Modulating the isotopic hydrogen-deuterium exchange in functionalized nanocellulose to optimize SANS contrast.

Contrast matching by isotopic exchange in cellulose allows visualizing functional groups, biomolecules, polymers and nanoparticles embedded in cellulosic composites. This isotopic exchange varies the scattering length density of cellulose to match its contrast with the background network. Here, contrast matching of microcrystalline-cellulose (MCC) and the functionalized nanocellulose-fiber (CNF) and cellulose nanocrystals (CNC) are elucidated by small angle neutron scattering (SANS). Results show no isotopic exchange occurs for the CNF surface functionalized with carboxyl nor for the CNC-High with a high sulfate groups concentration. Both CNC-Low, with low sulfate groups, and MCC exchange 1H with 1D in D2O. This is due to the high exchange probability of the labile C6 position primary -OH group. The structure of thermo-responsive poly-N-isopropylacrylamide (PNIPAM) chains grafted onto CNF (PNIPAM-grafted-CNF) was extracted by CNF contrast matching near the lower critical solution temperature. Contrast matching eradicates the CNF scattering to retain only the scattering from the grafted-PNIPAM chains. The coil to globule thermo-transition of PNIPAM was revealed by the power law variation from q-1.3 to q-4 in SANS. Isotopic exchange in functionalized cellulosic materials reveals the nano- and micro-scale structure of its individual components. This improved visualization by contrast matching can be extended to carbohydrate polymers to engineer biopharmaceutical and food applications.

A time-resolved investigation at multiple-length scales of the structure of liquid foam stabilized by albumins from pea.

HYPOTHESIS: The structural details of foams made with pea albumins are affected by the pH of the initial solution and followed heat treatment. EXPERIMENTS: An in situ, time-resolved investigation of foams prepared with pea albumins was conducted using small-angle neutron scattering (SANS) in combination with imaging and conductance measurements. Solutions were tested at pH three pH values (3, 4.5, and 8) before and after heating (90 °C for 1 and 5 min). FINDINGS: The characteristic structures present in the foam from the nano to the meso-scale differed during drainage depending on solution pH. Foams obtained at pH 3, had the largest bubble radius and thinnest plateau border, as well as the highest extent of liquid drainage. At pH 4.5, close to the isoelectric point of the proteins, foams displayed similar bubbles' behavior to those at pH 8, but with the largest film thickness. In this case, the proteins were extensively aggregated. Heating of the solutions prior to foaming did not significantly affect the foam aging regardless of pH. The quantification of specific surface areas and film thickness over time without sample disruption shows to be a powerful approach to designing foam structures.

Selective deuteration of an RNA:RNA complex for structural analysis using small-angle scattering.

The structures of RNA:RNA complexes regulate many biological processes. Despite their importance, protein-free RNA:RNA complexes represent a tiny fraction of experimentally-determined structures. Here, we describe a joint small-angle X-ray and neutron scattering (SAXS/SANS) approach to structurally interrogate conformational changes in a model RNA:RNA complex. Using SAXS, we measured the solution structures of the individual RNAs in their free state and of the overall RNA:RNA complex. With SANS, we demonstrate, as a proof-of-principle, that isotope labeling and contrast matching (CM) can be combined to probe the bound state structure of an RNA within a selectively deuterated RNA:RNA complex. Furthermore, we show that experimental scattering data can validate and improve predicted AlphaFold 3 RNA:RNA complex structures to reflect its solution structure. Our work demonstrates that in silico modeling, SAXS, and CM-SANS can be used in concert to directly analyze conformational changes within RNAs when in complex, enhancing our understanding of RNA structure in functional assemblies.

Differential Functional Changes in Visual Performance during Acute Exposure to Microgravity Analogue and Their Potential Links with Spaceflight-Associated Neuro-Ocular Syndrome.

BACKGROUND: Spaceflight-Associated Neuro-Ocular Syndrome (SANS) is a complex pathology threatening the health of astronauts, with incompletely understood causes and no current specific functional diagnostic or screening test. We investigated the use of the differential performance of the visual system (central vs. perimacular visual function) as a candidate marker of SANS-related pathology in a ground-based microgravity analogue. METHODS: We used a simple reaction time (SRT) task to visual stimuli, presented in the central and perimacular field of view, as a measure of the overall performance of the visual function, during acute settings (first 10 min) of vertical, bed rest (BR), -6°, and -15° head-down tilt (HDT) presentations in healthy participants (n = 8). We built dose-response models linking the gravitational component to SRT distribution parameters in the central vs. perimacular areas. RESULTS: Acute exposure to microgravity induces detectable changes between SRT distributions in the perimacular vs. central retina (increased mean, standard deviation, and tau component of the ex-Gaussian function) in HDT compared with vertical presentation. CONCLUSIONS: Functional testing of the perimacular retina might be beneficial for the earlier detection of SANS-related ailments in addition to regular testing of the central vision. Future diagnostic tests should consider the investigation of the extra-macular areas, particularly towards the optic disc.

Simulation of murine retinal hemodynamics in response to tail suspension.

The etiology of spaceflight-associated neuro-ocular syndrome (SANS) remains unclear. Recent murine studies indicate there may be a link between the space environment and retinal endothelial dysfunction. Post-fixed control (N = 4) and 14-day tail-suspended (TS) (N = 4) mice eye samples were stained and imaged for the vessel plexus and co-located regions of endothelial cell death. A custom workflow combined whole-mounted and tear reconstructed three-dimensional (3D) spherical retinal plexus models with computational fluid dynamics (CFD) simulation that accounted for the Fåhræus-Lindqvist effect and boundary conditions that accommodated TS fluid pressure measurements and deeper capillary layer blood flow distribution. TS samples exhibited reduced surface area (4.6 ± 0.5 mm2 vs. 3.5 ± 0.3 mm2, P = 0.010) and shorter lengths between branches in small vessels (<10 µm, 69.5 ± 0.6 µm vs. 60.4 ± 1.1 µm, P < 0.001). Wall shear stress (WSS) and pressure were higher in TS mice compared to controls, particularly in smaller vessels (<10 µm, WSS: 6.57 ± 1.08 Pa vs. 4.72 ± 0.67 Pa, P = 0.034, Pressure: 72.04 ± 3.14 mmHg vs. 50.64 ± 6.74 mmHg, P = 0.004). Rates of retinal endothelial cell death were variable in TS mice compared to controls. WSS and pressure were generally higher in cell death regions, both within and between cohorts, but significance was variable and limited to small to medium-sized vessels (<20 µm). These findings suggest a link may exist between emulated microgravity and retinal endothelial dysfunction that may have implications for SANS development. Future work with increased sample sizes of larger species or spaceflight cohorts should be considered.

Time-resolved small-angle neutron scattering for characterization of molecular exchange in lipid nanoparticle therapeutics.

HYPOTHESIS: Nano-scale dynamics of self-assembled therapeutics play a large role in their biological function. However, assessment of such dynamics remains absent from conventional pharmaceutical characterization. We hypothesize that time-resolved small-angle neutron scattering (TR-SANS) can reveal their kinetic properties. For lipid nanoparticles (LNP), limited molecular motion is important for avoiding degradation prior to entering cells while, intracellularly, enhanced molecular motion is then vital for effective endosomal escape. We propose TR-SANS for quantifying molecular exchange in LNPs and, therefore, enabling optimization of opposing molecular behaviors of a pharmaceutical in two distinct environments. EXPERIMENTS: We use TR-SANS in combination with traditional SANS and small-angle x-ray scattering (SAXS) to experimentally quantify nano-scale dynamics and provided unprecedented insight to molecular behavior of LNPs. FINDINGS: LNPs have molecular exchange dynamics relevant to storage and delivery which can be captured using TR-SANS. Cholesterol exchanges on the time-scale of hours even at neutral pH. As pH drops below the effective pKa of the ionizable lipid, molecular exchange occurs faster. The results give insight into behavior enabling delivery and provide a quantifiable metric by which to compare formulations. Successful analysis of this multi-component system also expands the opportunities for using TR-SANS to characterize complex therapeutics.

Quality assessment of the wide-angle detection option planned at the high-intensity/extended Q-range SANS diffractometer KWS-2 combining experiments and McStas simulations.

For a reliable characterization of materials and systems featuring multiple structural levels, a broad length scale from a few ångström to hundreds of nanometres must be analyzed and an extended Q range must be covered in X-ray and neutron scattering experiments. For certain samples or effects, it is advantageous to perform such characterization with a single instrument. Neutrons offer the unique advantage of contrast variation and matching by D-labeling, which is of great value in the characterization of natural or synthetic polymers. Some time-of-flight small-angle neutron scattering (TOF-SANS) instruments at neutron spallation sources can cover an extended Q range by using a broad wavelength band and a multitude of detectors. The detectors are arranged to cover a wide range of scattering angles with a resolution that allows both large-scale morphology and crystalline structure to be resolved simultaneously. However, for such analyses, the SANS instruments at steady-state sources operating in conventional monochromatic pinhole mode rely on additional wide-angle neutron scattering (WANS) detectors. The resolution must be tuned via a system of choppers and a TOF data acquisition option to reliably measure the atomic to mesoscale structures. The KWS-2 SANS diffractometer at Jülich Centre for Neutron Science allows the exploration of a wide Q range using conventional pinhole and lens focusing modes and an adjustable resolution Δλ/λ between 2 and 20%. This is achieved through the use of a versatile mechanical velocity selector combined with a variable slit opening and rotation frequency chopper. The installation of WANS detectors planned on the instrument required a detailed analysis of the quality of the data measured over a wide angular range with variable resolution. This article presents an assessment of the WANS performance by comparison with a McStas [Willendrup, Farhi & Lefmann (2004). Physica B, 350, E735-E737] simulation of ideal experimental conditions at the instrument.

Deuteration of non-labile protium in starch: Biosynthesis and characterisation from yeast-derived starch granules.

Deuterium labelling of the non-labile protium atoms in starch granules has been achieved for the first time, by growing genetically modified yeast on deuterated media. Mass spectrometry of the glucose monomers from digested starch showed 44 % average deuteration of the non-labile protium when grown on partially deuterated raffinose (with average deuteration 48 %); yielding starch with 26 % average overall deuteration. Non-labile deuteration was also demonstrated using D2O solvent in the culture medium. Solid-state NMR revealed that deuteration was not evenly distributed across the monomer, being highest at the C6 carbon and lowest at the C1 carbon. SANS revealed two structural features at q = 0.05 Å-1 and 0.4 Å-1, the first corresponding to a lamellar repeat of approximately 12-13 nm while the latter is consistent with B-type crystalline polymer packing. Furthermore, solvent contrast variation SANS analysis yielded a contrast match point of 66 mol% D2O indicative of approximately 30-35 % average deuteration of the bulk granules, consistent with mass spectroscopy. When coupled with the more traditional process of exchange of labile protium in the hydroxyl groups by D2O solvent exchange, the biosynthesis of highly deuterated starch opens new opportunities for neutron scattering experiments involving multicomponent starch-based systems.

Learning from virtual experiments to assist users of Small Angle Neutron Scattering in model selection.

In this work, we combine the advantages of virtual Small Angle Neutron Scattering (SANS) experiments carried out by Monte Carlo simulations with the recent advances in computer vision to generate a tool that can assist SANS users in small angle scattering model selection. We generate a dataset of almost 260.000 SANS virtual experiments of the SANS beamline KWS-1 at FRM-II, Germany, intended for Machine Learning purposes. Then, we train a recommendation system based on an ensemble of Convolutional Neural Networks to predict the SANS model from the two-dimensional scattering pattern measured at the position-sensitive detector of the beamline. The results show that the CNNs can learn the model prediction task, and that this recommendation system has a high accuracy in the classification task on 46 different SANS models. We also test the network with real data and explore the outcome. Finally, we discuss the reach of counting with the set of virtual experimental data presented here, and of such a recommendation system in the SANS user data analysis procedure.

Self-Generated Lower Body Negative Pressure Exercise: A Low Power Countermeasure for Acute Space Missions.

Microgravity in spaceflight produces headward fluid shifts which probably contribute to Spaceflight-Associated Neuro-Ocular Syndrome (SANS). Developing new methods to mitigate these shifts is crucial for preventing SANS. One possible strategy is the use of self-generated lower body negative pressure (LBNP). This study evaluates biological or physiological effects induced by bed rest to simulate adaptations to microgravity. Participants were tested during powered LBNP and dynamic self-generated (SELF) LBNP at 25 mmHg for 15 min. The results were compared to the physiologic responses observed in seated upright and supine positions without LBNP, which served as controls for normal gravitational effects on fluid dynamics. Eleven participants' (five male, six female) heart rates, blood pressures, and cross-sectional areas (CSA) of left and right internal jugular veins (IJV) were monitored. Self-generated LBNP, which requires mild to moderate physical activity, significantly elevated heart rate and blood pressure (p < 0.01). Self-generated LBNP also significantly reduced right IJV CSA compared to supine position (p = 0.005), though changes on the left side were not significant (p = 0.365). While the effects of SELF and traditional LBNP on IJV CSA were largely similar, traditional LBNP significantly reduced IJV CSA on both sides. Given its low mass, volume, and power requirements, SELF LBNP is a promising countermeasure against SANS. Results from this study warrant longer-term studies of SELF LBNP under simulated spaceflight conditions.

Imaging in spaceflight associated neuro-ocular syndrome (SANS): Current technology and future directions in modalities.

With plans for future long-duration crewed exploration, NASA has identified several high priority potential health risks to astronauts in space. One such risk is a collection of neurologic and ophthalmic findings termed spaceflight associated neuro-ocular syndrome (SANS). The findings of SANS include optic disc edema, globe flattening, retinal nerve fiber layer thickening, chorioretinal folds, hyperopic shifts, and cotton-wool spots. The cause of SANS was initially thought to be a cephalad fluid shift in microgravity leading to increased intracranial pressure, venous stasis and impaired CSF outflow, but the precise etiology of SANS remains ill defined. Recent studies have explored multiple possible pathogenic mechanisms for SANS including genetic and hormonal factors; a cephalad shift of fluid into the orbit and brain in microgravity; and disruption to the brain glymphatic system. Orbital, ocular, and cranial imaging, both on Earth and in space has been critical in the diagnosis and monitoring of SANS (e.g., fundus photography, optical coherence tomography (OCT), magnetic resonance imaging (MRI), and orbital/cranial ultrasound). In addition, we highlight near-infrared spectroscopy and diffusion tensor imaging, two newer modalities with potential use in future studies of SANS. In this manuscript we provide a review of these modalities, outline their current and potential use in space and on Earth, and review the reported major imaging findings in SANS.

Studying lipid flip-flop in asymmetric liposomes using 1H NMR and TR-SANS.

The specific spatial and temporal distribution of lipids in membranes play a crucial role in determining the biochemical and biophysical properties of the system. In nature, the asymmetric distribution of lipids is a dynamic process with ATP-dependent lipid transporters maintaining asymmetry, and passive transbilayer diffusion, that is, flip-flop, counteracting it. In this chapter, two probe-free techniques, 1H NMR and time-resolved small angle neutron scattering, are described in detail as methods of investigating lipid flip-flop rates in synthetic liposomes that have been generated with an asymmetric bilayer composition.

Random Field Ising Model Criticality in a Complex Binary Liquid System.

While Ising criticality in classical liquids has been firmly established both theoretically and experimentally, much less is known about criticality in liquids in which the growth of the correlation length is frustrated by finite-size effects. A theoretical approach for dealing with this issue is the random-field Ising model (RFIM). While experimental critical-exponent values have been reported for magnetic samples (here, we consider γ, ν and η), little experimental information is available for critical fluctuations in corresponding liquid systems. In this paper, we present a study on a binary liquid consisting of 3-methyl pyridine and heavy water in a very light-weight porous gel. We find that the experimental results are in agreement with the theoretical predictions from the RFIM.

Successful management of dry eye disease with a new eye drop formulation combining hyaluronic acid, trehalose, and N-acetyl-aspartyl-glutamic acid (NAAGA).

PURPOSE: To assess the clinical efficacy and safety of T2769, a new preservative-free eye drop combining hyaluronic acid (HA), trehalose and N-acetyl-aspartyl-glutamic acid (NAAGA), in dry eye patients. PATIENTS AND METHODS: This was a multicenter, non-comparative, open-label study. After a run-in period with NaCl 0.9% solution, 62 patients with moderate-to-severe dry eye disease (DED) were included and treated with T2769, 3 to 6 times/day for 42 days. The primary efficacy endpoint was the change in global ocular symptomatology assessed on a visual analog scale between Day 1 (D1) and D42. Other efficacy endpoints included ocular surface disease index (OSDI), soothing sensation, individual dry eye symptoms, conjunctival hyperemia, global ocular staining, tear break-up time, Schirmer test, and global efficacy assessed by the investigator. Safety was assessed throughout the study. RESULTS: A marked reduction in ocular symptomatology was observed from D1 to D42 with a mean change of -55.9±23.1mm (P<0.001). This was accompanied by a mean change in OSDI score from baseline of -44.6±15.9 (P<0.001) and a substantial soothing sensation in 82.3% of patients. Clinically significant improvements were observed for all ocular symptoms (mainly burning/irritation, stinging/pain, feeling of ocular dryness, foreign body sensation, itching/pruritus). Conjunctival hyperemia significantly decreased in 96.8% of patients (56.5% displayed no conjunctival hyperemia at D42 versus 0% at baseline). All signs and symptoms improved by D14 and further improved at D42. Investigators assessed the ocular efficacy of T2769 as very satisfactory or satisfactory for 91.9% of patients at D42. T2769 was well tolerated, with no ocular adverse events and only a few ocular symptoms upon instillation. CONCLUSION: Management of moderate-to-severe DED patients with the new formulation T2769, combining NAAGA to HA and trehalose, led to rapid and significant improvements in dry eye signs and symptoms with good tolerability.

Accelerated Recombination of Lophyl Radicals in Micelles: Rapid Controlled Self-Assembly of Micelles Formed by Amphiphilic Lophine Dimers and Release of Solubilized Substance by Photoirradiation.

Controlling the morphology of molecular assemblies formed by surfactants by photoirradiation enables the controlled release of incorporated substances, which can be applied to delivery systems for drugs and active ingredients. On the other hand, conventional photoresponsive surfactants and molecular assemblies have a slow response speed, making it difficult to control their functions at the desired time. In this review, I discuss our recent progress in the accelerated control of functions of photoresponsive molecular assemblies by using lophine dimer as a photochromic compound. The lophine dimer derivative dissociates into a pair of lophyl radicals that upon ultraviolet (UV) light irradiation, and these radical species thermally recombine although the recombination reaction is extremely slow due to the diffusion of lophyl radicals. By using the confined inner space of micelles formed by surfactants, the recombination reaction was extremely accelerated. With UV light irradiation, rapid morphological changes in micelles, formed by amphiphilic lophine dimers were observed by using in situ small-angle neutron scattering (in situ SANS) system. Moreover, the rapid controlled release of calcein as a model drug was achieved by UV light irradiation using the photoresponsive micelles. This rapid system can realize the controlled release of drugs truly at the desired time, developing an efficient and precise drug delivery system (DDS). Furthermore, it can be applied in a wide range of fields such as release control of active ingredients, efficient heat exchange control, and actuating systems.

Font Matters: Deciphering the Impact of Font Types on Attention and Working Memory.

Introduction Various types of fonts such as serif, sans serif, and script are used during writing and reading, which can affect the reader's attention and working memory, though there is only a subtle difference at the end of the letter. The study aimed to see the effect of font type on working memory and attention. Methods The study included healthy male adults between 18 and 40 years of age. After taking all the necessary precautions, a letter cancellation test and 2-back task in serif, sans serif, and script font types were done to evaluate subjects' attention and working memory. Results A total of 30 subjects participated in the study. The letter cancellation task (LCT) was statistically significant (P<0.05) between the three groups, where the time taken to complete the task was the shortest for serif fonts, indicating heightened attention to serif fonts. However, the accuracy of the N-back test did not show statistically significant differences (P>0.05) among the three font groups, indicating no significant change in working memory. Conclusion The type of font used can impact the reader's attention, with Times New Roman font demonstrating greater attention, particularly in the context of the letter cancellation task.

Barriers and facilitators to achieving employment in mainstream settings in adults with autism spectrum disorder without intellectual developmental disorders: A scoping review.

Autistic people without Intellectual Developmental Disorders (IDD) have a significantly lower employment rate compared to the general population even though employment favors social integration and quality of life. AIMS: To examine the barriers and facilitators to employability in mainstream settings for autistic adults without intellectual disability. METHODS: Following the scoping review guidelines, we searched the Cochrane, PubMed and PsycINFO databases for references published between 01/01/2000 to 01/08/2023. RESULTS: A review of the 44 identified articles suggests the existence of multiple individual and environmental factors influencing job access and retention. CONCLUSIONS: This is the first review to assess the facilitators and barriers to employment support for autistic people without intellectual disability. The results underline the need for studying strategies to promote access to employment and job retention for autistic people. Future research should explore the mediating and moderating factors leading to the improvement of employability of autistic people WIDD.

[A creative approach to psychoeducation for ADHD in adults]. / Une offre de soins créative de psychoéducation du TDAH chez l'adulte.

A group-based online psycho-education program for adults with attention deficit hyperactivity disorder (ADHD) and their families has been set up by a multi-professional psychiatric team. Feedback from users has mainly shown benefits in terms of improving self-esteem, destigmatization and accessibility to care. This suggests a real interest in developing this care offer in the pathway of ADHD adults.

Effect of cardiolipin on the lamellarity and elongation of liposomes hydrated in PBS.

Lamellarity and shape are important factors in the formation of vesicles and determine their role in biological systems and pharmaceutical applications. Cardiolipin (CL) is a major lipid in many biological membranes and exerts a great influence on their structural organization due to its particular structure and physico-chemical properties. Here, we used small-angle X-ray and neutron scattering to study the effects of CL with different acyl chain lengths and saturations (CL14:0, CL18:1, CL18:2) on vesicle morphology and lamellarity in membrane models containing mixtures of phosphatidylcholine and phosphatidylethanolamine with different acyl chain lengths and saturations (C14:0 and C 18:1). Measurements were performed in the presence of Phosphate Buffer Saline (PBS), at 37°C, to better reflect physiological conditions, which resulted in strong effects on vesicle morphology, depending on the type and amount of CL used. The presence of small quantities of CL (from 2.5%) reduced inter-membrane correlations and increased perturbation of the membrane, an effect which is enhanced in the presence of matched shorter saturated acyl chains, and mainly unilamellar vesicles (ULV) are formed. In extruded vesicles, employed for SANS experiments, flattened vesicles are observed partly due to the hypertonic effect of PBS, but also influenced by the type of CL added. Our experimental data from SAXS and SANS revealed a strong dependence on CL content in shaping the membrane microstructure, with an apparent optimum in the PC:CL mixture in terms of promoting reduced correlations, preferred curvature and elongation. However, the use of PBS caused distinct differences from previously published studies in water in terms of vesicle shape, and highlights the need to investigate vesicle formation under physiological conditions in order to be able to draw conclusions about membrane formation in biological systems.

Multiscale structure analysis of a pH-responsive gelatin/hydroxypropyl methylcellulose phthalate blend using small-angle scattering.

HYPOTHESIS: Hydroxypropyl methylcellulose phthalate (HPMCP) is an enteric polymer that has been employed in drug delivery systems to delay the release of the encapsulated active pharmaceutical ingredients through its pH-responsive solubility change. This has been recently demonstrated as an effective means for delaying the drug release from gelatin/HPMCP hydrogels at gastric pH values. However, structural characteristics of HPMCP agglomeration in gelatin/HPMCP hydrogels is not well understood thus limiting further tailoring of their material properties. EXPERIMENTS: We investigated the multiscale structure of a gelatin/HPMCP hydrogel (1:1 by weight) between pH 2 and 6 at 37 °C, i.e. above the upper critical solution transition temperature of gelatin, using small-angle X-ray scattering and contrast-variation small-angle neutron scattering to understand the pH-responsive structure of HPMCP and the cross-correlation between gelatin and HPMCP. FINDINGS: Agglomeration of HPMCP between pH 2 and 4 was evidenced by the formation of mass fractal structures, with a fractal dimension ranging from 1.5 to 2.7, comprising primary particles with a radius of gyration ranging from 70 to 140 Å. Blending with gelatin influenced the fractal structure of HPMCP and the primary particle size. Gelatin and HPMCP exhibited negative cross-correlation in all probed length scales and pH values, which was attributed to volume-exclusion interaction in a double-network-like solution architecture.