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"Ernst, P"
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Ernst Haas : on set
This volume considers the film-stills of Ernst Haas, transgressing the borders between static photography and the moving image. Haas worked with a variety of directors from Vittorio de Sica to John Huston, Gene Kelly and Michael Cimino covering movie genres from suspense ('The Third Man';'The Train') to the Western ('The Oregon Trail'; 'Little Big Man'), and from comedy ('Miracle in Milan'; 'Love and Death') to musicals ('West Side Story'; 'Hello Dolly'). While the photographic reference system known as the film-still has existed since the birth of cinema, inherent to the genre are precisely those parameters that are essential qualities of Haas photography, and which interact in a striking manner with his images made independently of film. On the one hand, we find photographs documenting shoots and depictions of individual scenes. On the other hand, it is Haas' clear ambition to inscribe a temporal dimension into these images; to impose filmic principles into the stills which, viewed in a sequence, generate movement and narrative.
BOOK
Cryo-EM structure of human rhodopsin bound to an inhibitory G protein
G-protein-coupled receptors comprise the largest family of mammalian transmembrane receptors. They mediate numerous cellular pathways by coupling with downstream signalling transducers, including the hetrotrimeric G proteins G
s
(stimulatory) and G
i
(inhibitory) and several arrestin proteins. The structural mechanisms that define how G-protein-coupled receptors selectively couple to a specific type of G protein or arrestin remain unknown. Here, using cryo-electron microscopy, we show that the major interactions between activated rhodopsin and G
i
are mediated by the C-terminal helix of the G
i
α-subunit, which is wedged into the cytoplasmic cavity of the transmembrane helix bundle and directly contacts the amino terminus of helix 8 of rhodopsin. Structural comparisons of inactive, G
i
-bound and arrestin-bound forms of rhodopsin with inactive and G
s
-bound forms of the β
2
-adrenergic receptor provide a foundation to understand the unique structural signatures that are associated with the recognition of G
s
, G
i
and arrestin by activated G-protein-coupled receptors.
The cryo-electron microscopy structure of human rhodopsin bound to the inhibitory G
i
protein-coupled receptor provides insights into ligand–receptor–G-protein interactions.
Journal Article
Local vibrational coherences drive the primary photochemistry of vision
The role of vibrational coherence—concerted vibrational motion on the excited-state potential energy surface—in the isomerization of retinal in the protein rhodopsin remains elusive, despite considerable experimental and theoretical efforts. We revisited this problem with resonant ultrafast heterodyne-detected transient-grating spectroscopy. The enhanced sensitivity that this technique provides allows us to probe directly the primary photochemical reaction of vision with sufficient temporal and spectral resolution to resolve all the relevant nuclear dynamics of the retinal chromophore during isomerization. We observed coherent photoproduct formation on a sub-50 fs timescale, and recovered a host of vibrational modes of the retinal chromophore that modulate the transient-grating signal during the isomerization reaction. Through Fourier filtering and subsequent time-domain analysis of the transient vibrational dynamics, the excited-state nuclear motions that drive the isomerization reaction were identified, and comprise stretching, torsional and out-of-plane wagging motions about the local C
11
=C
12
isomerization coordinate.
The isomerization of the retinal chromophore of rhodopsin is the photochemical process that initiates the sense of vision. Now, heterodyne-detected transient grating spectroscopy has been used to resolve coherent vibrational dynamics during this process, helping to identify strictly local vibrational motions as the origin of the coherent surface crossing, which occurs on a sub-50-fs timescale.
Journal Article
Mechanistic insights into allosteric regulation of the A2A adenosine G protein-coupled receptor by physiological cations
Cations play key roles in regulating G-protein-coupled receptors (GPCRs), although their mechanisms are poorly understood. Here,
19
F NMR is used to delineate the effects of cations on functional states of the adenosine A
2A
GPCR. While Na
+
reinforces an inactive ensemble and a partial-agonist stabilized state, Ca
2+
and Mg
2+
shift the equilibrium toward active states. Positive allosteric effects of divalent cations are more pronounced with agonist and a G-protein-derived peptide. In cell membranes, divalent cations enhance both the affinity and fraction of the high affinity agonist-bound state. Molecular dynamics simulations suggest high concentrations of divalent cations bridge specific extracellular acidic residues, bringing TM5 and TM6 together at the extracellular surface and allosterically driving open the G-protein-binding cleft as shown by rigidity-transmission allostery theory. An understanding of cation allostery should enable the design of allosteric agents and enhance our understanding of GPCR regulation in the cellular milieu.
G protein-coupled receptors (GPCRs) are membrane receptors and are important drug targets, whose regulation by cations is poorly understood. Here authors use NMR to elucidate effects of cations on functional states of the GPCR, adenosine A
2A
receptor (A
2A
R).
Journal Article
Single-Inhaler Triple versus Dual Bronchodilator Therapy in COPD: Real-World Comparative Effectiveness and Safety
Purpose: Randomized trials report that single-inhaler triple therapy is more effective than dial bronchodilators at reducing exacerbations in patients with chronic obstructive pulmonary disease (COPD). However, this effect may have been influenced by the forced withdrawal of inhaled corticosteroids (ICS) at randomization. We used an adaptive selection new-user design to compare single-inhaler triple therapy with dial bronchodilators in real-world clinical practice. Patients and Methods: We identified a cohort of COPD patients, 40 years or older, treated during 2017-2020, from the United Kingdom's Clinical Practice Research Datalink, a real-world practice setting. ICS-naive patients initiating single- inhaler triple therapy or dual bronchodilators were compared on the incidence of COPD exacerbation and pneumonia over one year, after adjustment by propensity score weighting. Results: The cohort included 4106 new users of single-inhaler triple therapy and 29,702 of dual bronchodilators. Single-inhaler triple therapy was the first maintenance treatment in 44% of the users and 43% had no COPD exacerbations in the prior year. The adjusted hazard ratio (HR) of a first moderate or severe exacerbation with triple therapy relative to dual bronchodilators was 1.08 (95% confidence interval (CI): 1.00-1.16). Among patients with two or more prior exacerbations the HR was 0.83 (95% CI: 0.74-0.92), while for those with prior asthma diagnosis it was 0.86 (95% CI: 0.70-1.06) and with blood eosinophil count >300 cells/([micro]L it was 0.89 (95% CI: 0.76-1.05). The incidence of severe pneumonia was increased with triple therapy (HR 1.50; 95% CI: 1.29-1.75). Conclusion: In a real-world setting of COPD treatment among ICS-naive patients, thus unaffected by ICS withdrawal, single-inhaler triple therapy was not more effective than dial bronchodilators at reducing the incidence of exacerbation, except among patients with multiple exacerbations. Single-inhaler triple therapy should be initiated mainly in patients with multiple exacerbations while, for most others, dual bronchodilators are just as effective whilst avoiding the excess risk of severe pneumonias. Keywords: cohort studies, COPD exacerbation, pneumonia, propensity scores, real-world evidence
Journal Article
Crystal structure of opsin in its G-protein-interacting conformation
Opsin, the ligand-free form of the G-protein-coupled receptor rhodopsin, at low pH adopts a conformationally distinct, active G-protein-binding state known as Ops*. A synthetic peptide derived from the main binding site of the heterotrimeric G protein—the carboxy terminus of the α-subunit (GαCT)—stabilizes Ops*. Here we present the 3.2 Å crystal structure of the bovine Ops*–GαCT peptide complex. GαCT binds to a site in opsin that is opened by an outward tilt of transmembrane helix (TM) 6, a pairing of TM5 and TM6, and a restructured TM7–helix 8 kink. Contacts along the inner surface of TM5 and TM6 induce an α-helical conformation in GαCT with a C-terminal reverse turn. Main-chain carbonyl groups in the reverse turn constitute the centre of a hydrogen-bonded network, which links the two receptor regions containing the conserved E(D)RY and NPxxY(x)
5,6
F motifs. On the basis of the Ops*–GαCT structure and known conformational changes in Gα, we discuss signal transfer from the receptor to the G protein nucleotide-binding site.
Opsin and the G proteins
Rhodopsin is a light-activated G-protein-coupled receptor. Recently, Oliver Ernst and his colleagues reported the structure of opsin, its ligand-free state, at 2.9 Å resolution. Here, they describe a similar resolution crystal structure of the same protein bound to a fragment of G-protein, the C-terminus of the Gα subunit. Within the active conformation of opsin, the G-protein interaction site is reorganized and there are long-range effects on the retinal-binding site. The work suggests a mechanism by which G-proteins might be activated by G-protein-coupled receptors.
Rhodopsin is a light-activated G-protein-coupled receptor. The structure of its ligand-free state at 2.9 Å resolution was reported recently. This paper describes a similar resolution crystal structure of the same protein bound to a fragment of G-protein and suggests a mechanism by which G-proteins might be activated by G-protein-coupled receptors.
Journal Article
A psychoacoustic application for the adjustment of electrical hearing thresholds in cochlear implant patients
Fitting cochlear implants, especially the precise determination of electrical hearing thresholds, is a time-consuming and complex task for patients as well as audiologists. Aim of the study was to develop a method that enables cochlear implant (CI) patients to determine their electrical hearing thresholds precisely and independently. Applicability and impact of this method on speech perception in noise at soft speech levels were evaluated.
An adaptive psychoacoustic procedure for precise hearing threshold determination (precT) was implemented using MatLab (MathWorks) and a graphical user interface was created. Sound signals were calibrated with a CIC4-Implant-Decoder. Study design: A prospective study including 15 experienced adult cochlear implant users was conducted. Electrical hearing thresholds were determined using the automated precT procedure (auto-precT). Speech perception in noise at 50 dB SPL presentation levels was measured for three conditions: (P1) T-levels kept at the previously established T-levels; (P2) T-levels set to the hearing thresholds determined using auto-precT application; (P3) T-levels set 10 cu below the values determined with auto-precT.
All subjects were able to perform the auto-precT application independently. T-levels were altered on average by an absolute value of 10.5 cu using auto-precT. Median speech reception thresholds were significantly improved from 2.5 dB SNR (P1) to 1.6 dB SNR (P2, p = 0.02). Speech perception was lowest using the globally lowered T-levels, median 2.9 dB SNR (P3, not significant compared to P1 and P2).
The applicability of the developed auto-precT application was confirmed in the present clinical study. Patients benefited from adjusting previously established T-levels to the threshold levels determined by the auto-precT application. The integration of the application in the clinical fitting routine as well as a remote fitting software approach is recommended. Furthermore, future possibilities of auto-precT include the implementation of the application on tablets or smart phones.
Journal Article