Large Changes Research Articles

Carbon taxes, CO2 emissions, and the economy: The effects of fuel taxation in the UK

Carbon taxes remain economists’ preferred policy tool to curb emissions, but they are often criticized by the wider public as ineffective and damaging to the economy. This paper provides new evidence of the effectiveness of carbon taxation through empirical ex-post analysis, using the synthetic control method. We base our quantitative work on a theoretical general equilibrium model with dirty and clean transportation. We take the predictions of the model to data on the UK Fuel Tax Escalator, and estimate the impact of the tax on CO2 emissions, GDP, and transport behaviour. With a potential control pool of OECD countries, we estimate the difference between the observed outcome in the UK and a synthetic counterfactual UK. We find that the tax has a large and significant impact on CO2 emissions from traffic, while there is no discernible impact on GDP or growth. We do not find large changes in driving behaviours, but the available evidence points to a possible switch to rail travel from road travel. Our results are relevant for energy policy makers as they show how a suitable pricing system can effectively reduce climate-damaging emissions without causing macroeconomic damage.

Climate change and disturbance interact to alter landscape reflectivity (albedo) in boreal forests across a large latitudinal gradient in Siberia

Boreal forests form the largest terrestrial biome globally. Climate change is expected to induce large changes in vegetation of high latitude ecosystems, but there is considerable uncertainty about where, when, and how those changes will occur. Such vegetation change produces major feedback to the climate system, including by modifying albedo (reflectivity). Our study used the LANDIS-II forest landscape model to project forest dynamics on four representative landscapes (1 M ha) for 280 years into the future under a range of climate scenarios across a broad latitudinal gradient in Siberia. The model estimated the albedo of the vegetation and any snow on each landscape grid-cell through time to quantify surface albedo change in response to climate change and disturbances. We found that the shortening of the snow-covered season (winter) decreased annual average albedo dramatically, and climate change facilitated the invasion of tundra by boreal trees in the northernmost landscape (reducing albedo in all seasons). However, in other landscapes, albedo increased in summer due to disturbances (fire, wind, insects, harvest), eliminating or reducing leaf area in the short-term, and in the mid-term by promoting more reflective forest types (deciduous, light conifers). This increased albedo was somewhat ephemeral and under climate change was overwhelmed by the shortening of the snow-covered season that greatly reduced albedo. We conclude that the primary driver of the overall reflectivity of boreal ecosystems is not vegetation, but rather, the length of the snow-covered season. Because climate change is likely to dramatically shorten the snow season, the concurrent reduction of albedo has the potential to act as a powerful positive feedback for climate change. Managing natural and anthropogenic disturbances may be the only tool with potential to mitigate the reduction of albedo by climate change in boreal ecosystems because management to encourage more reflective forest types has relatively small effect.

Augmented and Virtual Reality Based Segmentation Algorithm for Human Pose Detection in Wearable Cameras

Pose graph optimisation is a crucial method that helps reduce cumulative errors while estimating visual trajectories for wearable cameras. However, when the posture graph's size increases with each additional camera movement, the optimization's efficiency diminishes. In terms of ongoing sensitive applications, such as extended reality and computer-generated reality, direction assessment is a major test. This research proposes an incremental pose graph segmentation technique that accounts for camera orientation variations as a solution to this challenge. The computation only improves the cameras that have seen large direction changes by breaking the posture chart during these instances. As a result, pose graph optimisation is essentially slowed down and optimised more quickly. For every camera that hasn't been optimised using a pose graph, the algorithm employs the wearable cameras at the start and end of each camera's trajectory segment. The final camera in attendance is then determined by weighted average the various postures evaluated with these wearable cameras; this eliminates the need for lengthy nonlinear enhancement computations, reduces disturbance, and achieves excellent accuracy. Experiments on the EuRoC, TUM, and KITTI datasets demonstrate that pose graph optimisation scope is reduced while maintaining camera trajectories accuracy.

Computational study of the HLTF ATPase remodeling domain suggests its activity on dsDNA and implications in damage tolerance

The Helicase-Like Transcription Factor (HLTF) is member of the SWI/SNF-family of ATP dependent chromatin remodellers known primarily for maintaining genome stability. Biochemical and cellular assays support its multiple roles in DNA Damage Tolerance. However, the lack of sufficient structural data limits the comprehension of the molecular basis of its modes of action.In this work we have modelled and characterized the HLTF ATPase remodeling domain by using bioinformatic tools and all-atoms molecular dynamics simulations.In-silico results suggested that its binding to dsDNA is mainly mediated by the positively charged residues Arg563 and Lys913, found conserved in HLTF homologs, and Arg620 and Lys999, found only in HLTF. Interestingly, these residues are mutated in cancer cells. During translocation on dsDNA, HLTF remains persistently bound through the N-terminal ATPase subunit. However, DNA advancement occurs only in the presence of the synergic-anticorrelated action of both motor lobes. In contrast, the C-terminal facilitates substrate remodeling through DNA deformation and generation of bulges according to a wave-model. Finally, the large conformational change suggested between the two motor-remodeling subunits might be activated upon the release of PARP1 on stalled fork and be responsible for the intervention of HLTF-HIRAN in the formation of D-loop and 4-way junction DNA structures.

Extreme ultra-short-term changes in air temperature in January in southern Poland (the example of Sosnowiec) against the background of atmospheric circulation conditions

Abstract Large short-term changes in air temperature affect the functioning of living organisms in the environment and human activities. For this reason, a study of extreme positive and negative 10 min temperature changes and their causes related to atmospheric circulation was undertaken. Air temperature data for January in the period 2001–2017 in southern Poland (Sosnowiec) were analysed. Extreme ultra-short-term temperature changes were considered to be values less than or equal to 0.1 percentile (extreme temperature drops) and greater than or equal to 99.9 percentile (extreme temperature increases). The extreme ultra-short-term negative air temperature change was − 7.2°C/10 min, while the positive change was + 3.5 °C/10 min. Extreme ultra-short-term negative air temperature changes in southern Poland in January occur most frequently with the advection of air from the west (43% of cases), the inflow of maritime Polar old (transformed) air over Poland (25% of cases), western cyclonic (Wc) and north-western cyclonic (NWc) situations, a total of 34% of cases), the passage of the atmospheric front over southern Poland (59% of cases), especially a cold front (68% of cases with a front). Extreme ultra-short-term positive changes of air temperature in southern Poland in January occur most frequently with the advection of air from the south-west (43% of cases), the inflow of continental Polar air (42% of cases), anticyclonic situations (72% of cases), the occurrence of a high-pressure wedge over southern Poland (26% of cases), situations without atmospheric front (80% of cases). The direction of advection plays a secondary role in determining the values of extreme short-term changes in air temperature. More important is the speed of the influx of this air mass. Extreme ultra-short-term temperature changes are partly explained by circulation conditions. Rapid temperature changes can also occur as a result of small-scale processes in the atmosphere.

Complexity associated with caprylate binding to bovine serum albumin: Dimerization, allostery, and variance between the change in free energy and enthalpy of binding.

Isothermal titration calorimetry (ITC), differential scanning calorimetry (DSC), and pressure perturbation calorimetry (PPC) were used to study different aspects of the diverse interaction between the fatty acid caprylate and bovine serum albumin (BSA). The ITC thermogram was consistent with exothermic binding to a single site on BSA, which was electrostatic but had little or no hydrophobic contribution. ITC revealed that small changes to solution conditions and temperature were associated with apparent enthalpy-entropy compensation, causing large changes in enthalpy (ΔH) during binding, but with little corresponding changes in free energy (ΔG). ITC also detected a slower endothermic interaction at a low mole ratio. Dynamic light scattering suggested that this was due to dimerization or similar self-association. DSC demonstrated that further interactions took place at higher mole ratios. This was consistent with weak binding of caprylate to multiple binding sites which had a considerable impact on the structural conformation of BSA. PPC showed that the conformational change of BSA was accompanied with a reduction in surface hydrophobicity of the protein. PPC also demonstrated that in solution caprylate's hydrocarbon tail is hidden from water as no clathrate-like water is evident, which is consistent with the lack of hydrophobic contribution during binding. Cumulatively, the three calorimetric techniques offer a comprehensive view of caprylate and BSA interactions, highlighting the role of electrostatic interaction in binding accompanied by probably dimerization and considerable structural change associated with weaker binding to BSA.

Historical and Future Asymmetry of ENSO Teleconnections with Extremes

Abstract El Niño–Southern Oscillation (ENSO) is the dominant source of climate variability globally. Many of the most devastating impacts of ENSO are felt through extremes. Here, we present and describe a spatially complete global synthesis of extreme temperature and precipitation relationships with ENSO. We also investigate how these relationships evolve under a future warming scenario under high greenhouse gas emissions using 14 models from phase 6 of Coupled Model Intercomparison Project (CMIP6) ensemble. First, we demonstrate that models broadly capture observed ENSO teleconnections to mean and extreme climate using the Twentieth Century Reanalysis, version 3 (20CRv3). The models project that more regions will experience an amplification of the historical ENSO teleconnection with mean temperature and precipitation than a dampening under a high-emission climate scenario. The response of the ENSO teleconnection with extremes is very similar to the mean response, with even larger changes in some regions. Hence, regions that are predicted to experience an amplification of the ENSO teleconnection under future warming can also expect a comparable amplification in the intensity of extremes. Furthermore, models that suggest greater amplification of ENSO amplitude also tend to exhibit greater intensification of mean and extreme teleconnections. Future changes in regional climate variability may be better constrained if changes in ENSO itself are better understood.

Smallest Clinically Meaningful Improvement in Amputation-Related Pain and Brief Pain Inventory Scores as Defined by Patient Reports of Global Improvement After Cryoneurolysis: a Retrospective Analysis of a Randomized, Controlled Clinical Trial.

The smallest meaningful improvement in pain scores (minimal clinically important difference [MCID]) after an analgesic intervention is essential information when both interpreting published data and designing a clinical trial. However, limited information is available for patients with chronic pain conditions, and what is published is derived from studies involving pharmacologic and psychological interventions. We here calculate these values based on data collected from 144 participants of a previously published multicenter clinical trial investigating the effects of a single treatment with percutaneous cryoneurolysis. In the original trial, we enrolled patients with a lower-limb amputation and established phantom pain. Each received a single-injection femoral and sciatic nerve block with lidocaine and was subsequently randomized to receive either ultrasound-guided percutaneous cryoneurolysis or sham treatment at these same locations. Investigators, participants, and clinical staff were masked to treatment group assignment with the exception of the treating physician performing the cryoneurolysis, who had no subsequent participant interaction. At both baseline and 4 months (primary end point), participants rated their phantom limb pain based on a numeric rating scale (NRS) and their interference of pain on physical and emotional functioning as measured with the Brief Pain Inventory's interference subscale. They subsequently qualitatively defined the change using the 7-point ordinal Patient Global Impression of Change (PGIC). The smallest clinically meaningful improvements in phantom limb pain and Brief Pain Inventory scores were calculated using an anchor-based method based on the PGIC. The median (interquartile range [IQR]) phantom pain NRS (0-10) improvements at 4 months considered small, medium, and large were 1 [1-1], 3 [3-4], and 4 [3-6], respectively. The median improvements in the Brief Pain Inventory interference subscale (0-70) associated with a small, medium, and large analgesic changes were 16 [6-18], 24 [22-31], and 34 [22-46]. The proportions of patients that experienced PGIC ≥5 were 33% and 36% in the active and placebo groups, respectively. The relative risk of a patient experiencing PGIC ≥5 in the active group compared to the sham group with 95% confidence interval was 0.9 (0.6-1.4), P = .667. Amputees with phantom limb pain treated with percutaneous cryoneurolysis rate analgesic improvements as clinically meaningful similar to pharmacologic treatments, although their MCID for the Brief Pain Inventory was somewhat larger than previously published values. This information on patient-defined clinically meaningful improvements will facilitate interpretation of available studies and guide future trial design.

Proton irradiation Of Ga2O3 Schottky diodes and NiO/Ga2O3 heterojunctions.

p-NiO/n-Ga2O3 heterojunction (HJ) diodes exhibit much larger changes in their properties upon 1.1MeV proton irradiation than Schottky diodes (SDs) prepared on the same material. In p-NiO/Ga2O3 HJ diodes, the narrow region adjacent to the HJ boundary is found to contain a high density of relatively deep centers with levels near EC-0.17eV and a depleted region in the immediate vicinity of the HJ boundary. The series resistance of the HJ diodes is slightly higher than for the Schottky diodes and shows a temperature dependence with activation energy ~ 0.12eV, like the temperature dependence of the NiO film resistivity. Irradiation with 1.1MeV protons leads to a decrease of the hole concentration in the NiO, with a high carrier removal rate of ~ 1.3 × 105cm-1 and a strong compensation of the interfacial region where the concentration of the EC-0.17eV centers decreases with a high rate of ~ 7 × 103cm-1. The combined action of these two effects gives rise to the much stronger increase of the series resistance of the HJ diodes compared to Schottky diodes. The observed differences between the radiation response of the HJs and SDs cannot be credibly attributed to the changes of the density of any of the deep electron and hole traps detected in our experiments.

A physical perspective on lithium therapy.

Lithium salts have strong medical properties in neurological disorders such as bipolar disorder and lithium-responsive headaches (Pereira da Silva Neto and James Almeida, 2010; Lindner et al., 2023; Silva-Néto et al., 2019). They have recently gathered attention due to their potential preventive effect in viral infections (Ferensztajn-Rochowiak and Rybakowski, 2023; Rybakowski, 2022). Though the therapeutic effect of lithium was documented by Cade in the late 1940s, its underlying mechanism of action is still disputed (Malhi and Outhred, 2016). Acute lithium exposure has an activating effect on excitable organic tissue and organisms, and is highly toxic (Schou, 1957; Butler-Munro et al., 2010; Izsak et al., 2021; Yip and Yeung, 2007). Lithium exposure is associated with a strong metabolic response in the organism, with large changes in phospholipid and cholesterol expression (López-Corcuera et al., 1988; Pettegrew et al., 2001; Aliyazicioğlu et al., 2007). Opposite to acute exposure, this metabolic response alleviates excessive cellular activity (Mertens et al., 2015; Stern et al., 2018; Santos et al., 2021). The presence of lithium ions strongly affects lipid conformation and membrane phase unlike other alkali ions (Hauser and Shipley, 1983), with consequences for membrane permeability, buffer property and excitability. This review investigates how lithium ions affect lipid membrane composition and function, and how lithium response might in fact be the body's attempt to counteract the physical presence of lithium ions at cell level. Ideas for further research in microbiology and drug development are discussed.

Large changes in vegetation composition seen over the last 50 years in British limestone pavements

Abstract Limestone pavements contain a unique flora, dominated by ferns with a mix of herbaceous species more often found in woodlands, heathlands and grasslands. The crevices between the rocks are known as grikes, they provide a shaded habitat which, depending on pavement structure, can protect plants from grazing. Despite being of conservation importance and supporting a number of rare and scarce plant species there has been very little research into vegetation change in limestone pavements. This study repeated a survey originally conducted between 1972 and 1975. The Ward and Evans survey visited 535 limestone pavement units spread across England, Scotland and Wales and recorded grike vegetation. This study was able to resurvey 516 of those pavements and repeat the survey using the original methods. Expansion of tree and shrub cover has been observed in some pavements but not previously quantified so tree cover was assessed using historic aerial photographs and satellite imagery. On average species richness per pavement increased but there was a very wide range of change in species richness across individual pavement units ranging from a loss of 56 species to an increase of 38. Dissimilarity averaged 0.41. The area of pavement covered by trees or large shrubs increased by 62% between the two surveys but the number of pavements with zero tree cover also increased. Breaking down pavement units into those with low (<5%), medium (5%–30%) and high (>30%) current tree cover shows that species richness increased in open pavements but was reduced in pavements with high tree cover. Pavement units with high tree cover also showed higher dissimilarity and lower levels of indicators of disturbance. In pavements with high tree cover Ellenberg light (L) values were significantly lower than in open pavements. Open pavements showed higher levels of competitive species (based on Grime CSR values) but no change difference in Ellenberg nutrient (N) values. Vegetation in limestone pavements has changed considerably in the period between the two surveys with negative effects of high tree and shrub cover particularly problematic. There is an urgent need for investigation to support management decisions in this habitat. Read the free Plain Language Summary for this article on the Journal blog.

Multimodal signalling in manakins: lack of correlated evolution between acoustic, visual and behavioural traits

Sexual traits, such as visual adornments, sound‐based cues and courtship dances, are frequently displayed in combination as multimodal signals. Some hypotheses propose that different signals trade‐off with each other, potentially due to resource limitations (‘trade‐off’ or transfer hypothesis) or that these develop simultaneously to enhance communication effectiveness (‘joint evolution’ hypothesis). Alternatively, multiple cues may evolve independently to serve distinct functions or convey different information (‘multiple messages’ hypothesis). Here, we explored the interdependence between different signal modalities in manakins (Pipridae), which are known for great interspecific diversity in the degree of elaboration in courtship dance, song and plumage coloration. We also used comparative methods to explore the mode of evolution and the degree of conservatism of these signals. We found that song, plumage coloration and courtship dance evolved independently as there was no correlation between these traits. Song evolution in manakins was attracted to a single optimum and exhibited a weak phylogenetic signal in comparison with those of colour and behavioural diversity. The high support found for the speciational and κ models when analysing the multivariate estimates of trait variability suggests that these signals (especially colour and behaviour attributes) may have evolved in a punctuated manner, with large evolutionary changes at speciation events and minimal subsequent changes along the branches. Our results show that song, colour and dance diversity are each associated (or marginally associated) with different ecological factors, indicating that sexual signals in manakins might convey different information and/or respond to different selection pressures. Larger species and those with lower dispersal capacity tend to exhibit higher colour richness, which in turn differed among lek categories, being higher in species with ‘classic’ leks and lower in non‐lekking species. Overall, the present study supports the idea that correlation between signal modalities does not constitute a widespread pattern in songbirds.

Enhancing topological index of calcium chloride network through feature selection methods exploration.

With the chemical formula CaCl2, calcium chloride is a salt as well as an inorganic material. At room temperature, it has the consistency of a white, crystalline solid and is very water-soluble. It can be created by neutralizing calcium hydroxide with hydrochloric acid. Calcium chloride is a solution with a large enthalpy change. It is extensively utilized in research facilities, manufacturing facilities, and pharmaceuticals, including all types of food-graded applications, the treatment of acute illnesses, packaging for drying tubes, dust controllers, and de-icing, among other uses. In this paper, firstly we compute the topological indices, coindices, and reverse indices of CaCl2. Further, we employ machine learning strategies to capture the best suitable set of indices for the proximity of the prediction of distinct physio-chemical properties of CaCl2. To strengthen the results, different regression techniques are implemented to predict HOF of CaCl2 based on our features, and the most influential features were detected to verify our results.

Deep mutational scanning of H5 hemagglutinin to inform influenza virus surveillance.

H5 influenza is considered a potential pandemic threat. Recently, H5 viruses belonging to clade 2.3.4.4b have caused large outbreaks in avian and multiple nonhuman mammalian species. Previous studies have identified molecular phenotypes of the viral hemagglutinin (HA) protein that contribute to pandemic potential in humans, including cell entry, receptor preference, HA stability, and reduced neutralization by polyclonal sera. However, prior experimental work has only measured how these phenotypes are affected by a handful of the >10,000 different possible amino-acid mutations to HA. Here, we use pseudovirus deep mutational scanning to measure how all mutations to a 2.3.4.4b H5 HA affect each phenotype. We identify mutations that allow HA to better bind α2-6-linked sialic acids and show that some viruses already carry mutations that stabilize HA. We also measure how all HA mutations affect neutralization by sera from mice and ferrets vaccinated against or infected with 2.3.4.4b H5 viruses. These antigenic maps enable rapid assessment of when new viral strains have acquired mutations that may create mismatches with candidate vaccine virus, and we show that a mutation present in some recent H5 HAs causes a large antigenic change. Overall, the systematic nature of deep mutational scanning combined with the safety of pseudoviruses enables comprehensive measurements of the phenotypic effects of mutations that can inform real-time interpretation of viral variation observed during surveillance of H5 influenza.

Land-use competition in 1.5°C climate stabilization: is there enough land for all potential needs?

Achieving a low-carbon future requires a comprehensive approach that combines emission mitigation options from economic activities with the sustainable use of land for numerous needs: food production, energy production, carbon sequestration, nature preservation and broad ecosystem services. Using the MIT Integrated Global System (IGSM) framework we analyze land-use competition in a 1.5°C climate stabilization scenario, in which demand for bioenergy and natural sinks increase along with the need for sustainable farming and food production. We find that to address the numerous trade-offs, effective approaches to nature-based solutions (NBS) and agriculture practices are essential. With proper regulatory policies and radical changes in current practices, global land is sufficient to provide increased consumption of food per capita (without large diet changes) over the century while also utilizing 2.5–3.5 billion hectares (Gha) of land for NBS practices that provide a carbon sink of 3–6 gigatonnes (Gt) of CO2 per year as well as 0.4–0.6 Gha of land for energy production—0.2–0.3 Gha for 50–65 exajoules (EJ) per year of bioenergy and 0.2–0.35 Gha for 300–600 EJ/year of wind and solar power generation. We list the competing uses of land to reflect the trade-offs involved in land use decisions, and note that while there is sufficient land in our scenario, attaining this outcome, capable of delivering a 1.5°C future, requires effective policies and measures at national and global levels that promote efficient land use for food, energy and nature (including carbon sequestration) and ensure long-term commitments by decision makers from governments and industry in order to realize the benefits of climate change mitigation.

EPCO-26. LONGITUDINAL SINGLE-CELL ANALYSES IDENTIFY DRIVERS OF GENETIC, EPIGENOMIC, AND CELLULAR EVOLUTION IN IDH-MUTANT GLIOMA

Abstract Despite standard treatment, IDH-mutant gliomas inevitably recur. Previous studies suggest that therapeutic resistance may result from a combination of intratumoral cellular heterogeneity, epigenetic evolution, and acquired genetic alterations. However, how these multilayered molecular features interact to influence the evolutionary paths of IDH-mutant gliomas remains incompletely understood. To chart this evolution, 75 glioma samples were longitudinally collected from 35 patients (n = 13 oligodendroglioma, n = 22 astrocytoma) and profiled using single nucleus RNA sequencing, ATAC sequencing, and bulk DNA sequencing. Analysis of 331,016 nuclei (snRNA) revealed eight tumor microenvironment cell types and five pan-IDH-mutant malignant cellular states. The malignant states were distributed along a cellular hierarchy of stem-like populations (neural progenitor cell-like, oligodendrocyte progenitor cell-like, and undifferentiated) and more differentiated populations (mesenchymal-like and astrocyte-like) with cycling cells enriched in the stem-like populations. Joint open chromatin accessibility data (snATAC) was available for a subset of malignant cells (71,088 nuclei) and state-specific differentially accessible peaks supported that these states are epigenetically encoded. Across both subtypes, higher tumor grade was associated with reduced malignant cell differentiation and increased cycling populations. Between the two time points, we identified that there was a longitudinal increase in the cycling, undifferentiated, and mesenchymal-like populations with a corresponding decrease in the astrocyte-like population. Longitudinal genetic analysis revealed that 19 of 35 tumors acquired at least one of the following genetic alterations: treatment-associated hypermutation, cell cycle alteration, or large changes in copy number alterations. Importantly, tumors that acquired these key genetic alterations demonstrated significant shifts towards reduced differentiation and increased cycling populations while those tumors that did not had more stable malignant profiles. Collectively, our results suggest a common cellular hierarchy across IDH-mutant gliomas with a shift towards reduced differentiation, increased cycling populations during disease progression that is driven by acquired genetic alterations.

Assessment of the Concentration of Transforming Growth Factor Beta 1–3 in Degenerated Intervertebral Discs of the Lumbosacral Region of the Spine

The purpose of this study was to evaluate the feasibility of using the expression profile of transforming growth factor beta (TGF-β-1-3) to assess the progression of L/S spine degenerative disease. The study group consisted of 113 lumbosacral (L/S) intervertebral disc (IVD) degenerative disease patients from whom IVDs were collected during a microdiscectomy, whereas the control group consisted of 81 participants from whom IVDs were collected during a forensic autopsy or organ harvesting. Hematoxylin and eosin staining was performed to exclude degenerative changes in the IVDs collected from the control group. The molecular analysis consisted of reverse-transcription real-time quantitative polymerase chain reaction (RT-qPCR), an enzyme-linked immunosorbent assay (ELISA), Western blotting, and an immunohistochemical analysis (IHC). In degenerated IVDs, we noted an overexpression of all TGF-β-1-3 mRNA isoforms with the largest changes observed for TGF-β3 isoforms (fold change (FC) = 19.52 ± 2.87) and the smallest for TGF-β2 (FC = 2.26 ± 0.16). Changes in the transcriptional activity of TGF-β-1-3 were statistically significant (p < 0.05). Significantly higher concentrations of TGF-β1 (2797 ± 132 pg/mL vs. 276 ± 19 pg/mL; p < 0.05), TGF-β2 (1918 ± 176 pg/mL vs. 159 ± 17 pg/mL; p < 0.05), and TGF-β3 (2573 ± 102 pg/mL vs. 152 ± 11 pg/mL) were observed in degenerative IVDs compared with the control samples. Determining the concentration profiles of TGF-β1-3 appears to be a promising monitoring tool for the progression of degenerative disease as well as for evaluating its treatment or developing new treatment strategies with molecular targets.

Interplay of c- and a-domains on the anomalous electrocaloric effect in BaTiO3 (001) single crystals

Electrocaloric effects of adiabatic temperature change via the application of external electric fields are explored for energy-efficient solid-state refrigeration. These effects are typically estimated from the thermodynamic analyses of polarization and field in electrocaloric materials, which implies that higher field application gives larger temperature changes. However, this may not be always true. Here, using both indirect and direct methods, we report an anomalous effect where larger thermal changes occur by applications of lower fields in a multi-domain BaTiO3 (001) single crystal. A large temperature change of 1.9 K under a low field change of 8 kV/cm at 404 K is observed in a multi-domain BaTiO3 (001) single crystal in comparison to that of 1.4 K at a high field change of 30 kV/cm. We attribute this counterintuitive effect to the interplay of the c- and a-domains in the BaTiO3 (001) single crystal under the influence of temperature and field changes. This work provides a fundamental understanding of the complex role of domains in governing the electrocaloric response of ferroelectric materials which is often overlooked but critical for their practical applications.

Predicting binding events in very flexible, allosteric, multi-domain proteins.

Knowledge of the structures formed by proteins and small molecules is key to understand the molecular principles of chemotherapy and for designing new and more effective drugs. During the early stage of a drug discovery program, it is customary to predict ligand-protein complexes in silico , particularly when screening large compound databases. While virtual screening based on molecular docking is widely used for this purpose, it generally fails in mimicking binding events associated with large conformational changes in the protein, particularly when the latter involve multiple domains. In this work, we describe a new methodology to generate bound-like conformations of very flexible and allosteric proteins bearing multiple binding sites by exploiting only information on the unbound structure and the putative binding sites. The protocol is validated on the paradigm enzyme adenylate kinase, for which we generated a significant fraction of bound-like structures. A fraction of these conformations, employed in ensemble-docking calculations, allowed to find native-like poses of substrates and inhibitors (binding to the active form of the enzyme), as well as catalytically incompetent analogs (binding the inactive form). Our protocol provides a general framework for the generation of bound-like conformations of challenging drug targets that are suitable to host different ligands, demonstrating high sensitivity to the fine chemical details that regulate protein's activity. We foresee applications in virtual screening, in the prediction of the impact of amino acid mutations on structure and dynamics, and in protein engineering.

An integrated empirical and computational study to decipher help-seeking behaviors and vocal stigma

BackgroundProfessional voice users often experience stigma associated with voice disorders and are reluctant to seek medical help. This study deployed empirical and computational tools to (1) quantify the experience of vocal stigma and help-seeking behaviors in performers; and (2) predict their modulations with peer influences in social networks.MethodsExperience of vocal stigma and information-motivation-behavioral (IMB) skills were prospectively profiled using online surveys from a total of 403 Canadians (200 singers and actors and 203 controls). Data were used to formulate an agent-based network model of social interactions on vocal stigma (self-stigma and social-stigma) and help-seeking behaviors. Network analysis was performed to evaluate the effect of social network structure on the flow of IMB among virtual agents.ResultsLarger social networks are more likely to contribute to an increase in vocal stigma. For small social networks, total stigma is reduced with higher total IMB but not much so for large networks. For agents with high social-stigma and risk for voice disorder, their vocal stigma is resistant to large changes in IMB ( > 2 standard deviations). Agents with extreme IMB and stigma values are likely to polarize their networks faster in larger social groups.ConclusionsWe integrated empirical surveys and computational techniques to contextualize vocal stigma and IMB beyond theory and to quantify the interaction among stigma, health-seeking behavior and influence of social interactions. This work establishes an effective, predictable experimental platform to provide scientific evidence in developing interventions to reduce health stigma in voice disorders and other medical conditions.