The spatial and spectral structure of oscillatory networks in the brain provide a readout of the underlying neuronal function. Within and between subject variability in these networks can be highly informative but also poses a considerable analytic challenge. Here, we describe a method that simultaneously estimate spectral and spatial network structure without assumptions about either feature distorting estimation of the other. This enables analyses exploring how variability in the frequency and spatial structure of oscillatory networks might vary both across the brain and across individuals. The method performs a modal decomposition of an autoregressive model to describe the oscillatory signals present within a time-series based on their peak frequency and damping time. Moreover, an alternate mathematical formulation for the system transfer function can be written in terms of these oscillatory modes; describing the spatial topography and network structure of each component. We define a set of Spatio-Spectral Eigenmodes (SSEs) from these parameters to provide a parsimonious description of oscillatory networks. Crucially, the SSEs preserve the rich between-subject variability and are constructed without pre-averaging within specified frequency bands or limiting analyses to single channels or regions. After validating the method on simulated data, we explore the structure of whole brain oscillatory networks in eyes-open resting state MEG data from the Human Connectome Project. We are able to show a wide variability in peak frequency and network structure of alpha oscillations and reveal a distinction between occipital ‘high-frequency alpha’ and parietal ‘low-frequency alpha’. The frequency difference between occipital and parietal alpha components is present within individual participants but is partially masked by larger between subject variability; a 10Hz oscillation may represent the high-frequency occipital component in one participant and the low-frequency parietal component in another. This rich characterisation of individual neural phenotypes has the potential to enhance analyses into the relationship between neural dynamics and a person’s behavioural, cognitive or clinical state### Competing Interest StatementThe authors have declared no competing interest.

Between subject variability in the spatial and spectral structure of oscillatory networks can be highly informative but poses a considerable analytic challenge. Here, we describe a data-driven modal decomposition of a multivariate autoregressive model that simultaneously identifies oscillations by their peak frequency, damping time and network structure. We use this decomposition to define a set of Spatio-Spectral Eigenmodes (SSEs) providing a parsimonious description of oscillatory networks. We show that the multivariate system transfer function can be rewritten in these modal coordinates, and that the full transfer function is a linear superposition of all modes in the decomposition. The modal transfer function is a linear summation and therefore allows for single oscillatory signals to be isolated and analysed in terms of their spectral content, spatial distribution and network structure. We validate the method on simulated data and explore the structure of whole brain oscillatory networks in eyes-open resting state MEG data from the Human Connectome Project. We are able to show a wide between participant variability in peak frequency and network structure of alpha oscillations and show a distinction between occipital 'high-frequency alpha' and parietal 'low-frequency alpha'. The frequency difference between occipital and parietal alpha components is present within individual participants but is partially masked by larger between subject variability; a 10Hz oscillation may represent the high-frequency occipital component in one participant and the low-frequency parietal component in another. This rich characterisation of individual neural phenotypes has the potential to enhance analyses into the relationship between neural dynamics and a person's behavioural, cognitive or clinical state.

AIMS:Idiopathic pulmonary fibrosis (IPF) is a genetically mediated, age-associated, progressive form of pulmonary fibrosis characterised pathologically by a usual interstitial pneumonia (UIP) pattern of fibrosis. The UIP pattern is also found in pulmonary fibrosis attributable to clinical diagnoses other than IPF (non-IPF UIP), whose clinical course is similarly poor, suggesting common molecular drivers. This study investigates whether IPF and non-IPF UIP lungs similarly express markers of telomere dysfunction and senescence.METHODS AND RESULTS:To test whether patients with IPF and non-IPF UIP share molecular drivers, lung tissues from 169 IPF patients and 57 non-IPF UIP patients were histopathologically and molecularly compared. Histopathological changes in both IPF and non-IPF UIP patients included temporal heterogeneity, microscopic honeycombing, fibroblast foci, and dense collagen fibrosis. Non-IPF UIP lungs were more likely to have lymphocytic infiltration, non-caseating granulomas, airway-centred inflammation, or small airways disease. Telomeres were shorter in alveolar type II (AECII) cells of both IPF and non-IPF UIP lungs than in those of age-similar, unused donor, controls. Levels of molecular markers of senescence (p16 and p21) were elevated in lysates of IPF and non-IPF UIP lungs. Immunostaining localised expression of these proteins to AECII cells. The mucin 5B (MUC5B) gene promoter variant minor allele frequency was similar between IPF and non-IPF UIP patients, and MUC5B expression was similar in IPF and non-IPF UIP lungs.CONCLUSIONS:Molecular markers of telomere dysfunction and senescence are pathologically expressed in both IPF and non-IPF UIP lungs. These findings suggest that common molecular drivers may contribute to the pathogenesis of UIP-associated pulmonary fibrosis, regardless of the clinical diagnosis.

Purpose Telomere maintenance dysfunction has been implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF) and short telomere length (TL) is associated with worse survival in IPF. However, it is unknown whether telomere dysfunction is associated with pathogenesis of idiopathic nonspecific interstitial pneumonia (iNSIP). The purpose of this study was to determine whether TL is shortened in alveolar type 2 epithelial (AT2) cells of iNSIP. Methods Idiopathic NSIP were diagnosed at the University of California San Francisco and healthy control lungs were obtained from unused donor lungs. Fluorescence in situ hybridization (FISH) was performed in formalin fixed and paraffin embedded (FFPE) section of lungs. Telomeres were labeled with a telomere-Cy3 PNA probe and AT2 cells were labeled with surfactant protein C (SPC). Telomere fluorescent signal was quantified using the MetaMorph software. Results Age-matched 22 lung tissues (11 iNSIPs, 11 healthy controls) were used to measure TL. Age of the subjects ranges from 31 to 72. Representative FISH images of iNSIP and normal lungs were shown in Figure 1 (A: normal, B:iNSIP). Telomere signal had a tendency to decrease as age increase. However, there was no significant difference in TL of AT2 cells (median FISH-TL signal 11.5 vs. 13.0, p = 0.949) between iNSIP and normal lungs. Conclusion The telomere length was not shorter in the AT2 cells of iNSIP compared to healthy controls. Further study is needed to investigate the role of telomere in iNSIP.

Understanding the role of Tau protein aggregation in the pathogenesis of Alzheimer's disease is critical for the development of new Tau-based therapeutic strategies to slow or prevent dementia. We tested the hypothesis that Tau pathology is associated with functional organization of widespread neurophysiological networks. We used electro-magnetoencephalography with [18F]AV-1451 PET scanning to quantify Tau-dependent network changes. Using a graph theoretical approach to brain connectivity, we quantified nodal measures of functional segregation, centrality, and the efficiency of information transfer and tested them against levels of [18F]AV-1451. Higher Tau burden in early Alzheimer's disease was associated with a shift away from the optimal small-world organization and a more fragmented network in the beta and gamma bands, whereby parieto-occipital areas were disconnected from the anterior parts of the network. Similarly, higher Tau burden was associated with decreases in both local and global efficiency, especially in the gamma band. The results support the translational development of neurophysiological “signatures” of Alzheimer's disease, to understand disease mechanisms in humans and facilitate experimental medicine studies.

Telomere dysfunction is associated with multiple fibrotic lung processes, including chronic lung allograft dysfunction (CLAD)-the major limitation to long-term survival following lung transplantation. Although shorter donor telomere lengths are associated with an increased risk of CLAD, it is unknown whether short telomeres are a cause or consequence of CLAD pathology. Our objective was to test whether telomere dysfunction contributes to the pathologic changes observed in CLAD. Histopathologic and molecular analysis of human CLAD lungs demonstrated shortened telomeres in lung epithelial cells quantified by teloFISH, increased numbers of surfactant protein C immunoreactive type II alveolar epithelial cells, and increased expression of senescence markers (β-galactosidase, p16, p53, and p21) in lung epithelial cells. TRF1F/F (telomere repeat binding factor 1 flox/flox) mice were crossed with tamoxifen-inducible SCGB1a1-cre mice to generate SCGB1a1-creTRF1F/F mice. Following 9 months of tamoxifen-induced deletion of TRF1 in club cells, mice developed mixed obstructive and restrictive lung physiology, small airway obliteration on microcomputed tomography, a fourfold decrease in telomere length in airway epithelial cells, collagen deposition around bronchioles and adjacent lung parenchyma, increased type II aveolar epithelial cell numbers, expression of senescence-associated β-galactosidase in epithelial cells, and decreased SCGB1a1 expression in airway epithelial cells. These findings demonstrate that telomere dysfunction isolated to airway epithelial cells leads to airway-centric lung remodeling and fibrosis similar to that observed in patients with CLAD and suggest that lung epithelial cell telomere dysfunction may be a molecular driver of CLAD.

Shorter peripheral blood leukocyte (PBL) telomere length (TL) has been associated with poor outcomes in various chronic lung diseases. Whether PBL-TL is associated with survival from critical illness was tested in this study.We analysed data from a prospective observational cohort study of 937 critically ill patients at Vanderbilt University Medical Center (VUMC). PBL-TL was measured using quantitative PCR of DNA isolated from PBLs. Findings were validated in an independent cohort of 394 critically ill patients with sepsis admitted to the University of California San Francisco (UCSF).In the VUMC cohort, shorter PBL-TL was associated with worse 90-day survival (adjusted hazard ratio (aHR) 1.3, 95% CI 1.1–1.6 per 1 kb TL decrease; p=0.004); in subgroup analyses, shorter PBL-TL was associated with worse 90-day survival for patients with sepsis (aHR 1.5, 95% CI 1.2–2.0 per 1 kb TL decrease; p=0.001), but not trauma. Although not associated with development of acute respiratory distress syndrome (ARDS), among ARDS subjects, shorter PBL-TL was associated with more severe ARDS (OR 1.7, 95% CI 1.2–2.5 per 1 kb TL decrease; p=0.006). The associations of PBL-TL with survival (adjusted HR 1.6, 95% CI 1.2–2.1 per 1 kb TL decrease; p=0.003) and risk for developing severe ARDS (OR 2.5, 95% CI 1.1–6.3 per 1 kb TL decrease; p=0.044) were validated in the UCSF cohort.Short PBL-TL is strongly associated with worse survival and more severe ARDS in critically ill patients, especially patients with sepsis. These findings suggest that telomere dysfunction may contribute to outcomes from critical illness.

Journal of Labelled Compounds and RadiopharmaceuticalsVolume 61, Issue 5 p. 455-467 ABSTRACTS Abstracts of the 25th International Isotope Society (UK Group) symposium: Synthesis and applications of labelled compounds 2016 E. Aboagye, E. AboagyeSearch for more papers by this authorK. Alger, K. AlgerSearch for more papers by this authorS.J. Archibald, S.J. ArchibaldSearch for more papers by this authorN.B.A. Bakar, N.B.A. BakarSearch for more papers by this authorN. Barton, N. BartonSearch for more papers by this authorJ. Bergare, J. BergareSearch for more papers by this authorJ. Bloom, J. BloomSearch for more papers by this authorR. Bragg, R. BraggSearch for more papers by this authorB.P. Burke, B.P. BurkeSearch for more papers by this authorM.J. Burns, M.J. BurnsSearch for more papers by this authorL. Carroll, L. CarrollSearch for more papers by this authorD.G. Calatayud, D.G. CalatayudSearch for more papers by this authorC. Cawthorne, C. CawthorneSearch for more papers by this authorF. Cortezon-Tamarit, F. Cortezon-TamaritSearch for more papers by this authorC. Crean, C. CreanSearch for more papers by this authorM.P. Crump, M.P. CrumpSearch for more papers by this authorJ.R. Dilworth, J.R. DilworthSearch for more papers by this authorJ. Domarkas, J. DomarkasSearch for more papers by this authorS.B. Duckett, S.B. DuckettSearch for more papers by this authorI. Eggleston, I. EgglestonSearch for more papers by this authorC.S. Elmore, C.S. ElmoreSearch for more papers by this authorE.M. van Es, E.M. van EsSearch for more papers by this authorM. Fekete, M. FeketeSearch for more papers by this authorM. Goodwin, M. GoodwinSearch for more papers by this authorG.G.R. Green, G.G.R. GreenSearch for more papers by this authorG. Grönberg, G. GrönbergSearch for more papers by this authorC.J. Hayes, C.J. HayesSearch for more papers by this authorM.A. Hayes, M.A. HayesSearch for more papers by this authorS. Hollis, S. HollisSearch for more papers by this authorR. Hueting, R. HuetingSearch for more papers by this authorP. Ivanov, P. IvanovSearch for more papers by this authorG. Johnston, G. JohnstonSearch for more papers by this authorW.J. Kerr, W.J. KerrSearch for more papers by this authorA. Kohler, A. KohlerSearch for more papers by this authorG. Knox, G. KnoxSearch for more papers by this authorK. Lawrie, K. LawrieSearch for more papers by this authorR.E. Lee, R.E. LeeSearch for more papers by this authorW. Lewis, W. LewisSearch for more papers by this authorB. Lin, B. LinSearch for more papers by this authorW.J.S. Lockley, Corresponding Author W.J.S. Lockley w.lockley@surrey.ac.uk orcid.org/0000-0001-9667-6854 Correspondence W. J. S. Lockley, Department of Chemistry, Faculty of Engineering and Physical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UK. Email: w.lockley@surrey.ac.ukSearch for more papers by this authorE. López-Torres, E. López-TorresSearch for more papers by this authorK. Lv, K. LvSearch for more papers by this authorS. Maddocks, S. MaddocksSearch for more papers by this authorB.J. Marsh, B.J. MarshSearch for more papers by this authorA. Mendiola, A. MendiolaSearch for more papers by this authorV. Mirabello, V. MirabelloSearch for more papers by this authorC.S. Miranda, C.S. MirandaSearch for more papers by this authorP.L. Norcott, P.L. NorcottSearch for more papers by this authorD. O'Hagan, D. O'HaganSearch for more papers by this authorA.M. Olaru, A.M. OlaruSearch for more papers by this authorS.I. Pascu, S.I. PascuSearch for more papers by this authorP.J. Rayner, P.J. RaynerSearch for more papers by this authorD. Read, D. ReadSearch for more papers by this authorK. Ridge, K. RidgeSearch for more papers by this authorT. Ritter, T. RitterSearch for more papers by this authorI. Roberts, I. RobertsSearch for more papers by this authorN. Samuri, N. SamuriSearch for more papers by this authorS. Sarpaki, S. SarpakiSearch for more papers by this authorD. Somers, D. SomersSearch for more papers by this authorR. Taylor, R. TaylorSearch for more papers by this authorT. Tuttle, T. TuttleSearch for more papers by this authorJ.R. Varcoe, J.R. VarcoeSearch for more papers by this authorC.L. Willis, C.L. WillisSearch for more papers by this author E. Aboagye, E. AboagyeSearch for more papers by this authorK. Alger, K. AlgerSearch for more papers by this authorS.J. Archibald, S.J. ArchibaldSearch for more papers by this authorN.B.A. Bakar, N.B.A. BakarSearch for more papers by this authorN. Barton, N. BartonSearch for more papers by this authorJ. Bergare, J. BergareSearch for more papers by this authorJ. Bloom, J. BloomSearch for more papers by this authorR. Bragg, R. BraggSearch for more papers by this authorB.P. Burke, B.P. BurkeSearch for more papers by this authorM.J. Burns, M.J. BurnsSearch for more papers by this authorL. Carroll, L. CarrollSearch for more papers by this authorD.G. Calatayud, D.G. CalatayudSearch for more papers by this authorC. Cawthorne, C. CawthorneSearch for more papers by this authorF. Cortezon-Tamarit, F. Cortezon-TamaritSearch for more papers by this authorC. Crean, C. CreanSearch for more papers by this authorM.P. Crump, M.P. CrumpSearch for more papers by this authorJ.R. Dilworth, J.R. DilworthSearch for more papers by this authorJ. Domarkas, J. DomarkasSearch for more papers by this authorS.B. Duckett, S.B. DuckettSearch for more papers by this authorI. Eggleston, I. EgglestonSearch for more papers by this authorC.S. Elmore, C.S. ElmoreSearch for more papers by this authorE.M. van Es, E.M. van EsSearch for more papers by this authorM. Fekete, M. FeketeSearch for more papers by this authorM. Goodwin, M. GoodwinSearch for more papers by this authorG.G.R. Green, G.G.R. GreenSearch for more papers by this authorG. Grönberg, G. GrönbergSearch for more papers by this authorC.J. Hayes, C.J. HayesSearch for more papers by this authorM.A. Hayes, M.A. HayesSearch for more papers by this authorS. Hollis, S. HollisSearch for more papers by this authorR. Hueting, R. HuetingSearch for more papers by this authorP. Ivanov, P. IvanovSearch for more papers by this authorG. Johnston, G. JohnstonSearch for more papers by this authorW.J. Kerr, W.J. KerrSearch for more papers by this authorA. Kohler, A. KohlerSearch for more papers by this authorG. Knox, G. KnoxSearch for more papers by this authorK. Lawrie, K. LawrieSearch for more papers by this authorR.E. Lee, R.E. LeeSearch for more papers by this authorW. Lewis, W. LewisSearch for more papers by this authorB. Lin, B. LinSearch for more papers by this authorW.J.S. Lockley, Corresponding Author W.J.S. Lockley w.lockley@surrey.ac.uk orcid.org/0000-0001-9667-6854 Correspondence W. J. S. Lockley, Department of Chemistry, Faculty of Engineering and Physical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UK. Email: w.lockley@surrey.ac.ukSearch for more papers by this authorE. López-Torres, E. López-TorresSearch for more papers by this authorK. Lv, K. LvSearch for more papers by this authorS. Maddocks, S. MaddocksSearch for more papers by this authorB.J. Marsh, B.J. MarshSearch for more papers by this authorA. Mendiola, A. MendiolaSearch for more papers by this authorV. Mirabello, V. MirabelloSearch for more papers by this authorC.S. Miranda, C.S. MirandaSearch for more papers by this authorP.L. Norcott, P.L. NorcottSearch for more papers by this authorD. O'Hagan, D. O'HaganSearch for more papers by this authorA.M. Olaru, A.M. OlaruSearch for more papers by this authorS.I. Pascu, S.I. PascuSearch for more papers by this authorP.J. Rayner, P.J. RaynerSearch for more papers by this authorD. Read, D. ReadSearch for more papers by this authorK. Ridge, K. RidgeSearch for more papers by this authorT. Ritter, T. RitterSearch for more papers by this authorI. Roberts, I. RobertsSearch for more papers by this authorN. Samuri, N. SamuriSearch for more papers by this authorS. Sarpaki, S. SarpakiSearch for more papers by this authorD. Somers, D. SomersSearch for more papers by this authorR. Taylor, R. TaylorSearch for more papers by this authorT. Tuttle, T. TuttleSearch for more papers by this authorJ.R. Varcoe, J.R. VarcoeSearch for more papers by this authorC.L. Willis, C.L. WillisSearch for more papers by this author First published: 01 June 2017 https://doi.org/10.1002/jlcr.3523Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. 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The signal amplification by reversible exchange (SABRE) approach has been used to hyperpolarise the substrates indazole and imidazole in the presence of the co‐ligand acetonitrile through the action of the precataysts [IrCl(COD)(IMes)] and [IrCl(COD)(SIMes)]. 2H‐labelled forms of these catalysts were also examined. Our comparison of the two precatalysts [IrCl(COD)(IMes)] and [IrCl(COD)(SIMes)], coupled with 2H labelling of the N‐heterocyclic carbene and associated relaxation and polarisation field variation studies, demonstrates the critical and collective role these parameters play in controlling the efficiency of signal amplification by reversible exchange. Ultimately, with imidazole, a 700‐fold1H signal gain per proton is produced at 400 MHz, whilst for indazole, a 90‐fold increase per proton is achieved. The co‐ligand acetonitrile proved to optimally exhibit a 190‐fold signal gain per proton in these measurements, with the associated studies revealing the importance the substrate plays in controlling this value. Copyright © 2017 The Authors. Magnetic Resonance in Chemistry published by John Wiley & Sons Ltd.

Signal amplification by reversible exchange (SABRE) is shown to allow access to strongly enhanced 1 H NMR signals in a range of substrates in aqueous media. To achieve this outcome, phase-transfer catalysis is exploited, which leads to less than 1.5×10-6  mol dm-3 of the iridium catalyst in the aqueous phase. These observations reflect a compelling route to produce a saline-based hyperpolarized bolus in just a few seconds for subsequent in vivo MRI monitoring. The new process has been called catalyst separated hyperpolarization through signal amplification by reversible exchange or CASH-SABRE. We illustrate this method for the substrates pyrazine, 5-methylpyrimidine, 4,6-d2 -methyl nicotinate, 4,6-d2 -nicotinamide and pyridazine achieving 1 H signal gains of approximately 790-, 340-, 3000-, 260- and 380-fold per proton at 9.4 T at the time point at which phase separation is complete.

Abstract Nuclear magnetic resonance (NMR) and magnetic resonance imaging (MRI) suffer from low sensitivity and limited nuclear spin memory lifetimes. Although hyperpolarization techniques increase sensitivity, there is also a desire to increase relaxation times to expand the range of applications addressable by these methods. Here, we demonstrate a route to create hyperpolarized magnetization in 13C nuclear spin pairs that last much longer than normal lifetimes by storage in a singlet state. By combining molecular design and low‐field storage with para‐hydrogen derived hyperpolarization, we achieve more than three orders of signal amplification relative to equilibrium Zeeman polarization and an order of magnitude extension in state lifetime. These studies use a range of specifically synthesized pyridazine derivatives and dimethyl p‐tolyl phenyl pyridazine is the most successful, achieving a lifetime of about 190 s in low‐field, which leads to a 13C‐signal that is visible for 10 minutes.

Significance The study of molecules and materials is of great significance to both science and human welfare. The noninvasive techniques of NMR and MRI reflect two of the most important methods to study them. However, both of these approaches are insensitive, and hyperpolarization methods to improve sensitivity are needed to access new applications. The hyperpolarization approach signal amplification by reversible exchange is used to produce a signal that is 100,000 times larger than that which would be seen on a routine clinical MRI scanner under Boltzmann equilibrium conditions. By revealing the broad scope of this approach we demonstrate its potential for the future diagnostic detection of metabolites, drugs, and many other small molecules.

Telomere length (TL) decreases with cellular ageing and biological stressors. As advanced donor and recipient ages are risk factors for chronic lung allograft dysfunction (CLAD), we hypothesised that decreased age-adjusted donor TL would predict earlier onset of CLAD. Shorter donor TL was associated with increased risk of CLAD or death (HR 1.26 per 1 kb TL decrease, 95% CI 1.03 to 1.54), particularly for young donors. Recipient TL was associated with cytopenias but not CLAD. Shorter TL was also seen in airway epithelium for subjects progressing to CLAD (p=0.02). Allograft TL may contribute to CLAD pathogenesis and facilitate risk stratification.

Despite the successful use of isoniazid, rifampicin, pyrazinamide and ethambutol in the treatment of tuberculosis (TB), it is a disease of growing global concern. We illustrate here a series of methods that will dramatically improve the magnetic resonance imaging (MRI) detectability of nineteen TB-relevant agents. We note that the future probing of their uptake and distribution in vivo would be expected to significantly enhance their efficacy in disease treatment. This improvement in detectability is achieved by use of the parahydrogen based SABRE protocol in conjunction with the 2 H-labelling of key sites within their molecular structures and the 2 H-labelling of the magnetization transfer catalyst. The T1 relaxation times and polarization levels of these agents are quantified under test conditions to produce a protocol to identify structurally optimized motifs for future detection. For example, deuteration of the 6-position of a pyrazinamide analogue leads to a structural form that exhibits T1 values of 144.5 s for 5-H with up to 20 % polarization. This represents a >7-fold extension in relaxation time and almost 10-fold improvement in polarization level when compared to its unoptimized structure.

The hyperpolarisation of the 119Sn and 29Si nuclei in 5-(tributylstannyl)pyrimidine (ASn) and 5-(trimethylsilyl)pyrimidine (BSi) is achieved through their reaction with [IrCl(COD)(IMes)] (1a) or [IrCl(COD)(SIMes)] (1b) and parahydrogen via the SABRE process.

More than 4% net 1H-polarisation is created, in seconds, that is detectable for over 2 minutes.

Telomeres are short in type II alveolar epithelial cells (AECs) of patients with idiopathic pulmonary fibrosis (IPF). Whether dysfunctional telomeres contribute directly to development of lung fibrosis remains unknown. The objective of this study was to investigate whether telomere dysfunction in type II AECs, mediated by deletion of the telomere shelterin protein TRF1, leads to pulmonary fibrosis in mice (SPC-Cre TRF1fl/fl mice). Deletion of TRF1 in type II AECs for 2 weeks increased γH2AX DNA damage foci, but not histopathologic changes in the lung. Deletion of TRF1 in type II AECs for up to 9 months resulted in short telomeres and lung remodeling characterized by increased numbers of type II AECs, α-smooth muscle actin+ mesenchymal cells, collagen deposition, and accumulation of senescence-associated β-galactosidase+ lung epithelial cells. Deletion of TRF1 in collagen-expressing cells caused pulmonary edema, but not fibrosis. These results demonstrate that prolonged telomere dysfunction in type II AECs, but not collagen-expressing cells, leads to age-dependent lung remodeling and fibrosis. We conclude that telomere dysfunction in type II AECs is sufficient to cause lung fibrosis, and may be a dominant molecular defect causing IPF. SPC-Cre TRF1fl/fl mice will be useful for assessing cellular and molecular mechanisms of lung fibrosis mediated by telomere dysfunction.

[IrCl(COE)2]2 (1) reacts with pyridine (py) and H2 to form crystallographically characterized IrCl(H)2(COE)(py)2 (2). 2 undergoes py loss to form 16-electron IrCl(H)2(COE)(py) (3), with equivalent hydride ligands. When this reaction is studied with parahydrogen, 1 efficiently achieves hyperpolarization of free py (and nicotinamide, nicotine, 5-aminopyrimidine, and 3,5-lutudine) via signal amplification by reversible exchange (SABRE) and hence reflects a simple and readily available precatayst for this process. 2 reacts further over 48 h at 298 K to form crystallographically characterized (Cl)(H)(py)(μ-Cl)(μ-H)(κ-μ-NC5H4)Ir(H)(py)2 (4). This dimer is active in the hydrogen isotope exchange process that is used in radiopharmaceutical preparations. Furthermore, while [Ir(H)2(COE)(py)3]PF6 (6) forms upon the addition of AgPF6 to 2, its stability precludes its efficient involvement in SABRE.

AbstractNuclear magnetic resonance (NMR) and magnetic resonance imaging (MRI) are two extremely important techniques with applications ranging from molecular structure determination to human imaging. However, in many cases the applicability of NMR and MRI are limited by inherently poor sensitivity and insufficient nuclear spin lifetime. Here we demonstrate a cost‐efficient and fast technique that tackles both issues simultaneously. We use the signal amplification by reversible exchange (SABRE) technique to hyperpolarize the target 1H nuclei and store this polarization in long‐lived singlet (LLS) form after suitable radiofrequency (rf) pulses. Compared to the normal scenario, we achieve three orders of signal enhancement and one order of lifetime extension, leading to 1H NMR signal detection 15 minutes after the creation of the detected states. The creation of such hyperpolarized long‐lived polarization reflects an important step forward in the pipeline to see such agents used as clinical probes of disease.