matrix factors, including interferon regulatory factor (IRF)3 and casein kinase (CK)2, may decrease the migratory potential of these aggressive tumors.

  • Dissecting Glioma Invasiveness in a 3D-Organotypic Model
    Trends Mol. Med. (IF 10.732) Pub Date : 2017-08-03
    Paolo Codega, Ingo K. Mellinghoff

    Diffuse brain infiltration by tumor cells is a hallmark of glioma. Molecular mechanisms of brain invasion are poorly understood due to the difficulty to model this process in culture. A new study published in Cell Reports developed a three-dimensional organotypic model and identified interferon regulatory factor 3 (IRF3) as repressor of glioma invasion.

  • Viral Hijacking of Formins in Neurodevelopmental Pathologies
    Trends Mol. Med. (IF 10.732) Pub Date : 2017-08-10
    Karen Racicot, Sarah VanOeveren, Art Alberts

    The 2015 Zika virus (ZIKV) outbreak caused global concern when it was determined to cause microcephaly, hearing loss, and other neurodevelopmental manifestations upon fetal exposure. Significant progress has been made in our understanding of the interactions between ZIKV and the pregnant host, but there is still a critical need to understand how ZIKV and other neurotropic viruses affect fetal neurodevelopment. Diaphanous-related formins (Diaphs) have recently been identified as microcephaly-associated proteins in humans and mice. Mutations in Diaphs affect the function of neural progenitor cells, much like prenatal viral infection. We present a novel hypothesis that viruses ‘hijack’ Diaphs in neural progenitor cells, causing autonomous differentiation and apoptosis of neural progenitor cells, which could potentially contribute to virus-associated neurological pathologies.

  • Sphingosine Kinase 1: A Potential Therapeutic Target in Pulmonary Arterial Hypertension?
    Trends Mol. Med. (IF 10.732) Pub Date : 2017-08-05
    Nigel J. Pyne, Susan Pyne

    Sphingosine kinase 1 (SphK1) knockout mice are protected against pulmonary hypertension and expression levels of the enzyme are increased in the lungs of pulmonary arterial hypertensive (PAH) patients. Moreover, sphingosine 1-phosphate can promote vascular remodeling/vasoconstriction in rodent and human pulmonary arterial smooth muscle cell models. Therefore, SphK1 might be a novel target for treatment of PAH. However, in our opinion, more refined strategies to target SphK1 are needed because this enzyme is protective against endothelial dysfunction and can become resistant to SphK1 inhibitors in vascular smooth muscle, thereby potentially limiting their effectiveness in PAH. In addition, SphK1 is involved in maladaptive hypertrophy and we propose that heart failure might be an additional direct target for therapeutic intervention with SphK1 inhibitors.

  • HSC Niche Biology and HSC Expansion Ex Vivo
    Trends Mol. Med. (IF 10.732) Pub Date : 2017-08-08
    Sachin Kumar, Hartmut Geiger

    Hematopoietic stem cell (HSC) transplantation can restore a new functional hematopoietic system in recipients in cases where the system of the recipient is not functional or for example is leukemic. However, the number of available donor HSCs is often too low for successful transplantation. Expansion of HSCs and thus HSC self-renewal ex vivo would greatly improve transplantation therapy in the clinic. In vivo, HSCs expand significantly in the niche, but establishing protocols that result in HSC expansion ex vivo remains challenging. In this review we discuss current knowledge of niche biology, the intrinsic regulators of HSC self-renewal in vivo, and introduce novel niche-informed strategies of HSC expansion ex vivo.

  • Clinical Evaluation of Ebola Virus Disease Therapeutics
    Trends Mol. Med. (IF 10.732) Pub Date : 2017-08-17
    Guodong Liu, Gary Wong, Shuo Su, Yuhai Bi, Frank Plummer, George F. Gao, Gary Kobinger, Xiangguo Qiu

    Ebola virus disease (EVD) was first described over 40 years ago, but no treatment has been approved for humans. The 2013–2016 EVD outbreak in West Africa has expedited the clinical evaluation of several candidate therapeutics that act through different mechanisms, but with mixed results. Nevertheless, these studies are important because the accumulation of clinical data and valuable experience in conducting efficacy trials under emergency circumstances will lead to better implementation of similar studies in the future. Here, we summarize the results of EVD clinical trials, focus on the discussion of factors that may have potentially impeded the effectiveness of existing candidate therapeutics, and highlight considerations that may help meet the challenges ahead in the quest to develop clinically approved drugs.

  • Current Options for Cell Therapy in Spinal Cord Injury
    Trends Mol. Med. (IF 10.732) Pub Date : 2017-08-12
    Irma Vismara, Simonetta Papa, Filippo Rossi, Gianluigi Forloni, Pietro Veglianese

    Spinal cord injury (SCI) is a complex pathology that evolves after primary acute mechanical injury, causing further damage to the spinal cord tissue that exacerbates clinical outcomes. Based on encouraging results from preclinical experiments, some cell treatments being translated into clinical practice demonstrate promising and effective improvement in sensory/motor function. Combinatorial treatments of cell and drug/biological factors have been demonstrated to be more effective than cell treatments alone. Recent advances have led to the development of biomaterials aiming to promote in situ cell delivery for SCI, together with combinatorial strategies using drugs/biomolecules to achieve a maximized multitarget approach. This review provides an overview of single and combinatorial regenerative cell treatments as well as potential delivery options to treat SCI.

  • Molecular Sensors of Blood Flow in Endothelial Cells
    Trends Mol. Med. (IF 10.732) Pub Date : 2017-08-12
    Sara Baratchi, Khashayar Khoshmanesh, Owen L. Woodman, Simon Potocnik, Karlheinz Peter, Peter McIntyre

    Mechanical stress from blood flow has a significant effect on endothelial physiology, with a key role in initiating vasoregulatory signals. Disturbances in blood flow, such as in regions of disease-associated stenosis, arterial branch points, and sharp turns, can induce proatherogenic phenotypes in endothelial cells. The disruption of vascular homeostasis as a result of endothelial dysfunction may contribute to early and late stages of atherosclerosis, the underlying cause of coronary artery disease. In-depth knowledge of the mechanobiology of endothelial cells is essential to identifying mechanosensory complexes involved in the pathogenesis of atherosclerosis. In this review, we describe different blood flow patterns and summarize current knowledge on mechanosensory molecules regulating endothelial vasoregulatory functions, with clinical implications. Such information may help in the search for novel therapeutic approaches.

  • Lung Alveolar Repair: Not All Cells Are Equal
    Trends Mol. Med. (IF 10.732) Pub Date : 2017-09-01
    Charlotte H. Dean, Clare M. Lloyd

    The lungs are capable of repair but the extent to which this occurs varies widely. Recent data indicate that, following injury, different progenitor cell populations can arise, depending on the molecular environment. In turn, these result in either normal or aberrant alveolar repair. Thus, a key question in lung regenerative medicine is how to maintain a ‘Goldilocks zone’ of repair.

  • Neoantigen Vaccines Pass the Immunogenicity Test
    Trends Mol. Med. (IF 10.732) Pub Date : 2017-08-31
    Gerald P. Linette, Beatriz M. Carreno

    Neoantigens arising from tumor-specific genomic alterations constitute authentic non-self antigens and represent a new class of targets for cancer immunotherapy. Recent reports on various vaccine platforms targeting neoantigens suggest a basis for precision therapies customized to each patient’s tumor mutational profile.

  • Neutralizing the Threat: Pan-Ebolavirus Antibodies Close the Loop
    Trends Mol. Med. (IF 10.732) Pub Date : 2017-07-08
    Chad E. Mire, Thomas W. Geisbert

    The glycoprotein (GP) of ebolaviruses participates in a critical membrane fusion process to establish infection of a cell and therefore, represents an important target of both vaccines and antivirals. The latest reports on pan-ebolavirus monoclonal antibodies in small animal models may offer promising outcomes and insight into how best to target the GP in vaccine and antiviral discovery.

  • Selective Therapeutic Intervention: A Challenge against Off-Target Effects
    Trends Mol. Med. (IF 10.732) Pub Date : 2017-07-18
    Filip Rázga, Veronika Némethová

    Despite the massive global spend on biology-driven drug discovery, tackling the issue of side effects and adverse events resulting from drug promiscuity represents a persistent challenge. Although delivering authentic medical innovations today is more complex than ever, minimization of off-target effects should be a priority.

  • Obstructive Sleep Apnea and Hallmarks of Aging
    Trends Mol. Med. (IF 10.732) Pub Date : 2017-07-21
    Laetitia S. Gaspar, Ana Rita Álvaro, Joaquim Moita, Cláudia Cavadas

    Obstructive sleep apnea (OSA) is one of the most common sleep disorders. Since aging is a risk factor for OSA development, it is expected that its prevalence will increase with the current increase in life span. In recent years, several studies have shown that OSA potentially contributes to functional decline, mainly prompted by chronic intermittent hypoxia and sleep fragmentation. Here, we propose that OSA might anticipate/aggravate aging by inducing cellular and molecular impairments that characterize the aging process, such as stem cell exhaustion, telomere attrition and epigenetic changes. We suggest that further knowledge on the impact of OSA on aging mechanisms might contribute to a better understanding of how OSA might putatively accelerate aging and aging-related diseases.

  • Recent Advances in Mitochondrial Aminoacyl-tRNA Synthetases and Disease
    Trends Mol. Med. (IF 10.732) Pub Date : 2017-07-14
    Marie Sissler, Ligia Elena González-Serrano, Eric Westhof

    Dysfunctions in mitochondria – the powerhouses of the cell – lead to several human pathologies. Because mitochondria integrate nuclear and mitochondrial genetic systems, they are richly intertwined with cellular activities. The nucleus-encoded mitochondrial aminoacyl-tRNA synthetases (mt-aaRSs) are key components of the mitochondrial translation apparatus. Mutations in these enzymes predominantly affect the central nervous system (CNS) but also target other organs. Comparable mutations in mt-aaRSs can lead to vastly diverse diseases, occurring at different stages in life, and within different tissues; this represents a confounding issue. With newer information available, we propose that the pleiotropy and tissue-specificity of mt-aaRS-associated diseases result from the molecular integration of mitochondrial translation events within the cell; namely, through specific crosstalk between the cellular program and the energy demands of the cell. We place particular focus on neuronal cells.

  • Amylin Receptor: A Potential Therapeutic Target for Alzheimer’s Disease
    Trends Mol. Med. (IF 10.732) Pub Date : 2017-07-07
    Wen Fu, Aarti Patel, Ryoichi Kimura, Rania Soudy, Jack H. Jhamandas

    Alzheimer’sdisease (AD) is a progressive neurodegenerative disorder, characterized by senile plaques constituting extracellular deposits of β-amyloid (Aβ) fibrils. Since Aβ accumulation in the brain is considered an early event preceding, by decades, cognitive dysfunction, disease-modifying treatments are aimed at facilitating clearance of this protein from the brain or ameliorating its toxic effects. Recent studies have identified the amylin receptor as a capable mediator of the deleterious actions of Aβ and furthermore, administration of amylin receptor-based peptides has been shown to improve spatial memory and learning in transgenic mouse models of AD. Here, by discussing available evidence, we posit that the amylin receptor could be considered a potential therapeutic target for AD, and present the rationale for using amylin receptor antagonists to treat this debilitating condition.

  • miRNAs in B Cell Development and Lymphomagenesis
    Trends Mol. Med. (IF 10.732) Pub Date : 2017-07-07
    Maryaline Coffre, Sergei B. Koralov

    B lymphocytes are essential for an efficient immune response against a variety of pathogens. A large fraction of hematologic malignancies is of B cell origin, suggesting that the development and activation of B cells need to be tightly regulated. In recent years, increasing evidence has emerged demonstrating that microRNAs (miRNAs) – a class of non-coding RNAs that control gene expression – are involved in the regulation of B cell development and function. We provide here an overview of the current knowledge on the role of miRNAs and their relevant targets in B cell development, B cell activation, and B cell malignant transformation.

  • Osteosarcoma: Molecular Pathogenesis and iPSC Modeling
    Trends Mol. Med. (IF 10.732) Pub Date : 2017-07-20
    Yu-Hsuan Lin, Brittany E. Jewell, Julian Gingold, Linchao Lu, Ruiying Zhao, Lisa L. Wang, Dung-Fang Lee

    Rare hereditary disorders provide unequivocal evidence of the importance of genes in human disease pathogenesis. Familial syndromes that predispose to osteosarcomagenesis are invaluable in understanding the underlying genetics of this malignancy. Recently, patient-derived induced pluripotent stem cells (iPSCs) have been successfully utilized to model Li–Fraumeni syndrome (LFS)-associated bone malignancy, demonstrating that iPSCs can serve as an in vitro disease model to elucidate osteosarcoma etiology. We provide here an overview of osteosarcoma predisposition syndromes and review recently established iPSC disease models for these familial syndromes. Merging molecular information gathered from these models with the current knowledge of osteosarcoma biology will help us to gain a deeper understanding of the pathological mechanisms underlying osteosarcomagenesis and will potentially aid in the development of future patient therapies.

  • Molecular Pathophysiology of Gout
    Trends Mol. Med. (IF 10.732) Pub Date : 2017-07-18
    Jyaysi Desai, Stefanie Steiger, Hans-Joachim Anders

    Three contradictory clinical presentations of gout have puzzled clinicians and basic scientists for some time: first, the crescendo of sterile inflammation in acute gouty arthritis; second, its spontaneous resolution, despite monosodium urate (MSU) crystal persistence in the synovium; and third, immune anergy to MSU crystal masses observed in tophaceous or visceral gout. Here, we provide an update on the molecular pathophysiology of these gout manifestations, namely, how MSU crystals can trigger the auto-amplification loop of necroinflammation underlying the crescendo of acute gouty arthritis. We also discuss new findings, such as how aggregating neutrophil extracellular traps (NETs) might drive the resolution of arthritis and how these structures, together with granuloma formation, might support immune anergy, but yet promote tissue damage and remodeling during tophaceous gout.

  • Linc-ing the Noncoding Genome to Heart Function: Beating Hypertrophy
    Trends Mol. Med. (IF 10.732) Pub Date : 2017-05-30
    Shambhabi Chatterjee, Christian Bär, Thomas Thum

    The principal event of aberrant gene expression occurs in numerous disorders and syndromes, including heart failure. LncRNAs may constitute powerful treatment targets because they intensively interact with their genetic environment, as they are important regulators of genetic networks. Recent advances on the functional roles of lncRNAs in cardiac hypertrophy are expected to usher improved therapeutic strategies.

  • The Boosting Potential of Bacteria in Cancer Immunotherapy
    Trends Mol. Med. (IF 10.732) Pub Date : 2017-06-02
    David C. Binder, Derek A. Wainwright

    Salmonella Typhimurium, engineered to express flagellin B, recently demonstrated unprecedented tumor control through a TLR-dependent mechanism. Here, we review new observations that support the potential of utilizing modified bacteria to enhance antitumor immunity. We also discuss the implications of these findings for clinical applications, including immune checkpoint blockade therapies.

  • De Novo Gene Expression Reconstruction in Space
    Trends Mol. Med. (IF 10.732) Pub Date : 2017-05-29
    Je H. Lee

    The biological function of a gene often depends on spatial context, and an atlas of transcriptional regulation could be instrumental in defining functional elements across the genome. Despite recent advances in single-cell RNA sequencing and in situ RNA imaging, fundamental barriers limit the speed, genome-wide coverage, and resolution of de novo transcriptome assembly in space. Here, I discuss potential next-generation approaches for the de novo assembly of the transcriptome in space, and propose more efficient methods of detecting long-range spatial variations in gene expression. Finally, I discuss future in situ sequencing chemistries for visualizing biological pathways and processes in tissues so that genomics technologies might be more easily applied to conditions of human health and disease.

  • Early Detection of Cancer in Blood Using Single-Cell Analysis: A Proposal
    Trends Mol. Med. (IF 10.732) Pub Date : 2017-06-03
    Alexander Krasnitz, Jude Kendall, Joan Alexander, Dan Levy, Michael Wigler

    Here, we explore the potential of single-cell genomic analysis in blood for early detection of cancer; we consider a method that screens the presence of recurrent patterns of copy number (CN) alterations using sparse single-cell sequencing. We argue for feasibility, based on in silico analysis of existing single-cell data and cancer CN profiles. Sampling procedures from existing diploid single cells can render data for a cell with any given profile. Sampling from multiple published tumor profiles can interrogate cancer clonality via an algorithm that tests the multiplicity of close pairwise similarities among single-cell cancer genomes. The majority of common solid cancers would be detectable in this manner. As any early detection method must be verifiable and actionable, we describe how further analysis of suspect cells can aid in determining risk and anatomic origin. Future affordability rests on currently available procedures for tumor cell enrichment and inexpensive methods for single-cell analysis.

  • Uterine Fluid in Pregnancy: A Biological and Clinical Outlook
    Trends Mol. Med. (IF 10.732) Pub Date : 2017-06-22
    Ying Zhang, Qiang Wang, Hongmei Wang, Enkui Duan

    Once considered a simple medium for sperm and embryo transport, the functional spectrum of uterine fluid is now expanding. Novel molecular players, such as extracellular vesicles and mobile RNAs, have been detected in the uterine fluid of livestock, rodents, and humans. These novel molecules, together with previously known ions and proteins, ensure uterine fluid homeostasis and facilitate embryo–maternal interactions. Here, we propose that these molecules may also carry information that mirrors maternal environmental exposure and possibly relay such information to the embryo via uterine fluid, generating long-term epigenetic effects on the offspring via embryonic and placental programming. Moreover, the development of systematic profiling of uterine fluid molecular signatures may now hold promise, relying on high-throughput methods and non-invasive biomarkers for clinical use.

  • Pathogenesis of Human Systemic Lupus Erythematosus: A Cellular Perspective
    Trends Mol. Med. (IF 10.732) Pub Date : 2017-06-13
    Vaishali R. Moulton, Abel Suarez-Fueyo, Esra Meidan, Hao Li, Masayuki Mizui, George C. Tsokos

    Systemic lupus erythematosus (SLE) is a chronic autoimmune disease affecting multiple organs. A complex interaction of genetics, environment, and hormones leads to immune dysregulation and breakdown of tolerance to self-antigens, resulting in autoantibody production, inflammation, and destruction of end-organs. Emerging evidence on the role of these factors has increased our knowledge of this complex disease, guiding therapeutic strategies and identifying putative biomarkers. Recent findings include the characterization of genetic/epigenetic factors linked to SLE, as well as cellular effectors. Novel observations have provided an improved understanding of the contribution of tissue-specific factors and associated damage, T and B lymphocytes, as well as innate immune cell subsets and their corresponding abnormalities. The intricate web of involved factors and pathways dictates the adoption of tailored therapeutic approaches to conquer this disease.

  • Exosomes as Reconfigurable Therapeutic Systems
    Trends Mol. Med. (IF 10.732) Pub Date : 2017-06-22
    R. Steven Conlan, Simone Pisano, Marta I. Oliveira, Mauro Ferrari, Inês Mendes Pinto

    Historically, small molecules, including steroid hormones and cytokines, have been attributed a role in paracrine and endocrine signaling, and now include a new player: biological nanoparticles, or ‘exosomes’. Generated intracellularly, and defined simply as nanoparticulate packages of signaling moieties, exosomes have emerged as vehicles for highly specialized local and distant intercellular communication. Exosomes are increasingly being recognized as contributing factors in many diseases, and their potential as biomarkers and in therapeutics is rapidly emerging. This review highlights recent advances in the exploitation of exosomes in diagnostic and therapeutic applications. We discuss various facets of nanoparticles, namely the isolation and manipulation of exosomes, the construction of synthetic exosome-like particles in vivo, and their potential use in the treatment of various diseases.

  • Biomarkers of Human Pluripotent Stem Cell-Derived Cardiac Lineages
    Trends Mol. Med. (IF 10.732) Pub Date : 2017-05-30
    Rhys J.P. Skelton, Timothy J. Kamp, David A. Elliott, Reza Ardehali

    Human pluripotent stem cells (hPSCs) offer a practical source for the de novo generation of cardiac tissues and a unique opportunity to investigate cardiovascular lineage commitment. Numerous strategies have focused on the in vitro production of cardiomyocytes, smooth muscle, and endothelium from hPSCs. However, these differentiation protocols often yield undesired cell types. Thus, establishing a set of stage-specific markers for pure cardiac subpopulations will assist in defining the hierarchy of cardiac differentiation, aid in the development of cellular therapy, and facilitate drug screening and disease modeling. The recent characterization of many such markers is enabling the isolation of major cardiac lineages and subpopulations from differentiating hPSCs. We provide here a comprehensive review detailing the suite of biomarkers used to differentiate cardiac lineages from mixed hPSC-derived populations.

  • A CRISPR Approach to Neurodegenerative Diseases
    Trends Mol. Med. (IF 10.732) Pub Date : 2017-05-04
    Martin Kampmann

    A major barrier to developing effective therapies for neurodegenerative diseases is our incomplete understanding of the underlying cellular mechanisms. Genetic screens in human-induced pluripotent stem cell-derived neurons can elucidate such mechanisms. Genome-wide screens using CRISPR interference and CRISPR activation provide complementary biological insights and may reveal potential therapeutic targets.

  • Should We Stop Saying ‘Glia’ and ‘Neuroinflammation’?
    Trends Mol. Med. (IF 10.732) Pub Date : 2017-05-09
    Roser Masgrau, Carmen Guaza, Richard M. Ransohoff, Elena Galea

    Central nervous system (CNS) therapeutics based on the theoretical framework of neuroinflammation have only barely succeeded. We argue that a problem may be the wrong use of the term ‘neuroinflammation’ as a distinct nosological entity when, based on recent evidence, it may not explain CNS disease pathology. Indeed, the terms ‘neuroinflammation’ and ‘glia’ could be obsolete. First, unbiased molecular profiling of CNS cell populations and individual cells reveals striking phenotypic heterogeneity in health and disease. Second, astrocytes, microglia, oligodendrocytes, and NG2 cells may contribute to higher-brain functions by performing actions beyond housekeeping. We propose that CNS diseases be viewed as failed circuits caused in part by disease-specific dysfunction of cells traditionally called ‘glia’, and hence, favor therapies promoting their functional recovery.

  • Pathophysiology of TFII-I: Old Guard Wearing New Hats
    Trends Mol. Med. (IF 10.732) Pub Date : 2017-04-28
    Ananda L. Roy

    The biochemical properties of the signal-induced multifunctional transcription factor II-I (TFII-I) indicate that it is involved in a variety of gene regulatory processes. Although gene ablation in murine models and cell-based assays show that it is encoded by an essential gene, GTF2I/Gtf2i, its physiologic role in human disorders was relatively unknown until recently. Novel studies show that it is involved in an array of human diseases including neurocognitive disorders, systemic lupus erythematosus (SLE), and cancer. Here I bring together these diverse observations to illustrate its multiple pathophysiologic functions and further conjecture on how these could be related to its known biochemical properties. I expect that a better understanding of these ‘structure–function’ relationships would lead to future diagnostic and/or therapeutic potential.

  • TREM2, Microglia, and Neurodegenerative Diseases
    Trends Mol. Med. (IF 10.732) Pub Date : 2017-04-22
    Felix L. Yeh, David V. Hansen, Morgan Sheng

    Alzheimer’s disease (AD) is the most common form of dementia and the 6th leading cause of death in the US. The neuropathological hallmarks of the disease are extracellular amyloid-β (Aβ) plaques and intraneuronal hyperphosphorylated tau aggregates. Genetic variants of TREM2 (triggering receptor expressed on myeloid cells 2), a cell-surface receptor expressed selectively in myeloid cells, greatly increase the risk of AD, implicating microglia and the innate immune system as pivotal factors in AD pathogenesis. Recent studies have advanced our understanding of TREM2 biology and microglial activities in aging and neurodegenerative brains, providing new insights into TREM2 functions in amyloid plaque maintenance, microglial envelopment of plaque, microglia viability, and the identification of novel TREM2 ligands. Our increased understanding of TREM2 and microglia has opened new avenues for therapeutic intervention to delay or prevent the progression of AD.

  • The Exceptional Vulnerability of Humans to Alzheimer’s Disease
    Trends Mol. Med. (IF 10.732) Pub Date : 2017-05-05
    Lary C. Walker, Mathias Jucker

    Like many humans, non-human primates deposit copious misfolded Aβ protein in the brain as they age. Nevertheless, the complete behavioral and pathologic phenotype of Alzheimer’s disease, including Aβ plaques, neurofibrillary (tau) tangles, and dementia, has not yet been identified in a non-human species. Recent research suggests that the crucial link between Aβ aggregation and tauopathy is somehow disengaged in aged monkeys. Understanding why Alzheimer’s disease fails to develop in species that are biologically proximal to humans could disclose new therapeutic targets in the chain of events leading to neurodegeneration and dementia.

  • Emerging Role for Methylation in Multiple Sclerosis: Beyond DNA
    Trends Mol. Med. (IF 10.732) Pub Date : 2017-05-04
    Lindsay M. Webb, Mireia Guerau-de-Arellano

    Multiple Sclerosis (MS) is a chronic inflammatory disease of the central nervous system. The inflammatory and neurodegenerative pathways driving MS are modulated by DNA, lysine, and arginine methylation, as evidenced by studies made possible by novel tools for methylation detection or loss of function. We present evidence that MS is associated with genetic variants and metabolic changes that impact on methylation. Further, we comprehensively review current understanding of how methylation can impact on central nervous system (CNS) resilience and neuroregenerative potential, as well as inflammatory versus regulatory T helper (Th) cell balance. These findings are discussed in the context of therapeutic relevance for MS, with broad implications in other neurologic and immune-mediated diseases.

  • Single-Cell RNA Sequencing: Unraveling the Brain One Cell at a Time
    Trends Mol. Med. (IF 10.732) Pub Date : 2017-05-10
    Dimitry Ofengeim, Nikolaos Giagtzoglou, Dann Huh, Chengyu Zou, Junying Yuan

    Single-cell RNA sequencing (scRNA-seq) is an exciting new technology allowing the analysis of transcriptomes from individual cells, and is ideally suited to address the inherent complexity and dynamics of the central nervous system. scRNA-seq has already been applied to the study of molecular taxonomy of the brain. These works have paved the way to expanding our understanding of the nervous system and provide insights into cellular susceptibilities and molecular mechanisms in neurological and neurodegenerative diseases. We discuss recent progress and challenges in applying this technology to advance our understanding of the brain. We advocate the application of scRNA-seq in the discovery of targets and biomarkers as a new approach in developing novel therapeutics for the treatment of neurodegenerative diseases.

  • KRAS Allelic Imbalance: Strengths and Weaknesses in Numbers
    Trends Mol. Med. (IF 10.732) Pub Date : 2017-03-31
    Gary J. Doherty, Emma M. Kerr, Carla P. Martins

    The identification of therapeutic vulnerabilities in mutant KRAS tumors has proven difficult to achieve. Burgess and colleagues recently reported in Cell that mutant/wild-type Kras allelic dosage determines clonal fitness and MEK inhibitor sensitivity in a leukemia model, demonstrating that KRAS allelic imbalance is likely an important and overlooked variable.

  • Microbial Tuning of the Mammalian Immune System
    Trends Mol. Med. (IF 10.732) Pub Date : 2017-03-31
    Eric G. Pamer

    Bacterial species constituting the intestinal microbiota are implicated in maintenance of health but also pathogenesis of inflammatory disease. The compositional complexity of the microbiota and metabolic interdependencies of microbial species challenge our ability to attribute host responses to specific bacterial strains. Studies using gnotobiotic mice, however, are providing important insights.

Some contents have been Reproduced with permission of the American Chemical Society.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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