Terahertz Vibrational Dynamics and DFT Calculations for the Quantum Spin Chain Linarite, PbCuSO4(OH)2.

The low-dimensional quantum-magnet, linarite, PbCuS4(OH)2, has been investigated using terahertz (THz) spectroscopy coupled with detailed density functional theory (DFT) calculations in order to explore the effects of the temperature on its lattice vibrations. Linarite is characterized by largely isolated CuO chains propagating along the crystallographic b-axis, which at very low temperatures are responsible for exotic, quasi-1D magnetism in this material. To better understand the synergy between the structural bonds and lattice oscillations that contribute to these chains, polarized THz spectroscopic measurements were performed. Consolidating these results with detailed DFT calculations has revealed that the anisotropic vibrational motion for the THz modes is correlated with extreme motion associated with the crystallographic b-axis. An unexpected feature observed in the infrared spectrum is attributed to subtle lattice distortions which break the centro-symmetry in linarite at high temperatures. This phenomenon has not previously been observed in linarite and likely results from anharmonicity in lattice oscillations.

Determination of Vibrational Modes of l-Alanine Single Crystals by a Combination of Terahertz Spectroscopy Measurements and Density Functional Calculations.

Density-functional theory may be used to predict both the frequency and the dipole moment of the fundamental oscillations of molecular crystals. Suitably polarized photons at those frequencies excite such oscillations. Thus, in principle, terahertz spectroscopy may confirm the calculated fundamental modes of amino acids. However, reports to date have multiple shortcomings: (a) material of uncertain purity and morphology and diluted in a binder material is employed; (b) consequently, vibrations along all crystal axes are excited simultaneously; (c) data are restricted to room temperature, where resonances are broad and the background dominant; and (d) comparison with theory has been unsatisfactory (in part because the theory assumes zero temperature). Here, we overcome all four obstacles, in reporting detailed low-temperature polarized THz spectra of single-crystal l-alanine, assigning vibrational modes using density-functional theory, and comparing the calculated dipole moment vector direction to the electric field polarization of the measured spectra. Our direct and detailed comparison of theory with experiment corrects previous mode assignments for l-alanine, and reveals unreported modes, previously obscured by closely spaced spectral absorptions. The fundamental modes are thereby determined.

Theoretical modeling of the terahertz spectrum of l-tyrosine leads to experimental verification of previously unobserved vibrational mode.

We have calculated the theoretical terahertz spectrum of the amino acid l-tyrosine using density functional theory (DFT). We tried two electron density functionals, Perdew-Burke-Ernzerhof (PBE) and PBE-d3. PBE-d3 includes dispersion corrections to build in van der Waals interactions, which play a role in intermolecular bonding. Both DFT models predicted a low-frequency mode that has not been previously reported. We designed an experiment to search for this mode. Using a deliberately thick sample, intense synchrotron radiation, low temperatures, and temperature variation has enabled us to observe a new resonance at 1.79 ±0.01 THz. While the PBE and PBE-d3 spectra are similar and both match the low-energy experimental data, overall the PBE-d3 appears to be slightly superior. Further refinement still of the functional may lead to even better agreement with experiment above 2.4 THz.

Quantifying production losses associated with foot and mouth disease outbreaks on large-scale dairy farms in Rift valley, Kenya.

Foot and Mouth Disease (FMD) is a contagious viral disease to which dairy cattle are highly susceptible. An outbreak of FMD in a dairy herds can cause a drop in milk yield, increase mastitis infections, and force culling. These production losses can be substantial, but farmers undervalue the magnitude of the loss that they incur. The study quantified the association of FMD outbreaks with milk yield, mastitis incidences, and culling rates. The data was from three large-scale dairy farms with a recent history (2008 to 2018) of FMD outbreaks in a region endemic for the prevalence of serotype C of the FMD virus since the mid-1980s in the Rift valley of Kenya. A total of 507 cows were monitored for three consecutive periods of six weeks before, during, and after FMD outbreaks. Relative to the period before and after the disease outbreak, production losses were marked during the outbreak. A disease outbreak was associated with up to 4.7% of the cows drying off (n = 24) and milk production dropped by 16.1%. The incidence of mastitis increased from 5.4% to 21.5% (OR = 3.31, CI = 2.27, 4.83) and culling rates increased from 0.59% to 3.8% (OR = 6.71, CI = 1.99, 22.58).

Terahertz response of DL-alanine: experiment and theory.

The terahertz (THz) spectrum of dl-alanine has been measured for the first time at cryogenic temperatures and with a pure sample. Several sharp absorptions are observed, over a wide frequency range (0.8-4.8 THz), at 8 K. The sample structure and purity were confirmed with both Raman spectroscopy and X-ray diffraction. Temperature dependent spectra revealed redshifting, with increasing temperature, for all modes except one at 2.70 THz. This mode exhibits blueshifting until ≈120 K, where it starts to redshift. A Bose-Einstein distribution has been used to model the frequency shift with temperature for the four lowest energy modes. Strong correlations between the fits and data indicate that these modes are caused by phonon excitation in an anharmonic potential. Density functional theory has also been used to identify the origin of these low frequency modes. They are attributed to large scale molecular vibrations.

High-quality, temperature-dependent terahertz spectroscopy of single crystalline L-alanine: Experiment and density-functional theory.

For the first time, the terahertz transmittance spectra of l-alanine have been measured using a single crystal. Measurements were obtained over a large temperature range (12-300 K) and revealed 18 absorptions between 20 and 250 cm-1. These modes were sharp and symmetric, a feature of single crystals and low temperatures. The spectra were directly compared to those of a powdered pellet sample. Raman spectroscopy and x-ray diffraction were used to confirm the sample's structure and purity. With increasing temperature, all modes exhibit spectral redshift, well described by a Bose-Einstein model, indicating the phonon origin of the absorptions. The exceptions are the 91 and 128 cm-1 modes. The former blueshifts. The latter initially blueshifts but transitions to redshifting. Both behaviors are anomalous. Density-functional theory modeling helped assign all the observed modes.

Patient-reported outcomes with subcutaneous immunoglobulin in chronic inflammatory demyelinating polyneuropathy: the PATH study.

BACKGROUND AND PURPOSE: Chronic inflammatory demyelinating polyneuropathy (CIDP) causes weakness which adversely impacts function and quality of life (QOL). CIDP often requires long-term management with intravenous or subcutaneous immunoglobulin. The Polyneuropathy and Treatment with Hizentra® (PATH) study showed that subcutaneous immunoglobulin (SCIG) was efficacious in CIDP maintenance. Here, patient-reported outcomes in patients on SCIG are assessed. METHODS: Subjects stabilized on intravenous immunoglobulin were randomly allocated to receive weekly 0.2 or 0.4 g/kg bodyweight of 20% SCIG (IgPro20) or placebo. Overall QOL/health status was assessed using the EuroQoL 5-Dimension (EQ-5D) health profile and visual analog scale, treatment satisfaction was assessed with the Treatment Satisfaction Questionnaire for Medicine (TSQM) and work-related impact was assessed with the Work Productivity and Activity Impairment Questionnaire for General Health (WPAI-GH). The EQ-5D health profile was assessed in terms of the percentage of subjects maintained or improved at week 25 of SCIG therapy on each of the EQ-5D domains versus baseline after intravenous immunoglobulin stabilization. TSQM and WPAI-GH were assessed by median score changes from baseline to week 25. RESULTS: In total, 172 subjects were randomized to placebo (n = 57), 0.2 g/kg IgPro20 (n = 57) and 0.4 g/kg IgPro20 (n = 58). Significantly higher proportions of IgPro20-treated subjects improved/maintained their health status on the EQ-5D usual activities dimension, and in additional dimensions (mobility and pain/discomfort) in sensitivity analyses. TSQM and WPAI-GH scores were more stable with IgPro20 treatment compared with placebo. CONCLUSIONS: IgPro20 maintained or improved QOL in most subjects with CIDP, consistent with the PATH study findings that both IgPro20 doses were efficacious in maintaining CIDP.

Identifying and explaining vibrational modes of quinacridones via temperature-resolved terahertz spectroscopy: absorption experiments and solid-state density functional theory simulations.

Quinacridone and its substituted analogs are pigments widely used in art and industry. The temperature dependence of the crystal structures of two quinacridone polymorphs (ß and γ), along with the common variant 2,9-dimethylquinacridone, were investigated using powder X-ray diffraction and terahertz spectroscopy. These were then compared with solid-state density functional theory simulations of both structures and vibrations. X-ray patterns were collected at eight temperatures in the range 13-298 K and terahertz spectra at fifteen temperatures in the range 20-300 K. Simulations were at absolute zero and at appropriate expansions to model room temperature. It was found that some of the powder X-ray diffraction features in only ß-quinacridone (15.7°, 19.7° and 31.2° at 13 K) underwent anomalous shifting with temperature change. We attribute this to the unique coplanar hydrogen bonding pattern of ß-quinacridone compared to the other solids, with the unusual diffraction peaks originating from crystallographic planes perpendicular to the a axis intermolecular hydrogen bonds. This observation coincides with a contraction of the a axis with heating and results from its relatively weak N-HO hydrogen bonds and significant C-HH-C repulsions. Associated with this anomalous contraction, for ß-quinacridone only spectral peaks are seen to increase in energy with temperature.

Superficial and Fundamental Correspondences in the Terahertz/IR (6-15 THz) Absorption Spectra of Aspirin and Benzoic Acid.

The terahertz absorption spectra of aspirin and benzoic acid have been measured in the range 200-500 cm-1 (6-15 THz). Density-functional theory (DFT) modeling has assigned fundamental vibrational modes to the observed absorption bands. Hydrogen bonds between the crystalline planes of aspirin resulted in better agreement between the experimental and modeled spectra than for benzoic acid. The similar structure of these two molecules suggests a similar absorption spectrum, which indeed was obtained experimentally. However, the detailed crystal structure and molecular differences result in some of the apparently common absorption bands being assigned to different vibrational modes through the DFT modeling. Thus, our study importantly reveals that even though crystalline forms of two similar molecules may have similar experimental terahertz spectra, the resemblance may be superficial rather than fundamental.

Distinguishing Quinacridone Pigments via Terahertz Spectroscopy: Absorption Experiments and Solid-State Density Functional Theory Simulations.

Through a combined experimental and theoretical investigation we determine that the fundamental modes of three quinacridones fall in the terahertz spectral range (1-10 THz, ∼30-300 cm-1). In each spectrum the terahertz resonances correspond to wagging, rocking, or twisting of the quinacridone rings, with the most intense absorption being an in-plane rocking vibration of the carbonyl oxygens. In spite of these spectral similarities, we demonstrate that terahertz measurements readily differentiate ß-quinacridone, γ-quinacridone, and 2,9-dimethylquinacridone. The spectrum of ß-quinacridone has a group of closely spaced modes at ∼4 THz, whereas in contrast the spectrum of γ-quinacridone displays a widely spaced series of modes spread over the range ∼1-5 THz. Both of these have the strongest mode at ∼9 THz, whereas in contrast 2,9-dimethylquinacridone exhibits the strongest mode at ∼7 THz. Because quinacridones are the basis of widely used synthetic pigments of relatively recent origin, our findings offer promising applications in the identification and dating of modern art.

Terahertz spectroscopy of 2,4-dinitrotoluene over a wide temperature range (7-245 K).

Previous THz spectroscopy of the TNT explosive precursor, 2,4-dinitrotoluene (DNT), has been restricted to room temperature (apart from one set of data at 11 K). Here, for the first time, we investigate the spectrum as the temperature is systematically varied, from 7 to 245 K. Many new features appear in the spectrum on cooling below room temperature. As well as the five absorption lines observed previously, we observe five additional lines. In addition, a new room-temperature line at 8.52 THz (281 cm(-1)) is observed. Six of the lines red-shift with temperature and four of them blue-shift. The blue shift is explained by interplay between intramolecular and intermolecular hydrogen bonds. The variation in line width and line intensity with temperature is not systematic, although a conspicuous decrease in line intensity with temperature is observed in all cases. Modeling with hybrid PBE0 and TPSSh functionals helps identify absorption modes.

7th International Immunoglobulin Conference: Neurology.

Immunoglobulin (Ig) therapy has been used and studied as a treatment for a variety of neurological conditions for decades. In some of these disorders Ig therapy has a significant role as a first-line treatment. This session explores the use of Ig therapy in immune-mediated peripheral neuropathies and various central nervous system (CNS) diseases. Informative practice points relating to the management and treatment of these diseases are discussed. Potential future neurological indications for Ig therapy, as well as data on efficacy and possible mechanisms of action, are also presented. In peripheral immune-mediated neuropathies, data show good response rates to Ig therapy and it is often used as a first-line treatment. Intravenous immunoglobulin (IVIg) and subcutaneous immunoglobulin (SCIg) are both well tolerated, but dose and dosing frequency should be based on individual clinical responses. In Alzheimer's disease, although clinical data show no significant differences between IVIg and placebo, biomarker studies indicate that plasma-derived antibodies may be involved in clearance of amyloid aggregates from the brain. Data suggest that the use of high IVIg doses in early-stage Alzheimer's treatment may warrant further investigation. Ig therapy is considered a valuable option for autoimmune encephalitis, an antibody-mediated CNS disease. Combination treatment with IVIg and corticosteroids shows promising results and is proposed as a first-line treatment in these disorders. Until recently, very little was understood about the pathogenesis of chronic pain disorders. Data now indicate that perpetuation of the pain response may be underpinned by central immune activation. Some data suggest that Ig therapy may mitigate this effect, with good response rates in a number of studies, but these data need confirmation.

7th International Immunoglobulin Conference: Neurology.

Data presented demonstrate the versatility of immunoglobulin (Ig) therapy for a variety of neurological disorders with different pathogenesis and presentations. In indications where the efficacy of Ig is well established, the neurology community is striving to improve the use of this valuable and limited resource by perfecting best practice guidelines, individualizing dosing schemes and investigating combination therapies to enhance treatment benefit. The data showing the efficacy of Ig therapy in conditions such as chronic pain and autoimmune encephalitis are promising. Future challenges for Ig use in neurological disorders were also outlined. Ongoing and upcoming randomized controlled trials will be pivotal to the use of Ig in the future, by identifying responder groups and elucidating the most effective administration practices. As our understanding and use of the therapy increases, it is essential that we collect data on the effects of long-term Ig treatment in neurological conditions, of which very little currently exists.

Laser-induced oxidation kinetics of bismuth surface microdroplets on GaAsBi studied in situ by Raman microprobe analysis.

We report the cw-laser-induced oxidation of molecular-beam-epitaxy grown GaAsBi bismuth surface microdroplets investigated in situ by micro-Raman spectroscopy under ambient conditions as a function of irradiation power and time. Our results reveal the surface droplets are high-purity crystalline bismuth and the resultant Bi2O3 transformation to be ß-phase and stable at room temperature. A detailed Raman study of Bi microdroplet oxidation kinetics yields insights into the laser-induced oxidation process and offers useful real-time diagnostics. The temporal evolution of new ß-Bi2O3 Raman modes is shown to be well described by Johnson-Mehl-Avrami-Kolmogorov kinetic transformation theory and while this study limits itself to the laser-induced oxidation of GaAsBi bismuth surface droplets, the results will find application within the wider context of bismuth laser-induced oxidation and direct Raman laser processing.

Raman scattering reveals strong LO-phonon-hole-plasmon coupling in nominally undoped GaAsBi: optical determination of carrier concentration.

We report room-temperature Raman scattering studies of nominally undoped (100) GaAs1−xBix epitaxial layers exhibiting Bi-induced (p-type) longitudinal-optical-plasmon-coupled (LOPC) modes for 0.018 ≤ x ≤ 0.048. Redshifts in the GaAs-like optical modes due to alloying are evaluated and are paralleled by strong damping of the LOPC. The relative integrated Raman intensities of LO(Γ) and LOPC ALO/ALOPC are characteristic of heavily doped p-GaAs, with a remarkable near total screening of the LO(Γ) phonon (ALO/ALOPC → 0) for larger Bi concentrations. A method of spectral analysis is set out which yields estimates of hole concentrations in excess of 5×1017cm−3 and correlates with the Bi molar fraction. These findings are in general agreement with recent electrical transport measurements performed on the alloy, and while the absolute size of the hole concentrations differ, likely origins for the discrepancy are discussed. We conclude that the damped LO-phonon-hole-plasmon coupling phenomena plays a dominant role in Raman scattering from unpassivated nominally undoped GaAsBi.

Collective librations of water molecules in the crystal lattice of rubidium bromide: experiment and simulation.

Terahertz spectroscopy of RbBr reveals four prominent absorption lines at room temperature and a further 15 lines at 10 K. Via density-functional-theory (DFT) numerical modelling using the PBE0 hybrid GGA functional, all the absorptions are identified as correlated librations of water molecules in the RbBr lattice. Each libration mode is a combination of rocking, wagging and twisting motions of the water molecules. The number of libration lines and numerical modelling show that the C2v symmetry of water in RbBr is broken. Our modelling shows that the distribution of libration amplitudes and phases for different water molecules in the RbBr unit cell varies greatly between the different modes. All librational lines red-shift with increasing temperature. The rate of change for most lines is in the range 60-90 MHz K(-1) (or (2-3) × 10(-3) cm(-1) K(-1)). Two lines shift more rapidly with temperature, at rates of 240 and 300 MHz K(-1) (or (8 and 10) × 10(-3) cm(-1) K(-1)), respectively. Furthermore, the temperature dependence of the linewidth distinguishes two groups of lines. For one group, with weak linear temperature dependence of linewidth, cubic anharmonic terms in the RbBr crystal field are significant. This group is mainly associated with fully symmetric correlated librations. For the second group, with strong non-linear temperature dependence of the linewidth, quartic anharmonic terms in the RbBr crystal field are significant. However, the distribution of libration amplitudes, as well as the type of libration modes, influence the temperature dependence of the red shift, the linewidth, and the intensity, as well. Our combined experimental and theoretical investigation confirms the necessity of obtaining low-temperature data to observe all the calculated modes; moreover, the richness of detail in the temperature dependence of the data invites further modelling spanning a range of temperatures.

Bardet-Biedl syndrome is linked to DNA markers on chromosome 11q and is genetically heterogeneous.

Bardet-Biedl syndrome (BBS) is an uncommon autosomal recessive condition characterized by mental retardation, post-axial polydactylia, obesity and pigmentary retinopathy. We performed linkage analysis in 31 multiplex BBS families and report significant linkage with two markers on chromosome 11q, PYGM and AFM164zf12 (D11S913). Homogeneity testing demonstrates genetic heterogeneity within our set of families. Our data imply that a major gene, BBS1, is located on chromosome 11q, although mutations at other loci may also be associated with this phenotype.

Cloning of the gene for ocular albinism type 1 from the distal short arm of the X chromosome.

Ocular albinism type 1 (OA1) is an X-linked disorder characterized by severe impairment of visual acuity, retinal hypopigmentation and the presence of macromelanosomes. We isolated a novel transcript from the OA1 critical region in Xp22.3-22.2 which is expressed at high levels in RNA samples from retina, including the retinal pigment epithelium, and from melanoma. This gene encodes a protein of 424 amino acids displaying several putative transmembrane domains and sharing no similarities with previously identified molecules. Five intragenic deletions and a 2 bp insertion resulting in a premature stop codon were identified from DNA analysis of patients with OA1, indicating that we have identified the OA1 gene.

Mutations in MKKS cause obesity, retinal dystrophy and renal malformations associated with Bardet-Biedl syndrome.

Bardet-Biedl syndrome (BBS) is an autosomal recessive disorder predominantly characterized by obesity, retinal dystrophy, polydactyly, learning difficulties, hypogenitalism and renal malformations, with secondary features that include diabetes mellitus, endocrinological dysfunction and behavioural abnormalities. Despite an initial expectation of genetic homogeneity due to relative clinical uniformity, five BBS loci have been reported, with evidence for additional loci in the human genome; however, no genes for BBS have yet been identified. We performed a genome screen with BBS families from Newfoundland that were excluded from BBS1-5 and identified linkage with D20S189. Fine-mapping reduced the critical interval to 1.9 cM between D20S851 and D20S189, encompassing a chaperonin-like gene. Mutations in this gene were recently reported to be associated with McKusick-Kaufman syndrome (MKKS; ref. 8). Given both the mapping position and clinical similarities of these two syndromes, we screened MKKS and identified mutations in five Newfoundland and two European-American BBS pedigrees. Most are frameshift alleles that are likely to result in a non-functional protein. Our data suggest that a complete loss of function of the MKKS product, and thus an inability to fold a range of target proteins, is responsible for the clinical manifestations of BBS.

A photoreceptor cell-specific ATP-binding transporter gene (ABCR) is mutated in recessive Stargardt macular dystrophy.

Stargardt disease (STGD, also known as fundus flavimaculatus; FFM) is an autosomal recessive retinal disorder characterized by a juvenile-onset macular dystrophy, alterations of the peripheral retina, and subretinal deposition of lipofuscin-like material. A gene encoding an ATP-binding cassette (ABC) transporter was mapped to the 2-cM (centiMorgan) interval at 1p13-p21 previously shown by linkage analysis to harbour the STGD gene. This gene, ABCR, is expressed exclusively and at high levels in the retina, in rod but not cone photoreceptors, as detected by in situ hybridization. Mutational analysis of ABCR in STGD families revealed a total of 19 different mutations including homozygous mutations in two families with consanguineous parentage. These data indicate that ABCR is the causal gene of STGD/FFM.