Multimodal assessment of mitochondrial function in Parkinson's disease.

The heterogenous aetiology of Parkinson's disease is increasingly recognized; both mitochondrial and lysosomal dysfunction have been implicated. Powerful, clinically applicable tools are required to enable mechanistic stratification for future precision medicine approaches. The aim of this study was to characterize bioenergetic dysfunction in Parkinson's disease by applying a multimodal approach, combining standardized clinical assessment with midbrain and putaminal 31-phosphorus magnetic resonance spectroscopy (31P-MRS) and deep phenotyping of mitochondrial and lysosomal function in peripheral tissue in patients with recent-onset Parkinson's disease and control subjects. Sixty participants (35 patients with Parkinson's disease and 25 healthy controls) underwent 31P-MRS for quantification of energy-rich metabolites [ATP, inorganic phosphate (Pi) and phosphocreatine] in putamen and midbrain. In parallel, skin biopsies were obtained from all research participants to establish fibroblast cell lines for subsequent quantification of total intracellular ATP and mitochondrial membrane potential (MMP) as well as mitochondrial and lysosomal morphology, using high content live cell imaging. Lower MMP correlated with higher intracellular ATP (r = -0.55, P = 0.0016), higher mitochondrial counts (r = -0.72, P < 0.0001) and higher lysosomal counts (r = -0.62, P = 0.0002) in Parkinson's disease patient-derived fibroblasts only, consistent with impaired mitophagy and mitochondrial uncoupling. 31P-MRS-derived posterior putaminal Pi/ATP ratio variance was considerably greater in Parkinson's disease than in healthy controls (F-tests, P = 0.0036). Furthermore, elevated 31P-MRS-derived putaminal, but not midbrain Pi/ATP ratios (indicative of impaired oxidative phosphorylation) correlated with both greater mitochondrial (r = 0.37, P = 0.0319) and lysosomal counts (r = 0.48, P = 0.0044) as well as lower MMP in both short (r = -0.52, P = 0.0016) and long (r = -0.47, P = 0.0052) mitochondria in Parkinson's disease. Higher 31P-MRS midbrain phosphocreatine correlated with greater risk of rapid disease progression (r = 0.47, P = 0.0384). Our data suggest that impaired oxidative phosphorylation in the striatal dopaminergic nerve terminals exceeds mitochondrial dysfunction in the midbrain of patients with early Parkinson's disease. Our data further support the hypothesis of a prominent link between impaired mitophagy and impaired striatal energy homeostasis as a key event in early Parkinson's disease.

Absolute Electronic Energetics and Quantitative Work Functions of Liquids from Photoelectron Spectroscopy.

Liquid-jet photoelectron spectroscopy (LJ-PES) enabled a breakthrough in the experimental study of the electronic structure of liquid water, aqueous solutions, and volatile liquids more generally. The novelty of this technique, dating back over 25 years, lies in stabilizing a continuous, micron-diameter LJ in a vacuum environment to enable PES studies. A key quantity in PES is the most probable energy associated with vertical promotion of an electron into vacuum: the vertical ionization energy, VIE, for neutrals and cations, or vertical detachment energy, VDE, for anions. These quantities can be used to identify species, their chemical states and bonding environments, and their structural properties in solution. The ability to accurately measure VIEs and VDEs is correspondingly crucial. An associated principal challenge is the determination of these quantities with respect to well-defined energy references. Only with recently developed methods are such measurements routinely and generally viable for liquids. Practically, these methods involve the application of condensed-matter concepts to the acquisition of photoelectron (PE) spectra from liquid samples, rather than solely relying on molecular-physics treatments that have been commonly implemented since the first LJ-PES experiments. This includes explicit consideration of the traversal of electrons to and through the liquid's surface, prior to free-electron detection. Our approach to measuring VIEs and VDEs with respect to the liquid vacuum level specifically involves detecting the lowest-energy electrons emitted from the sample, which have barely enough energy to surmount the surface potential and accumulate in the low-energy tail of the liquid-phase spectrum. By applying a sufficient bias potential to the liquid sample, this low-energy spectral tail can generally be exposed, with its sharp, low-energy cutoff revealing the genuine kinetic-energy-zero in a measured spectrum, independent of any perturbing intrinsic or extrinsic potentials in the experiment. Together with a precisely known ionizing photon energy, this feature enables the straightforward determination of VIEs or VDEs, with respect to the liquid-phase vacuum level, from any PE feature of interest. Furthermore, by additionally determining solution-phase VIEs and VDEs with respect to the common equilibrated energy level in condensed matter, the Fermi level─the generally implemented reference energy in solid-state PES─solution work functions, eΦ, and liquid-vacuum surface dipole effects can be quantified. With LJs, the Fermi level can only be properly accessed by controlling unwanted surface charging and all other extrinsic potentials, which lead to energy shifts of all PE features and preclude access to accurate electronic energetics. More specifically, conditions must be engineered to minimize all undesirable potentials, while maintaining the equilibrated, intrinsic (contact) potential difference between the sample and apparatus. The establishment of these liquid-phase, accurate energy-referencing protocols importantly enables VIE and VDE determinations from near-arbitrary solutions and the quantitative distinction between bulk electronic structure and interfacial effects. We will review and exemplify these protocols for liquid water and several exemplary aqueous solutions here, with a focus on the lowest-ionization- or lowest-detachment-energy PE peaks, which importantly relate to the oxidative stabilities of aqueous-phase species.

Ultrafast Molecular Frame Quantum Tomography.

We develop and experimentally demonstrate a methodology for a full molecular frame quantum tomography (MFQT) of dynamical polyatomic systems. We exemplify this approach through the complete characterization of an electronically nonadiabatic wave packet in ammonia (NH_{3}). The method exploits both energy and time-domain spectroscopic data, and yields the lab frame density matrix (LFDM) for the system, the elements of which are populations and coherences. The LFDM fully characterizes electronic and nuclear dynamics in the molecular frame, yielding the time- and orientation-angle dependent expectation values of any relevant operator. For example, the time-dependent molecular frame electronic probability density may be constructed, yielding information on electronic dynamics in the molecular frame. In NH_{3}, we observe that electronic coherences are induced by nuclear dynamics which nonadiabatically drive electronic motions (charge migration) in the molecular frame. Here, the nuclear dynamics are rotational and it is nonadiabatic Coriolis coupling which drives the coherences. Interestingly, the nuclear-driven electronic coherence is preserved over longer timescales. In general, MFQT can help quantify entanglement between electronic and nuclear degrees of freedom, and provide new routes to the study of ultrafast molecular dynamics, charge migration, quantum information processing, and optimal control schemes.

In memory of Professor Iain Wilkinson: cognitive and neuroimaging endophenotypes in a consanguineous schizophrenia multiplex family.

BACKGROUND: Schizophrenia endophenotypes may help elucidate functional effects of genetic risk variants in multiply affected consanguineous families that segregate recessive risk alleles of large effect size. We studied the association between a schizophrenia risk locus involving a 6.1Mb homozygous region on chromosome 13q22-31 in a consanguineous multiplex family and cognitive functioning, haemodynamic response and white matter integrity using neuroimaging. METHODS: We performed CANTAB neuropsychological testing on four affected family members (all homozygous for the risk locus), ten unaffected family members (seven homozygous and three heterozygous) and ten healthy volunteers, and tested neuronal responses on fMRI during an n-back working memory task, and white matter integrity on diffusion tensor imaging (DTI) on four affected and six unaffected family members (four homozygous and two heterozygous) and three healthy volunteers. For cognitive comparisons we used a linear mixed model (Kruskal-Wallis) test, followed by posthoc Dunn's pairwise tests with a Bonferroni adjustment. For fMRI analysis, we counted voxels exceeding the p < 0.05 corrected threshold. DTI analysis was observational. RESULTS: Family members with schizophrenia and unaffected family members homozygous for the risk haplotype showed attention (p < 0.01) and working memory deficits (p < 0.01) compared with healthy controls; a neural activation laterality bias towards the right prefrontal cortex (voxels reaching p < 0.05, corrected) and observed lower fractional anisotropy in the anterior cingulate cortex and left dorsolateral prefrontal cortex. CONCLUSIONS: In this family, homozygosity at the 13q risk locus was associated with impaired cognition, white matter integrity, and altered laterality of neural activation.

Ultrafast dynamics in polymeric carbon nitride thin films probed by time-resolved EUV photoemission and UV-Vis transient absorption spectroscopy.

The ground- and excited-state electronic structures of four polymeric carbon nitride (PCN) materials have been investigated using a combination of photoemission and optical absorption spectroscopy. To establish the driving forces for photocatalytic water-splitting reactions, the ground-state data was used to produce a band diagram of the PCN materials and the triethanolamine electron scavenger, commonly implemented in water-splitting devices. The ultrafast charge-carrier dynamics of the same PCN materials were also investigated using two femtosecond-time-resolved pump-probe techniques: extreme-ultraviolet (EUV) photoemission and ultraviolet-visible (UV-Vis) transient absorption spectroscopy. The complementary combination of these surface- and bulk-sensitive methods facilitated photoinduced kinetic measurements spanning the sub-picosecond to few nanosecond time range. The results show that 400 nm (3.1 eV) excitation sequentially populates a pair of short-lived transient species, which subsequently produce two different long-lived excited states on a sub-picosecond time scale. Based on the spectro-temporal characteristics of the long-lived signals, they are assigned to singlet-exciton and charge-transfer states. The associated charge-separation efficiency was inferred to be between 65% and 78% for the different studied materials. A comparison of results from differently synthesized PCNs revealed that the early-time processes do not differ qualitatively between sample batches, but that materials of more voluminous character tend to have higher charge separation efficiencies, compared to exfoliated colloidal materials. This finding was corroborated via a series of experiments that revealed an absence of any pump-fluence dependence of the initial excited-state decay kinetics and characteristic carrier-concentration effects that emerge beyond few-picosecond timescales. The initial dynamics of the photoinduced charge carriers in the PCNs are correspondingly determined to be spatially localised in the immediate vicinity of the lattice-constituting motif, while the long-time behaviour is dominated by charge-transport and recombination processes. Suppressing the latter by confining excited species within nanoscale volumes should therefore affect the usability of PCN materials in photocatalytic devices.

Valence and Core Photoelectron Spectra of Aqueous I3- from Multi-Reference Quantum Chemistry.

The I3- molecule is known to undergo substantial structural reorganization upon solvation by a protic solvent, e.g., water. However, the details of this process are still controversially discussed in the literature. In the present study, we combined experimental and theoretical efforts to disentangle this controversy. The valence (5p), N4,5 (4d), and M4,5 (3d) edge photoelectron spectra were measured in an aqueous solution and computed using high-level multi-reference methods. Our previous publication mainly focused on obtaining reliable experimental evidence, whereas in the present article, we focused primarily on theoretical aspects. The complex electronic structure of I3- requires the inclusion of both static and dynamic correlation, e.g., via the multi-configurational perturbation theory treatment. However, the resulting photoelectron spectra appear to be very sensitive to problems with variational stability and intruder states. We attempted to obtain artifact-free spectra, allowing for a more reliable interpretation of experiments. Finally, we concluded that the 3d Photoelectron Spectrum (PES) is particularly informative, evidencing an almost linear structure with a smaller degree of bond asymmetry than previously reported.

Assessment of the Precision in Measuring Glutathione at 3 T With a MEGA-PRESS Sequence in Primary Motor Cortex and Occipital Cortex.

BACKGROUND: Glutathione (GSH) is an important brain antioxidant and a number of studies have reported its measurement by edited and nonedited localized 1 H spectroscopy techniques within a range of applications in healthy volunteers and disease states. Good test-retest reproducibility is key when assessing the efficacy of treatments aimed at modulating GSH levels within the central nervous system or when noninvasively assessing changes in GSH content over time. PURPOSE: To evaluate the intraday (in vitro and in vivo) and 1-month apart (in vivo) test-retest reproducibility of GSH measurements from GSH-edited MEGA-PRESS acquisitions at 3 T in a phantom and in the brain of a cohort of middle-aged and older healthy volunteers. STUDY TYPE: Prospective. SUBJECTS/PHANTOMS: A phantom containing physiological concentrations of GSH and metabolites with overlapping spectral signatures and 10 healthy volunteers (4 F, 6 M, 55 ± 14 years old). FIELD STRENGTH/SEQUENCE: GSH-edited spectra were acquired at 3 T using the MEGA-PRESS sequence. ASSESSMENT: The phantom was scanned twice and the healthy subjects were scanned three times (on two separate days, 1 month apart). GSH was quantified from each acquisition, with the in vivo voxels placed at the primary motor cortex (PMC) and the occipital cortex (OCC). STATISTICAL TESTS: Mean coefficients of variation (CV) were used to assess short-term (in vitro and in vivo) and longer-term (in vivo) test-retest reproducibility. RESULTS: In vitro, the CV was 2.3%. In vivo, the mean intraday CV was 3.3% in the PMC and 2.4% in the OCC, while the CVs at 1 month apart were 4.6% in the PMC and 7.8% in the OCC. DATA CONCLUSION: GSH-edited MEGA-PRESS spectroscopy allows measurement of GSH with excellent precision. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 2.

Probing the molecular structure of aqueous triiodide via X-ray photoelectron spectroscopy and correlated electron phenomena.

Liquid-microjet-based X-ray photoelectron spectroscopy was applied to aqueous triiodide solutions, I3-(aq.), to investigate the anion's valence- and core-level electronic structure, ionization dynamics, associated electron-correlation effects, and nuclear geometric structure. The roles of multi-active-electron (shake-up) ionization processes - with noted sensitivity to the solute geometric structure - were investigated through I3-(aq.) solution valence, I 4d, and I 3d core-level measurements. The experimental spectra were interpreted with the aid of simulated photoelectron spectra, built upon multi-reference ab initio electronic structure calculations associated with different I3-(aq.) molecular geometries. A comparison of the single-to-multi-active-electron ionization signal ratios extracted from the experimental and theoretical core-level photoemission spectra suggests that the ground state of the solute adopts a near-linear average geometry in aqueous solutions. This contrasts with the interpretation of time-resolved X-ray solution scattering studies, but is found to be fully consistent with the rest of the solution-phase I3-(aq.) literature. Comparing the results of low- and high-photon-energy photoemission measurements, we further suggest that the aqueous anion adopts a more asymmetric geometry at the aqueous-solution-gas interface than in the aqueous bulk.

Quantitative electronic structure and work-function changes of liquid water induced by solute.

Recent advancement in quantitative liquid-jet photoelectron spectroscopy enables the accurate determination of the absolute-scale electronic energetics of liquids and species in solution. The major objective of the present work is the determination of the absolute lowest-ionization energy of liquid water, corresponding to the 1b1 orbital electron liberation, which is found to vary upon solute addition, and depends on the solute concentration. We discuss two prototypical aqueous salt solutions, NaI(aq) and tetrabutylammonium iodide, TBAI(aq), with the latter being a strong surfactant. Our results reveal considerably different behavior of the liquid water 1b1 binding energy in each case. In the NaI(aq) solutions, the 1b1 energy increases by about 0.3 eV upon increasing the salt concentration from very dilute to near-saturation concentrations, whereas for TBAI the energy decreases by about 0.7 eV upon formation of a TBAI surface layer. The photoelectron spectra also allow us to quantify the solute-induced effects on the solute binding energies, as inferred from concentration-dependent energy shifts of the I- 5p binding energy. For NaI(aq), an almost identical I- 5p shift is found as for the water 1b1 binding energy, with a larger shift occurring in the opposite direction for the TBAI(aq) solution. We show that the evolution of the water 1b1 energy in the NaI(aq) solutions can be primarily assigned to a change of water's electronic structure in the solution bulk. In contrast, apparent changes of the 1b1 energy for TBAI(aq) solutions can be related to changes of the solution work function which could arise from surface molecular dipoles. Furthermore, for both of the solutions studied here, the measured water 1b1 binding energies can be correlated with the extensive solution molecular structure changes occurring at high salt concentrations, where in the case of NaI(aq), too few water molecules exist to hydrate individual ions and the solution adopts a crystalline-like phase. We also comment on the concentration-dependent shape of the second, 3a1 orbital liquid water ionization feature which is a sensitive signature of water-water hydrogen bond interactions.

Probing aqueous ions with non-local Auger relaxation.

Non-local analogues of Auger decay are increasingly recognized as important relaxation processes in the condensed phase. Here, we explore non-local autoionization, specifically Intermolecular Coulombic Decay (ICD), of a series of aqueous-phase isoelectronic cations following 1s core-level ionization. In particular, we focus on Na+, Mg2+, and Al3+ ions. We unambiguously identify the ICD contribution to the K-edge Auger spectrum. The different strength of the ion-water interactions is manifested by varying intensities of the respective signals: the ICD signal intensity is greatest for the Al3+ case, weaker for Mg2+, and absent for weakly-solvent-bound Na+. With the assistance of ab initio calculations and molecular dynamics simulations, we provide a microscopic understanding of the non-local decay processes. We assign the ICD signals to decay processes ending in two-hole states, delocalized between the central ion and neighbouring water. Importantly, these processes are shown to be highly selective with respect to the promoted water solvent ionization channels. Furthermore, using a core-hole-clock analysis, the associated ICD timescales are estimated to be around 76 fs for Mg2+ and 34 fs for Al3+. Building on these results, we argue that Auger and ICD spectroscopy represents a unique tool for the exploration of intra- and inter-molecular structure in the liquid phase, simultaneously providing both structural and electronic information.

Photoelectron circular dichroism in angle-resolved photoemission from liquid fenchone.

We present an experimental X-ray photoelectron circular dichroism (PECD) study of liquid fenchone at the C 1s edge. A novel setup to enable PECD measurements on a liquid microjet [Malerz et al., Rev. Sci. Instrum., 2022, 93, 015101] was used. For the C 1s line assigned to fenchone's carbonyl carbon, a non-vanishing asymmetry is found in the intensity of photoelectron spectra acquired under a fixed angle in the backward-scattering plane. This experiment paves the way towards an innovative probe of the chirality of organic/biological molecules in aqueous solution.

Loneliness and Depression among Community Older Adults during the COVID-19 Pandemic: A cross-sectional study.

BACKGROUND: Social isolation has been recommended for reducing older adults' mortality and severe cases of COVID illness. That has resulted in unavoidable consequences of mental ill-health. This study aimed to examine the impact of the COVID-19 lockdown on the development of loneliness and depression and to analyse the factors associated with these conditions among community-dwelling older adults in Jordan. METHODS: A cross-sectional survey was conducted with a random sample of 456 community older adults contacted by telephone three weeks after the first pandemic lockdown in April 2020. The study instrument included the screening three-item UCLA Loneliness Scale, the Geriatric Depression Scale, and relevant medical and functional history. RESULTS: The mean age was 72.48 ± 6.84 years, and 50.2% were women. 41.4% were lonely, and of those 62% had a positive screen for depression. The mean UCLA score was significantly higher during the lockdown than before. Loneliness was significantly associated with being unmarried, having never worked previously, and being functionally dependent. Lonely participants were 1.65 times more likely to have depression. Likewise, a previous history of depression and cognitive impairment, multimorbidity, poor self-perceived health, and concern about contracting COVID infection were significant predictors of depression. CONCLUSION: The COVID-19 pandemic has had a heavy toll on older adults' mental health, particularly those with multimorbidity, baseline functional dependence, and those with a previous history of depression and cognitive impairment. Targeting these high-risk groups is important in order to minimize loneliness, depression, and subsequent increased morbidity. Using all-inclusive language might minimize ageism and the fear of catching an infection.

Somatosensory network functional connectivity differentiates clinical pain phenotypes in diabetic neuropathy.

AIMS/HYPOTHESIS: The aim of this work was to investigate whether different clinical pain phenotypes of diabetic polyneuropathy (DPN) are distinguished by functional connectivity at rest. METHODS: This was an observational, cohort study of 43 individuals with painful DPN, divided into irritable (IR, n = 10) and non-irritable (NIR, n = 33) nociceptor phenotypes using the German Research Network of Neuropathic Pain quantitative sensory testing protocol. In-situ brain MRI included 3D T1-weighted anatomical and 6 min resting-state functional MRI scans. Subgroup differences in resting-state functional connectivity in brain regions involved with somatic (thalamus, primary somatosensory cortex, motor cortex) and non-somatic (insular and anterior cingulate cortices) pain processing were examined. Multidimensional reduction of MRI datasets was performed using a machine-learning approach to classify individuals into each clinical pain phenotype. RESULTS: Individuals with the IR nociceptor phenotype had significantly greater thalamic-insular cortex (p false discovery rate [FDR] = 0.03) and reduced thalamus-somatosensory cortex functional connectivity (p-FDR = 0.03). We observed a double dissociation such that self-reported neuropathic pain score was more associated with greater thalamus-insular cortex functional connectivity (r = 0.41; p = 0.01) whereas more severe nerve function deficits were more related to lower thalamus-somatosensory cortex functional connectivity (r = -0.35; p = 0.03). Machine-learning group classification performance to identify individuals with the NIR nociceptor phenotype achieved an accuracy of 0.92 (95% CI 0.08) and sensitivity of 90%. CONCLUSIONS/INTERPRETATION: This study demonstrates differences in functional connectivity in nociceptive processing brain regions between IR and NIR phenotypes in painful DPN. We also establish proof of concept for the utility of multimodal MRI as a biomarker for painful DPN by using a machine-learning approach to classify individuals into sensory phenotypes.

A quantum molecular movie: polyad predissociation dynamics in the VUV excited 3pσ2Σu state of NO2.

The optical formation of coherent superposition states, a wavepacket, can allow the study of zeroth-order states, the evolution of which exhibit structural and electronic changes as a function of time: this leads to the notion of a molecular movie. Intramolecular vibrational energy redistribution, due to anharmonic coupling between modes, is the molecular movie considered here. There is no guarantee, however, that the formed superposition will behave semi-classically (e.g. Gaussian wavepacket dynamics) or even as an intuitively useful zeroth-order state. Here we present time-resolved photoelectron spectroscopy (TRPES) studies of an electronically excited triatomic molecule wherein the vibrational dynamics must be treated quantum mechanically and the simple picture of population flow between coupled normal modes fails. Specifically, we report on vibronic wavepacket dynamics in the zeroth-order 3pσ2Σu Rydberg state of NO2. This wavepacket exemplifies two general features of excited state dynamics in polyatomic molecules: anharmonic multimodal vibrational coupling (forming polyads); nonadiabatic coupling between nuclear and electronic coordinates, leading to predissociation. The latter suggests that the polyad vibrational states in the zeroth-order 3p Rydberg manifold are quasi-bound and best understood to be scattering resonances. We observed a rapid dephasing of an initially prepared 'bright' valence state into the relatively long-lived 3p Rydberg state whose multimodal vibrational dynamics and decay we monitor as a function of time. Our quantum simulations, based on an effective spectroscopic Hamiltonian, describe the essential features of the multimodal Fermi resonance-driven vibrational dynamics in the 3p state. We also present evidence of polyad-specificity in the state-dependent predissociation rates, leading to free atomic and molecular fragments. We emphasize that a quantum molecular movie is required to visualize wavepacket dynamics in the 3pσ2Σu Rydberg state of NO2.

Magnetic resonance spectroscopy reveals mitochondrial dysfunction in amyotrophic lateral sclerosis.

Mitochondrial dysfunction is postulated to be central to amyotrophic lateral sclerosis (ALS) pathophysiology. Evidence comes primarily from disease models and conclusive data to support bioenergetic dysfunction in vivo in patients is currently lacking. This study is the first to assess mitochondrial dysfunction in brain and muscle in individuals living with ALS using 31P-magnetic resonance spectroscopy (MRS), the modality of choice to assess energy metabolism in vivo. We recruited 20 patients and 10 healthy age and gender-matched control subjects in this cross-sectional clinico-radiological study. 31P-MRS was acquired from cerebral motor regions and from tibialis anterior during rest and exercise. Bioenergetic parameter estimates were derived including: ATP, phosphocreatine, inorganic phosphate, adenosine diphosphate, Gibbs free energy of ATP hydrolysis (ΔGATP), phosphomonoesters, phosphodiesters, pH, free magnesium concentration, and muscle dynamic recovery constants. Linear regression was used to test for associations between brain data and clinical parameters (revised amyotrophic functional rating scale, slow vital capacity, and upper motor neuron score) and between muscle data and clinico-neurophysiological measures (motor unit number and size indices, force of contraction, and speed of walking). Evidence for primary dysfunction of mitochondrial oxidative phosphorylation was detected in the brainstem where ΔGATP and phosphocreatine were reduced. Alterations were also detected in skeletal muscle in patients where resting inorganic phosphate, pH, and phosphomonoesters were increased, whereas resting ΔGATP, magnesium, and dynamic phosphocreatine to inorganic phosphate recovery were decreased. Phosphocreatine in brainstem correlated with respiratory dysfunction and disability; in muscle, energy metabolites correlated with motor unit number index, muscle power, and speed of walking. This study provides in vivo evidence for bioenergetic dysfunction in ALS in brain and skeletal muscle, which appears clinically and electrophysiologically relevant. 31P-MRS represents a promising technique to assess the pathophysiology of mitochondrial function in vivo in ALS and a potential tool for future clinical trials targeting bioenergetic dysfunction.

Low-energy constraints on photoelectron spectra measured from liquid water and aqueous solutions.

We report on the effects of electron collision and indirect ionization processes, occurring at photoexcitation and electron kinetic energies well below 30 eV, on the photoemission spectra of liquid water. We show that the nascent photoelectron spectrum and, hence, the inferred electron binding energy can only be accurately determined if electron energies are large enough that cross sections for quasi-elastic scattering processes, such as vibrational excitation, are negligible. Otherwise, quasi-elastic scattering leads to strong, down-to-few-meV kinetic energy scattering losses from the direct photoelectron features, which manifest in severely distorted intrinsic photoelectron peak shapes. The associated cross-over point from predominant (known) electronically inelastic to quasi-elastic scattering seems to arise at surprisingly large electron kinetic energies, of approximately 10-14 eV. Concomitantly, we present evidence for the onset of indirect, autoionization phenomena (occurring via superexcited states) within a few eV of the primary and secondary ionization thresholds. These processes are inferred to compete with the direct ionization channels and primarily produce low-energy photoelectrons at photon and electron impact excitation energies below ∼15 eV. Our results highlight that vibrational inelastic electron scattering processes and neutral photoexcitation and autoionization channels become increasingly important when photon and electron kinetic energies are decreased towards the ionization threshold. Correspondingly, we show that for neat water and aqueous solutions, great care must be taken when quantitatively analyzing photoelectron spectra measured too close to the ionization threshold. Such care is essential for the accurate determination of solvent and solute ionization energies as well as photoelectron branching ratios and peak magnitudes.

Following in Emil Fischer's Footsteps: A Site-Selective Probe of Glucose Acid-Base Chemistry.

Liquid-jet photoelectron spectroscopy was applied to determine the first acid dissociation constant (pKa) of aqueous-phase glucose while simultaneously identifying the spectroscopic signature of the respective deprotonation site. Valence spectra from solutions at pH values below and above the first pKa reveal a change in glucose's lowest ionization energy upon the deprotonation of neutral glucose and the subsequent emergence of its anionic counterpart. Site-specific insights into the solution-pH-dependent molecular structure changes are also shown to be accessible via C 1s photoelectron spectroscopy. The spectra reveal a considerably lower C 1s binding energy of the carbon site associated with the deprotonated hydroxyl group. The occurrence of photoelectron spectral fingerprints of cyclic and linear glucose prior to and upon deprotonation are also discussed. The experimental data are interpreted with the aid of electronic structure calculations. Our findings highlight the potential of liquid-jet photoelectron spectroscopy to act as a site-selective probe of the molecular structures that underpin the acid-base chemistry of polyprotic systems with relevance to environmental chemistry and biochemistry.

The informalization of doctor-patient relations in a Finnish setting: New social figurations and emergent possibilities.

This article features data drawn from interviews with doctors working in the Finnish occupational health-care system. These are used to explore the value of an Eliasian approach towards interpreting and assessing the moral meanings and social dynamics of relationships between health practitioners and their patients. We attend to spiralling 'formalizing' and 'informalizing' processes and how these are operating to reconfigure doctor-patient relationships. We document some of the ways in which Finnish doctors are adapting to these processes. While data drawn from a British context suggest both doctor and patients are inclined to adopt positions of mutual distrust and hostility, by contrast we note that in this Finnish setting more concerted attempts are being made to renegotiate social roles, cultural meanings and individual responsibilities. We propose that this can be taken as an instance where informalization is accompanied by revitalized currents of formalization and new syntheses of moral codes and conduct.

The electronic structure of the aqueous permanganate ion: aqueous-phase energetics and molecular bonding studied using liquid jet photoelectron spectroscopy.

Permanganate aqueous solutions, MnO4-(aq.), were studied using liquid-micro-jet-based soft X-ray non-resonant and resonant photoelectron spectroscopy to determine valence and core-level binding energies. To identify possible differences in the energetics between the aqueous bulk and the solution-gas interface, non-resonant spectra were recorded at two different probing depths. Similar experiments were performed with different counter ions, Na+ and K+, with the two solutions yielding indistinguishable anion electron binding energies. Our resonant photoelectron spectroscopy measurements, performed near the Mn LII,III- and O K-edges, selectively probed valence charge distributions between the Mn metal center, O ligands, and first solvation shell in the aqueous bulk. Associated resonantly-enhanced solute ionisation signals revealed hybridisation of the solute constituents' atomic orbitals, including the inner valence Mn 3p and O 2s. We identified intermolecular coulombic decay relaxation processes following resonant X-ray excitation of the solute that highlight valence MnO4-(aq.)-H2O(l) electronic couplings. Furthermore, our results allowed us to infer oxidative reorganisation energies of MnO4˙(aq.) and adiabatic valence ionisation energies of MnO4-(aq.), revealing the Gibbs free energy of oxidation and permitting estimation of the vertical electron affinity of MnO4˙(aq.). Finally, the Gibbs free energy of hydration of isolated MnO4- was determined. Our results and analysis allowed a near-complete binding-energy-scaled MnO4-(aq.) molecular orbital and a valence energy level diagram to be produced for the MnO4-(aq.)/MnO4˙(aq.) system. Cumulatively, our mapping of the aqueous-phase electronic structure of MnO4- is expected to contribute to a deeper understanding of the exceptional redox properties of this widely applied aqueous transition-metal complex ion.

Threshold concepts: A portal into new ways of thinking and practising in psychiatry.

Introduction: The theory of threshold concepts conjectures that there are areas in every educational curriculum that are challenging; however, mastering these areas transform the learner's view of the subject. In psychiatry, research into threshold concepts can inform educators so that they can better support students with mastering these challenging areas.Purpose: To identify threshold concepts, we conducted semi-structured interviews with six psychiatry educators and free-text surveys with medical students. To identify avenues for improving the curriculum, we discussed with educators, ways of improving understanding and looked at different approaches to learning.Materials and methods: From our analysis of all responses, we derived three threshold concepts: Therapeutic Risk-Taking, the Biopsychosocial Model, and the Concept of Diagnosis in psychiatry. The majority of students experienced difficulties grasping these concepts and applying them in their patient interactions.Results and conclusions: Hence, we propose focused teaching activities that can help students cross these thresholds: student Balint groups exploring therapeutic risk, student Balint groups exploring the role of a psychiatrist, exposure to psychological therapies/psychotherapy skills and explicit diagnostic reasoning. These activities can be integrated into the undergraduate curriculum to help medical students develop a better understanding and appreciation of psychiatry.