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Background: Siponimod is approved for use in people with secondary progressive multiple sclerosis (pwSPMS). An integrated digital platform, MSGo, was developed for pwSPMS and clinicians to help navigate the multiple steps of the pre-siponimod work-up. Objective: To explore real-world onboarding experiences of siponimod amongst pwSPMS in Australia. Methods: Retrospective, non-interventional, longitudinal, secondary analysis of data extracted from MSGo (20 April 2022). The primary endpoint was the average time for siponimod onboarding; secondary endpoints were adherence and sub-group analyses of variables influencing onboarding. Results: Mixed-cure modelling estimated that 58% of participants (N = 368, females 71%, median age of 59 years) registered in MSGo would ever initiate siponimod. The median time to initiation was 56 days (95% CI [47–59] days). Half of the participants cited 'waiting for vaccination' as the reason for initiation delay. Cox regression analyses found participants with a nominated care partner had faster onboarding (HR 2.1, 95% CI [1.5–3.0]) and were more likely to continue self-reporting daily siponimod dosing than were those without a care partner (HR 2.2, 95% CI [1.3–3.7]). Conclusions: Despite the limitations of self-reported data and the challenges of the COVID-19 pandemic, this study provides insights into siponimod onboarding in Australia and demonstrates the positive impact of care partner support. [ABSTRACT FROM AUTHOR]

Abstract Stratospheric aerosol injection (SAI) has been shown in climate models to reduce some impacts of global warming in the Arctic, including the loss of sea ice, permafrost thaw, and reduction of Greenland Ice Sheet (GrIS) mass; SAI at high latitudes could preferentially target these impacts. In this study, we use the Community Earth System Model to simulate two Arctic‐focused SAI strategies, which inject at 60°N latitude each spring with injection rates adjusted to either maintain September Arctic sea ice at 2030 levels (“Arctic Low”) or restore it to 2010 levels (“Arctic High”). Both simulations maintain or restore September sea ice to within 10% of their respective targets, reduce permafrost thaw, and increase GrIS surface mass balance by reducing runoff. Arctic High reduces these impacts more effectively than a globally focused SAI strategy that injects similar quantities of SO2 at lower latitudes. However, Arctic‐focused SAI is not merely a “reset button” for the Arctic climate, but brings about a novel climate state, including changes to the seasonal cycles of Northern Hemisphere temperature and sea ice and less high‐latitude carbon uptake relative to SSP2‐4.5. Additionally, while Arctic‐focused SAI produces the most cooling near the pole, its effects are not confined to the Arctic, including detectable cooling throughout most of the northern hemisphere for both simulations, increased mid‐latitude sulfur deposition, and a southward shift of the location of the Intertropical Convergence Zone. For these reasons, it would be incorrect to consider Arctic‐focused SAI as “local” geoengineering, even when compared to a globally focused strategy.

Surface tension, conductivity, and dynamic light scattering (DLS) measurements were used to examine the surface and bulk solution behaviors of three members of the PFAS family, perfluorooctanoic acid (PFOA), perfluorobutanesulfonic acid (PFBS), and the potassium salt of perfluorooctanesulfonic acid (PFOS). Measurements were carried out in solutions having variable (acidic) pH and in solutions buffered to pH = 8.0. Surface tension data show traditional soluble surfactant behavior, and results illustrate that PFOA, PFBS, and PFOS surface activity depends sensitively on solution phase pH. The tightly packed monolayers formed by PFOA in mildly acidic solutions imply that the surface pH of PFOA solutions is several units lower than bulk. Results from conductivity experiments generally show increasing conductivity with increasing bulk solution surfactant concentration. In pH = 8.0 solutions, changes in conductivity slope with surfactant concentration suggest the onset of micelle formation at concentrations <1 mM, markedly lower than reported in literature. In general, apparent critical micelle concentrations (CMCs) determined from conductivity data agree with similar predictions made from surface tension results. DLS measurements show that at concentrations close to the predicted PFAS CMCs, objects with diameters ≤10 nm start to form. However, unlike micelles, these objects continue to grow with increasing bulk solute concentration. These aggregates form structures having diameters of 50-150 nm. Aggregate size shrinks modestly as solution phase temperature increases, and this behavior is reversible. Cryo-EM images of PFOA solutions confirm a broad distribution of particles, supporting the DLS measurements. Findings reported in this work represent the first evidence that these three EPA-regulated PFAS surfactants form aggregates rather than micelles in solution. Findings also begin to reconcile differences in reported surface behaviors that have led to CMC predictions in the literature varying by more than an order of magnitude.

Resonance enhanced Second Harmonic Generation (SHG) was employed to assess if conduction band electrons in silicon (Si) will promote molecular adsorption of ambient species and how such adsorption depends on temperature. Experiments were performed with three types of Si (n-doped or n-Si, p-doped or p-Si, and undoped Si) at temperatures between 18 and 260 °C and under atmospheres of dry N2 and dry (cylinder) air. All Si types were covered with a 2-4 nm thick native oxide layer. Under N2, all Si types behave similarly, with SHG intensity [I(2ω)] diminishing with increasing temperature. This effect was reversible and attributed to electron-phonon scattering. In the presence of O2, I(2ω) from n-Si at room temperature is enhanced significantly. Neither p-doped Silicon (p-Si) nor undoped Si show similar effects at room temperature, with I(2ω) being independent of gas phase composition. At temperatures ≥175 °C, all three Si types behaved similarly with no dependence on atmospheric O2 content. Varying the amount of O2 above n-Si at room temperature and measuring I(2ω) suggested that O2 adsorption to n-Si could be described with a Langmuir isotherm and an adsorption energy of -0.13 ± 0.05 eV. Increasing n-Si's oxide thickness (to 600 nm) rendered the substrate insensitive to ambient gas phase composition. Taken together, these findings support a description of Si's surface electronic structure that is controlled by n-Si conduction band electrons backbonding into the π* orbitals of adjacent O2 and imply that these conduction band electrons can affect adsorption despite the presence of a native oxide film., (© 2024 Author(s). Published under an exclusive license by AIP Publishing.)

Little is known about shifts in the fecal microbiome of dairy calves preceding and following the incidence of gastrointestinal disease. The objective of this cohort study was to describe the fecal microbiome of preweaned dairy calves before, during, and after gastrointestinal disease. A total of 111 Holstein dairy calves were enrolled on 2 dairies (D1 and D2) and followed until 5 weeks old. Health assessments were performed weekly and fecal samples were collected every other week. Of the 111 calves, 12 calves from D1 and 12 calves from D2 were retrospectively defined as healthy, and 7 calves from D1 and 11 calves from D2 were defined as diarrheic. Samples from these calves were sequenced targeting the 16S rRNA gene and compared based on health status within age groups and farms: healthy (0-1 week old) vs. pre-diarrheic (0-1 week old), healthy (2-3 weeks old) vs. diarrheic (2-3 weeks old), and healthy (4-5 weeks old) vs. post-diarrheic (4-5 weeks old) calves. Healthy and diarrheic samples clustered together based on age rather than health status on both farms. Based on linear discriminant analysis, a few species were identified to be differently enriched when comparing health status within age groups and farm. Among them, Bifidobacterium sp. was differently enriched in pre-diarrheic calves at D1 (0-1 week old) whereas healthy calves of the same age group and farm showed a higher abundance of Escherichia coli . Bifidobacterium sp. was identified as a biomarker of fecal samples from healthy calves (2-3 weeks old) on D1 when compared with diarrheic calves of the same age group and farm. Feces from diarrheic calves on D2 (2-3 weeks old) were characterized by taxa from Peptostreptococcus and Anaerovibrio genera whereas fecal samples of age-matched healthy calves were characterized by Collinsella aerofaciens and Bifidobacterium longum . After resolution of uncomplicated diarrhea (4-5 weeks old), Collinsella aerofaciens was more abundant in D2 calves whereas Bacteriodes uniformis was more abundant in D1 calves. Taken together, these findings suggest that the age of the preweaned calf is the major driver of changes to fecal microbiome composition and diversity even in the face of uncomplicated gastrointestinal disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Claus-Walker, Slanzon, Elder, Hinnant, Mandella, Parrish, Trombetta and McConnel.)

Time-resolved fluorescence spectroscopy in combination with differential scanning calorimetry (DSC) was used to study the chemical interactions that occur when l-phenylalanine is introduced to solutions containing phosphatidylcholine vesicles. Studies reported in this work address open questions about l-Phe's affinity for lipid vesicle bilayers, the effects of l-Phe partitioning on bilayer properties, l-Phe's solvation within a lipid bilayer, and the amount of l-Phe within that local solvation environment. DSC data show that l-Phe reduces the amount of heat necessary to melt saturated phosphatidylcholine bilayers from their gel to liquid-crystalline state but does not change the transition temperature ( T gel-lc ). Time-resolved emission shows only a single l-Phe lifetime at low temperatures corresponding to l-Phe remaining solvated in aqueous solution. At temperatures close to T gel-lc , a second, shorter lifetime appears that is assigned to l-Phe already embedded within the membrane that becomes hydrated as water starts to permeate the lipid bilayer. This new lifetime is attributed to a conformationally restricted rotamer in the bilayer's polar headgroup region and accounts for up to 30% of the emission amplitude. Results reported for dipalmitoylphosphatidylcholine (DPPC, 16:0) lipid vesicles prove to be general, with similar effects observed for dimyristoylphosphatidylcholine (DMPC, 14:0) and distearoylphosphatidylcholine (DSPC, 18:0) vesicles. Taken together, these results create a complete and compelling picture of how l-Phe associates with model biological membranes. Furthermore, this approach to examining amino acid partitioning into membranes and the resulting solvation forces points to new strategies for studying the structure and chemistry of membrane-soluble peptides and selected membrane proteins.

Bovine respiratory disease (BRD) is a leading cause of calf morbidity and mortality, and prevalence remains high despite current management practices. Differential gene expression (DGE) provides detailed insight into individual immune responses and can illuminate enriched pathways and biomarkers that contribute to disease susceptibility and outcomes. The aims of this study were to investigate differences in peripheral leukocyte gene expression in Holstein preweaned heifer calves 1) with and without BRD, and 2) across weeks of age. Calves were enrolled for this short-term longitudinal study on two commercial dairies in Washington State. Calves were assessed every two weeks throughout the pre-weaning period using clinical respiratory scoring (CRS) and thoracic ultrasonography (TUS), and blood samples were collected. Calves were selected that were either healthy (n = 10) or had BRD diagnosed by CRS (n = 7), TUS (n = 6), or both (n = 6) in weeks 5 or 7 of life). Three consecutive time point samples were analyzed for each BRD calf consisting of PRE, ONSET, and POST samples. Nineteen genes of interest were selected based on previous gene expression studies in cattle: ALOX15, BPI, CATHL6, CXCL8, DHX58, GZMB, HPGD, IFNG, IL17D, IL1R2, ISG15, LCN2, LIF, MX1, OAS2, PGLYRP1, S100A8, SELP, and TNF. Comparisons were made between age and disease time point matched BRD and healthy calves as well as between calf weeks of age. No DGE was observed between diseased and healthy calves; however, DGE was observed between calf weeks of age regardless of disease state. Developmental differences in leukocyte gene expression, phenotype, and functionality make pre-weaned calves immunologically distinct from mature cattle, and early life shifts in calf leukocyte populations likely contribute to the age-related gene expression differences we observed. Age overshadows disease impacts to influence gene expression in young calves, and immune development progresses upon a common trajectory regardless of disease during the preweaning period., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Elder et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Polyhydroxylated fullerene (PHF) surface activity and aggregation behavior at the air-water interface were examined using surface tension and resonance-enhanced second harmonic generation (SHG). Surface tension data showed that PHFs are surface active with a limiting surface excess corresponding to 130 Å 2 /molecule in aqueous (Millipore water) solutions. Increasing the solution-phase ionic strength (through the addition of NaCl) reduces the PHF surface excess. Conductivity measurements show that PHFs carry a single charge, presumably negative. Surface-specific SHG experiments show a small but measurable fixed wavelength, nonlinear response from solutions having surface excess coverages as low as ∼400 Å 2 /molecule. The SHG response of PHF solutions in the low-concentration limit shows unexpected behavior, implying that at bulk concentrations below 0.06 mg/mL, PHF monomers adsorb to the surface and interfere destructively with the intrinsic nonlinear susceptibility of the aqueous/vapor interface, leading to a ∼75% reduction in the SH signal. Above a PHF concentration of 0.0.06 mg/mL, the SH signal begins to rise in the Millipore and 50 mM NaCl solutions but remains very low in the 500 mM NaCl solutions. From this behavior, we infer that an increased nonlinear optical response is due to adsorbed aggregates.

Surface specific vibrational spectroscopy experiments together with surface tension measurements and spectroscopic ellipsometry data were used to characterize the effects of soluble carbon particulates on compressed and partially compressed lipid monolayers adsorbed to the water-air interface. The lipid monolayers consisted of 1,2-dimyristoyl- sn -glycero-3-phosphocholine (DPPC), and measurements were made for both tightly packed monolayers (40 Å 2 /molecule) and monolayers in their liquid condensed state (55 Å 2 /molecule). Langmuir trough data show that very small amounts of PHF (0.0075 mg/mL or 6.4 × 10 -6 M) decrease lipid film compressibility. This finding supports a cooperative adsorption mechanism whereby the soluble PHFs are drawn to the surface and associate with the insoluble DPPC monolayer. Excess free energies (Δ G mix E ) were positive, consistent with the cooperative adsorption mechanism, and although the excess free energies are small (≤1 kJ/mol), adsorbed PHF has measurable effects on monolayer structure. Further support for the cooperative adsorption mechanism at the water-air interface comes from vibrational sum frequency generation (VSFG) experiments. Low PHF concentrations (≤0.06 mg/mL) increase DPPC acyl chain ordering in liquid condensed lipid films and decrease DPPC acyl chain ordering and film thickness in tightly packed lipid films.

Vibrational sum frequency generation (VSFG) spectroscopy, conductometric titration measurements, and EDX elemental mapping were used to examine surfactant adsorption to the gypsum (010) surface and assess the effects of surfactant adsorption on gypsum solubility in aqueous solutions. Sodium dodecyl sulfate (SDS) and dodecyltrimethylammonium chloride (DTAC) were used as anionic and cationic surfactants, respectively. Gypsum/SDS interactions result in an ordered precipitate layer on the gypsum surface after water evaporation; gypsum/DTAC interaction did not show a similar effect, despite exposure of gypsum to equivalent amounts of surfactant. VSFG spectra showed that SDS molecules adsorb with their chains parallel to the gypsum surface; spectra from gypsum surfaces treated with DTAC, however, showed no measurable response, implying that these surfactants form disorganized aggregates with no polar ordering. Vibrational data were supported by independent EDX measurements that show a uniform distribution of SDS across the gypsum surface. In contrast, element-specific EDX images showed that DTAC clustered in tightly localized patches that left most of the gypsum surface exposed. The uniform adsorption of SDS on the gypsum surface suppresses long-term dissolution up to 40% when compared to samples exposed to DTAC. Gypsum samples in DTAC-containing solutions lose approximately the same amount of material to dissolution as samples immersed in pure water.

The dorsal raphe nucleus (DRN) contains the largest population of serotonin (5-HT) neurons in the central nervous system. 5-HT, synthesized via tryptophan hydroxylase 2 (Tph2), is a widely functioning neuromodulator implicated in fear learning. Here, we sought to investigate whether DRN 5-HT is necessary to reduce fear via negative prediction error (-PE). Using male and female TPH2-cre rats, DRN tph2+ cells were selectively deleted via cre-caspase (rAAV5-Flex-taCasp3-TEVp) in experiment 1. Rats then underwent fear discrimination during which three cues were associated with unique foot shock probabilities: safety p  = 0.00, uncertainty p  = 0.375, and danger p  = 1.00. Rats then received selective extinction to the uncertainty cue, a behavioral manipulation designed to probe -PE. Deleting DRN tph2+ cells had no impact on initial discrimination but slowed selective extinction. In experiment 2, we used a within-subjects optogenetic inhibition design to causally implicate DRN tph2+ cells in prediction error signaling. Male and female TPH2-cre rats received intra-DRN infusions of cre-dependent halorhodopsin (rAAV5-Ef1a-DIO-eNpHR3.0-eYFP) or cre-YFP. DRN tph2+ cells were inhibited specifically during the time of prediction error or a control period. Illumination during either positive prediction error (+PE) or control periods had no impact on fear to the uncertainty cue. Inhibition of DRN tph2+ cells at the time of -PE did not impact immediate fear, but facilitated selective extinction in postillumination sessions. Together, these results demonstrate a role for DRN tph2+ cells in using, but not generating, -PE to weaken cue-shock associations., (Copyright © 2022 Walker et al.)