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The article discusses the outcomes of the "World Knowledge Dialogue 2023" international congress, focusing on the future of culture in the digital age. Experts from various disciplines reflected on innovative solutions for financing and governance in the arts, particularly in response to digital technologies. Recommendations included separating content providers from distributors, promoting transparency in cultural production, and exploring Web3 technology for artist remuneration. The conference aimed to improve artists' creativity, remuneration, and ultimately cultural diversity in the digital era. [Extracted from the article]

Introduction: Short post‐learning breaks, lasting from 5 to 30 min, transiently enhance procedural motor memory performance in adults. However, the impact of activity type (active vs. passive) during the offline break on sequential motor performance remains poorly investigated in children. Method: This study examined the impact of active versus passive post‐learning breaks on procedural motor memory in 116 healthy participants (58 children, aged 9.03 ± 1.19; 58 adults, aged 22.89 ± 1.77 years). Participants practiced a Finger Tapping Task, reproducing a five‐element keypress sequence as fast and accurately as possible. The task included two sessions (S1 and S2) separated by either a short (30 min) or long (4 h) break. The first 30‐min of the post‐learning break included either a passive (remaining still) or an active (engaging in daily activities) condition. Results: Repeated‐measures ANOVA revealed significant Session × Age group × Break duration and Session × Break type interaction effects (ps < 0.05). Post hoc analyses indicated Session effects in adults after both Break types, but only after short Break duration (S1 < S2, p < 0.001; long delay p = 0.1). In children, Session effects were observed after both short and long breaks, but only in the active Break type (S1 < S2, ps < 0.001; passive condition p = 0.1). Conclusion: These results revealed spontaneous post‐learning motor performance improvements at both short and long delays in children, but only in the active post‐training condition, unlike adults who showed improvements only at short delays, regardless of activity type. This suggests developmental differences in offline conditions (duration and activity) linked to plasticity mechanisms underlying procedural motor memory consolidation. [ABSTRACT FROM AUTHOR]

The article discusses the role of anaplastic lymphoma kinase (ALK) as a potential therapeutic target for inflammatory itch in skin conditions. The study found increased expression of Alkal2 and pAlk in mouse models of inflammatory itch, suggesting a potential role in itch development. Inhibiting Alk with lorlatinib alleviated itch symptoms in mice without affecting inflammation, indicating a promising therapeutic approach for chronic inflammatory itch. The research highlights the importance of the neuronal Alkal2-Alk axis in the development of itch and proposes targeting Alkal2 as a potential treatment strategy. [Extracted from the article]

In this study we describe an adult left first pollical (thumb) proximal phalanx (I2-104) from the Baume de Moula-Guercy (Ardèche, France) and we evaluate its taxonomic status. We first describe this bone in detail, taking into account its pathology, before comparing it, through multivariate analyses, with a diverse sample of recent and fossil humans. Based on metric and morphological comparisons, we show that this phalanx belongs to a Neandertal individual who suffered from osteoarthritis. Osteoarthritis can have different origins, including overuse, degeneration, trauma and infection. Each of these possible etiologies is explored in our study. Although the cause is difficult to identify, the pathology in this individual may represent an inflammatory reaction caused by repeated and intense vibrations provoked by the high-frequency knapping of the left hand over time. [ABSTRACT FROM AUTHOR]

[Display omitted] Protein body (PB) formation in wheat seeds is a critical process influencing seed content and nutritional quality. In this study, we investigate the potential mechanisms governing PB formation through an in vitro approach, focusing on γ-gliadin, a key wheat storage protein. We used a microfluidic technique to encapsulate γ-gliadin within giant unilamellar vesicles (GUVs) and tune the physicochemical conditions in a controlled and rapid way. We examined the influence of pH and protein concentration on LLPS and protein-membrane interactions using various microscopy and spectroscopy techniques. We showed that γ-gliadin encapsulated in GUVs can undergo a pH-triggered liquid–liquid phase separation (LLPS) by two distinct mechanisms depending on the γ-gliadin concentration. At low protein concentrations, γ-gliadins phase separate by a nucleation and growth-like process, while, at higher protein concentration and pH above 6.0, γ-gliadin formed a bi-continuous phase suggesting a spinodal decomposition-like mechanism. Fluorescence and microscopy data suggested that γ-gliadin dense phase exhibited affinity for the GUV membrane, forming a layer at the interface and affecting the reversibility of the phase separation. [ABSTRACT FROM AUTHOR]

This study examined the relationship between exposure to community violence and HIV care engagement among 107 Black gay or bisexual men living with HIV in Chicago. Measures assessed the importance of demographic covariates (age, annual income, health insurance status, and years living with HIV), community violence exposures, mental health, social support, in explaining variations in missed doses of antiretroviral therapy (ART) medication and missed HIV care appointments. Results showed that participants who reported higher rates of exposure to community violence were two times more likely to have missed ART doses and HIV care appointments. Participants who reported depression scores were two times more likely to have greater non-ART adherence. Finally, older participants were more likely to report fewer missed ART doses. More research is needed to clarify the mechanisms between age or depression and ART adherence given community violence exposure. Health care providers should screen for depression when attempting to promote better ART adherence and keeping HIV care appointments for Black gay and bisexual men living with HIV. Younger Black gay and bisexual men living with HIV may be more vulnerable than older men for missed ART doses and may require additional screening and follow-up. [ABSTRACT FROM AUTHOR]

In 2008, the Council for Social Work Education re-envisioned its accreditation framework. The primary intent was to advance more equitable social work educational environments, which required highlighting curriculum content, and the culture of human interchange. Still, little has been provided regarding their intersectional effects on classroom culture, or students' educational experiences. To respond to this gap, this study explores the realities of 17 African-American male social work students attending predominantly White collegiate institutions. Interpretive phenomenological analysis, social dominance theory, and Foucauldian power were used to explore and contextualize participants' experiences. Major findings highlight the nuanced ways gender and race intersect with power, curriculum, and pedagogical practices to protect and promote historically normative structures of racial dominance within social work education. [ABSTRACT FROM AUTHOR]

Advance care planning (ACP) supports individuals in aligning their medical care with personal values and preferences in the face of serious illness. The variety of ACP tools available reflects diverse strategies intended to facilitate these critical conversations, yet evaluations of their effectiveness often show mixed results. Following the Arskey and O'Malley framework, this scoping review aims to synthesize the range of ACP tools targeted at patients and families, highlighting their characteristics and delivery methods to better understand their impact and development over time. Studies included focused on patient-facing ACP tools across all settings and mediums. Exclusions were applied to studies solely targeting healthcare providers or those only aiming at completion of advance directives without broader ACP discussions. Searches were conducted across PubMed, Embase, CINAHL, The Cochrane Library, and Web of Science. Data were extracted using a predesigned spreadsheet, capturing study population, setting, intervention modality, and intervention theme. Tools were categorized by delivery method and further analyzed through a year-wise distribution to track trends and developments. We identified 99 unique patient-facing tools, with those focusing on counseling (31) and video technologies (21) being the most prevalent while others incorporated online platforms, print materials, games, or some combination of different delivery methods. Over half the tools were designed for specific patient groups, especially for various diseases and racial or ethnic communities. Recent years showed a surge in tool variety and innovation, including integrated patient portals and psychological techniques. The review demonstrates a broad array of innovative ACP tools that facilitate personalized and effective ACP. Our findings contribute to an enhanced understanding of their utilization and potential impacts, offering valuable insights for future tool development and policy making in ACP. Plain language summary: Scanning the landscape of tools to assist patients with advance care planning This review investigates the variety of tools, programs, and interventions designed to help patients plan their healthcare in advance, a process known as advance care planning (ACP). ACP is crucial because it ensures individuals receive medical care aligned with their wishes, especially during serious illness or near the end of life. Our study gathered information from various sources, focusing on tools aimed directly at patients and their families. We found 99 unique tools that assist in ACP, including individual counseling sessions, video-based tools, and digital platforms. Some tools are designed specifically for certain patient groups, such as those with particular diseases or belonging to diverse racial and ethnic communities. Our review highlights the recent surge in the variety and innovation of these tools, such as integrated patient portals and methods incorporating psychological techniques, suggesting a growing effort to make ACP more accessible and tailored to individual needs. However, despite this variety, more research is needed to understand how these tools impact healthcare outcomes and how they can be effectively implemented in different care settings. Our findings aim to guide future development of ACP tools, improve their integration into healthcare practices, and ensure they meet the diverse needs of patients and families. [ABSTRACT FROM AUTHOR]

This scoping review examined peer-reviewed and gray literature to explore what a "no-to-low external input" statement means for regenerative agriculture. Five organic amendment inputs (compost extract, manure, mulch, biochar, food systems waste) and four land management processes (livestock management and integration, crop diversity, tillage reduction, comprehensive approach) were identified. Findings include "no-to-low external input" models arising from processes which function to displace external inputs (e.g., synthetic fertilizer). Organic amendment inputs and regenerative land management processes promote biology and improve nutrient cycling at soil, farm, and landscape scales. Regenerative agriculture overlaps with other farming practices including those associated with agroecology and conservation agriculture. [ABSTRACT FROM AUTHOR]

Exercise training prevents age‐related decline in muscle function. Targeting epigenetic aging is a promising actionable mechanism and late‐life exercise mitigates epigenetic aging in rodent muscle. Whether exercise training can decelerate, or reverse epigenetic aging in humans is unknown. Here, we performed a powerful meta‐analysis of the methylome and transcriptome of an unprecedented number of human skeletal muscle samples (n = 3176). We show that: (1) individuals with higher baseline aerobic fitness have younger epigenetic and transcriptomic profiles, (2) exercise training leads to significant shifts of epigenetic and transcriptomic patterns toward a younger profile, and (3) muscle disuse "ages" the transcriptome. Higher fitness levels were associated with attenuated differential methylation and transcription during aging. Furthermore, both epigenetic and transcriptomic profiles shifted toward a younger state after exercise training interventions, while the transcriptome shifted toward an older state after forced muscle disuse. We demonstrate that exercise training targets many of the age‐related transcripts and DNA methylation loci to maintain younger methylome and transcriptome profiles, specifically in genes related to muscle structure, metabolism, and mitochondrial function. Our comprehensive analysis will inform future studies aiming to identify the best combination of therapeutics and exercise regimes to optimize longevity. [ABSTRACT FROM AUTHOR]

The nucleoskeleton forms a filamentous meshwork under the nuclear envelope and contributes to the regulation of nuclear shape and gene expression. To understand how the Arabidopsis (Arabidopsis thaliana) nucleoskeleton physically connects to the nuclear periphery in plants, we investigated the Arabidopsis nucleoskeleton protein KAKU4 and sought for functional regions responsible for its localization at the nuclear periphery. We identified 3 conserved peptide motifs within the N-terminal region of KAKU4, which are required for intermolecular interactions of KAKU4 with itself, interaction with the nucleoskeleton protein CROWDED NUCLEI (CRWN), localization at the nuclear periphery, and nuclear elongation in differentiated tissues. Unexpectedly, we find these motifs to be present also in NUP82 and NUP136, 2 plant-specific nucleoporins from the nuclear pore basket. We further show that NUP82, NUP136, and KAKU4 have a common evolutionary history predating nonvascular land plants with KAKU4 mainly localizing outside the nuclear pore suggesting its divergence from an ancient nucleoporin into a new nucleoskeleton component. Finally, we demonstrate that both NUP82 and NUP136, through their shared N-terminal motifs, interact with CRWN and KAKU4 proteins revealing the existence of a physical continuum between the nuclear pore and the nucleoskeleton in plants. The KAKU4 protein, a component of the plant nucleoskeleton, diverged from an ancestral nucleoporin and provides a continuum between the nucleoskeleton and the nuclear pore complex basket via short peptide motifs. [ABSTRACT FROM AUTHOR]

Background: Adults with neuromuscular diseases like spinal muscular atrophy or Duchenne muscular dystrophy require full-time use of a wheelchair (WC) and perform all activities of daily living in a sitting position. Optimal configuration of the WC and seating system is essential to maintain the health and quality of life of users. However, few recommendations for configuration exist. The aim of this study was to identify and select 10 WC seating criteria that ensure an optimal sitting posture for health and quality of life. Methods: A four round Delphi method was used to collect the opinions of WC users and health professionals (HP), separately. First, the HP were asked if they believed that different criteria would apply to each disease. Then the HP and SMA II and DMD WC user experts responded to electronic surveys in 4 rounds. Results: Overall, 74 experts took part: 31 HP, 21 WC users with SMA II and 22 WC users with DMD. In total, 52% of HP believed that different criteria would apply to each disease. Ten criteria were identified by the HP for SMA II and 10 for DMD. Of the 40 criteria selected, 30 (75%) were common to each panel. Six topics were similar across panels: comfort, access to the joystick, prevention of pain, stability, pressure management and power seat functions. However, power seat functions did not reach consensus between HP and WC users (30–33% of agreement for HP and 93–100% for the WC user panels, p < 0.001). Conclusion: Adults with SMA II and DMD had similar WC seating needs. Therefore, the same recommendations can be applied to these groups. Further research is necessary to understand the impact of cost on the prescription of power seat functions by health professionals. [ABSTRACT FROM AUTHOR]

Aims. Assuming fast radio bursts (FRBs) are produced by matter travelling ultra-relativistically in a localised region of a smooth bundle of streamlines, we study the constraints applied by geometry to the morphology and polarisation of the burst in time and frequency independently of the intrinsic radiative process. Methods. We express the problem only in terms of the local properties of direction and curvature of a streamline. This allowed us to cast the general results to any desired geometry. By applying this framework to two geometries inspired by pulsar and magnetar magnetospheres, we namely illustrate the dipolar polar-cap region and a magnetic dipole with an additional toroidal component. Results. Geometry constrains bursts to occur within an envelope in the frequency versus time plane (dynamic spectrum). This envelope notably characterises spectral occupancy and frequency drifts (both burst-to-burst and within an individual burst). We illustrate how one can simulate bursts by specifying some basic properties of an intrinsic emission process. In particular we show that the typical properties of one-off bursts can be produced in polar-cap geometry by a star with a spin period > 1 s, while bursts from repeating sources are better accounted for with an additional strong toroidal component and a sub-second spin period. Conclusions. We propose that a relationship between burst morphologies and the properties of the source, such as its spin period and magnetospheric properties, can be established at least qualitatively based on geometrical considerations. Our results favour models where repeaters are younger and faster magnetars with highly twisted magnetospheres. [ABSTRACT FROM AUTHOR]

CD59 is a GPI-anchored cell surface receptor that serves as a gatekeeper to controlling pore formation. It is the only membrane-bound inhibitor of the complement membrane attack complex (MAC), an immune pore that can damage human cells. While CD59 blocks MAC pores, the receptor is co-opted by bacterial pore-forming proteins to target human cells. Recent structures of CD59 in complexes with binding partners showed dramatic differences in the orientation of its ectodomain relative to the membrane. Here, we show how GPI-anchored CD59 can satisfy this diversity in binding modes. We present a PyLipID analysis of coarse-grain molecular dynamics simulations of a CD59-inhibited MAC to reveal residues of complement proteins (C6:Y285, C6:R407 C6:K412, C7:F224, C8β:F202, C8β:K326) that likely interact with lipids. Using modules of the MDAnalysis package to investigate atomistic simulations of GPI-anchored CD59, we discover properties of CD59 that encode the flexibility necessary to bind both complement proteins and bacterial virulence factors. [ABSTRACT FROM AUTHOR]

HBr emissions from volcanoes lead rapidly to the formation of BrO within volcanic plumes and have an impact on tropospheric chemistry, at least at the local and regional scales. The motivation of this paper is to prepare a framework for further 3D modelling of volcanic halogen emissions in order to determine their fate within the volcanic plume and then in the atmosphere at the regional and global scales. The main aim is to evaluate the ability of the model to produce a realistic partitioning of bromine species within a grid box size typical of MOCAGE (Model Of atmospheric Chemistry At larGE scale) 3D (0.5 ∘ × 0.5 ∘). This work is based on a 1D single-column configuration of the global chemistry-transport model MOCAGE that has low enough computational cost to allow us to perform a large set of sensitivity simulations. This paper uses the emissions from the Mount Etna eruption on 10 May 2008. Several reactions are added to MOCAGE to represent the volcanic plume halogen chemistry. A simple plume parameterisation is also implemented and tested. The use of this parameterisation tends to only slightly limit the efficiency of BrO net production. Both simulations with and without the parameterisation give results for the partitioning of the bromine species, of ozone depletion and of the BrO/SO2 ratio that are consistent with previous studies. A series of test experiments were performed to evaluate the sensitivity of the results to the composition of the emissions (primary sulfate aerosols, Br radical and NO) and to the effective radius assumed for the volcanic sulfate aerosols. Simulations show that the plume chemistry is sensitive to all these parameters. We also find that the maximum altitude of the eruption changes the BrO production, which is linked to the vertical variability of the concentrations of oxidants in the background air. These sensitivity tests display changes in the bromine chemistry cycles that are generally at least as important as the plume parameterisation. Overall, the version of the MOCAGE chemistry developed for this study is suitable to produce the expected halogen chemistry in volcanic plumes during daytime and night-time. [ABSTRACT FROM AUTHOR]

The rise of Industry 4.0 technologies has revolutionized industries, enabled seamless data access, and fostered data-driven methodologies for improving key production processes such as maintenance. Predictive maintenance has notably advanced by aligning decisions with real-time system degradation. However, data-driven approaches confront challenges such as data availability and complexity, particularly at the system level. Most approaches address component-level issues, but system complexity exacerbates problems. In the realm of predictive maintenance, this paper proposes a framework for addressing drift detection and diagnosis in heterogeneous manufacturing processes. The originality of the paper is twofold. First, this paper proposes algorithms for handling drift detection and diagnosing heterogeneous processes. Second, the proposed framework leverages several machine learning techniques (e.g., novelty detection, ensemble learning, and continuous learning) and algorithms (e.g., K-Nearest Neighbors, Support Vector Machine, Random Forest and Long-Short Term Memory) for enabling the concrete implementation and scalability of drift detection and diagnostics on industrial processes. The effectiveness of the proposed framework is validated through metrics such as accuracy, precision, recall, F1-score, and variance. Furthermore, this paper demonstrates the relevance of combining machine learning and deep learning algorithms in a production process of SEW USOCOME, a French manufacturer of electric gearmotors and a market leader. The results indicate a satisfactory level of accuracy in detecting and diagnosing drifts, and the adaptive learning loop effectively identifies new drift and nominal profiles, thereby validating the robustness of the framework in real industrial settings. [ABSTRACT FROM AUTHOR]

Predicting the remaining useful life of equipment can help organizations improve efficiency, reduce costs and enhance safety by enabling them to plan maintenance and repairs, and optimize their use of equipment. A major challenge in this field is the development of accurate deep learning models, particularly when data is limited to a few run-to-failure trajectories. Traditional methods, such as pre-training on a larger dataset followed by fine-tuning on the main data, often fall short under these constraints. To address this challenge, we propose an auxiliary training approach that integrates auxiliary objectives from related but distinct datasets. This approach enriches the learning process, utilizing knowledge from a broader data range and acting as a regularization mechanism to improve generalization from limited data. The effectiveness of the proposed method is demonstrated by experiments on two well-known public datasets, CMAPSS and N-CMAPSS, across eight distinct settings, and is shown to outperform state-of-the-art approaches such as single-task learning and pre-training followed by fine-tuning. [ABSTRACT FROM AUTHOR]

[Display omitted] Aggregates of charged metal particles obtained by electrostatic coupling with a compound of opposite charge in the vicinity of the net zero charge ratio are of interest in the field of plasmonics because the inter-particle distance is minimal, which favours plasmonic coupling. However, these structures present a low colloidal stability limiting the development of applications. In this article we show that globally neutral aggregates formed by electrostatic complexation of citrate-stabilized gold particles and a quaternized chitosan (i.e., polycation) around the net zero charge ratio could be stabilized at a nanometric size by the subsequent addition of polyelectrolyte chains. Furthermore, the sign of the charge carried by the stabilizing chains determines the sign of the global charge carried by the stabilized complexes. The stabilization is demonstrated in saline environment on a broad pH range as well as in a cell culture media over periods of several days. Contrarily to stabilization by charged particles, our stabilized complexes are found to retain their initial characteristics (i.e. shape, size, internal structure and optical properties) after stabilization. Hence, the plasmonic coupling allows to maximize the optical absorption around the 800 nm wavelength at which the lasers used for thermoplasmonic and surface enhanced Raman scattering analysis operate. [ABSTRACT FROM AUTHOR]

[Display omitted] Aggregates of charged metal particles obtained by electrostatic coupling with a compound of opposite charge in the vicinity of the net zero charge ratio are of interest in the field of plasmonics because the inter-particle distance is minimal, which favours plasmonic coupling. However, these structures present a low colloidal stability limiting the development of applications. In this article we show that globally neutral aggregates formed by electrostatic complexation of citrate-stabilized gold particles and a quaternized chitosan (i.e., polycation) around the net zero charge ratio could be stabilized at a nanometric size by the subsequent addition of polyelectrolyte chains. Furthermore, the sign of the charge carried by the stabilizing chains determines the sign of the global charge carried by the stabilized complexes. The stabilization is demonstrated in saline environment on a broad pH range as well as in a cell culture media over periods of several days. Contrarily to stabilization by charged particles, our stabilized complexes are found to retain their initial characteristics (i.e. shape, size, internal structure and optical properties) after stabilization. Hence, the plasmonic coupling allows to maximize the optical absorption around the 800 nm wavelength at which the lasers used for thermoplasmonic and surface enhanced Raman scattering analysis operate. [ABSTRACT FROM AUTHOR]

Simple Summary: This review provides an update on recent evidence supporting the role of various microbiomes mediating the interactions that occur between dietary factors, inflammation, and various cancers. Microbiomes interact with localized and systemic host cell populations where they help to maintain immune homeostasis. Microbiota use different dietary factors for energy and in turn produce by-products that impact the host cell populations. Dietary factors can also influence the composition and diversity of microbiota populations, in turn impacting the interactions of the microbiomes with host. Perturbations in this system, commonly referred to as dysbiosis, have been associated with various diseases including cancer. Cancer is the second leading cause of death globally, and there is a growing appreciation for the complex involvement of diet, microbiomes, and inflammatory processes culminating in tumorigenesis. Although research has significantly improved our understanding of the various factors involved in different cancers, the underlying mechanisms through which these factors influence tumor cells and their microenvironment remain to be completely understood. In particular, interactions between the different microbiomes, specific dietary factors, and host cells mediate both local and systemic immune responses, thereby influencing inflammation and tumorigenesis. Developing an improved understanding of how different microbiomes, beyond just the colonic microbiome, can interact with dietary factors to influence inflammatory processes and tumorigenesis will support our ability to better understand the potential for microbe-altering and dietary interventions for these patients in future. [ABSTRACT FROM AUTHOR]

Current state‐of‐the art procedures for studying modeled submesoscale oceanographic features have made a strong assumption of independence between features identified at different times. Therefore, all submesoscale eddies identified in a time series were studied in aggregate. Statistics from these methods are illuminating but oversample identified features and cannot determine the lifetime evolution of the transient submesoscale processes. To this end, the authors apply the Topological Feature Tracking (TFT) algorithm to the problem of identifying and tracking submesoscale eddies over time. TFT identifies critical points on a set of time‐ordered scalar fields and associates those points between consecutive timesteps. The procedure yields tracklets which represent spatio‐temporal displacement of eddies. In this way we study the time‐dependent behavior of submesoscale eddies, which are generated by a 1‐km resolution submesoscale‐permitting model. We summarize the submesoscale eddy data set produced by TFT, which yields unique, time‐varying statistics. Plain Language Summary: Current state‐of‐the art procedures for studying small‐scale features in the ocean do not take the effects of time into account. Instead, features like small vortices are studied as a single population across many points in time. This method has provided oceanographers with many valuable insights. New insights can be added by identifying vortices and then tracking them over time to study their behavior through an algorithm designed to identify and track features on a grid. Key Points: Topological Feature Tracking is introduced as a way to identify features in scalar fields and associate those features through timeWe identify and track submesoscale eddies over 1‐year of ocean surface velocity data computed via the Navy Coastal Ocean ModelEddy statistics provide insight on lifetime, speed, and distance traversed for understanding eddy motions and scale interactions [ABSTRACT FROM AUTHOR]

The role of surgery in recurrent glioblastoma multiforme (GBM) remains a controversial topic. The goal of this study was to perform a case control analysis including time to tumor recurrence as an additional prognostic factor in order to determine which patients benefit most from repeat surgery. Our brain tumor database was reviewed over a 10-year period for all adult (≥18 years old) patients with primary isocitrate dehydrogenase wildtype GBM who received surgery for recurrent disease. These patients were then age, sex, and treatment matched to case controls from our institution who received medical therapy for recurrent disease. A total of 174 adult patients with GBM were included in the study, 87 patients who received surgery for recurrent GBM (surgery cohort) and 87 patients who did not receive surgery for recurrent GBM (nonsurgery cohort). The surgery cohort had longer overall survival (P = 0.0003) and postrecurrence survival (P = 0.001) than the nonsurgery cohort. When the surgery cohort was split into 2 groups on the basis of time to tumor recurrence, the long time to recurrence group (>6 months) demonstrated significantly increased survival compared with the short time to recurrence group (P < 0.0001). Multivariate analysis of both cohorts demonstrated surgery for recurrent GBM was independently significant after adjusting for age, Karnofsky Performance Scale, and time to tumor recurrence (P < 0.0001). Surgery for recurrent GBM leads to improved survival independent of age, Karnofsky Performance Scale, and time to tumor recurrence. Patients with time to tumor recurrence >6 months benefit most from additional surgery. [ABSTRACT FROM AUTHOR]

Age-related macular degeneration (AMD) is characterized by visual impairment observed in elderly population. Two forms of the disease are generally described, the atrophic (AMDa) and exudative forms (AMDe). Up until now, no curative treatment is available for this disease. The retinal pigment epithelium (RPE) plays a central role in the pathogenesis of age-related macular degeneration. Here, involvement of RPE dysfunction in AMD onset and progression was analyzed by a comparison of transcriptome profiles of hiPSC-RPE derived from healthy individuals or individuals affected by AMDa or AMDe. The analysis highlighted almost 1000 genes differentially expressed between the three comparison groups. Among these genes, 33 genes were already known to be involved in AMD pathogenesis. To establish an AMD genetic signature, we focused on genes differentially expressed in both AMDa/e cell lines compared to control cells and focused on the three genes (ABCA1, RPN2, RB1CC1) that were related to lipidic homeostasis. Differences in level expression of these three genes are found not only in control and AMDa/e cell lines, but also between AMDa and AMDe populations. • Genes involved in lipidic homeostasis are linked to AMD. • Lipid accumulation is higher in cells derived from AMD patients. • HiPSC-RPE AMD cells have a typical disease phenotype. [ABSTRACT FROM AUTHOR]

Volcanoes are a known source of halogens to the atmosphere. HBr volcanic emissions lead rapidly to the formation of BrO within volcanic plumes. BrO, having a longer residence time in the atmosphere than HBr, is expected to have an impact on tropospheric chemistry, at least at the local and regional scales. The objective of this paper is to prepare a framework for further 3-D modelling of volcanic halogen emissions in order to determine their fate within the volcanic plume and then in the atmosphere at the regional and global scales. This work is based on a 1-D configuration of the global chemistry transport model MOCAGE whose low computational cost allows us to perform a large set of sensitivity simulations. This paper studies the Mount Etna eruption on 10 May, 2008. Several reactions are added to MOCAGE to represent the halogen chemistry occurring within the volcanic plume. A simple sub-grid scale parameterization of the volcanic plume is also implemented and tested. The use of this parameterization tends to limit slightly the efficiency of BrO net production. Both simulations with and without the parameterization give similar results for the partitioning of the bromine species, ozone depletion and of the BrO/SO2 ratio that are consistent with previous studies and with the BrO/SO2 ratio in the volcanic plume estimated from GOME-2 spaceborne observations. A series of test experiments were performed to evaluate the sensitivity of the results to the composition of the emissions, and, in particular, primary sulphate aerosols, the Br radical, and NO. Simulations show that the plume chemistry is sensitive to these assumptions. Another series of tests on the effective radius assumed for the volcanic sulphate aerosols shows that BrO net production is sensitive to this parameter with lower BrO concentrations reached when larger aerosols (smaller total surface area) are assumed. We also find that the maximum altitude of the eruption changes the BrO production, which is linked to the vertical variability of the concentrations of oxidants. These sensitivity tests display changes in the bromine chemistry cycles that are generally at least as important as the subgrid scale plume parameterization. Overall, the version of the MOCAGE chemistry developed for this study is suitable to produce the expected halogen chemistry in volcanic plumes during daytime and night. These results will be used to guide the implementation of volcanic halogen emissions in the 3-D configuration of MOCAGE for regional and global simulations. [ABSTRACT FROM AUTHOR]

The question of neutrality at school, about environmental issues, is at the confluence of several horizons: disciplinary didactics, professional didactics, epistemology and even philosophy. This article aims to give an overview of the works, questions and current issues on neutrality in education for socially acute questions. The challenge is to open up new research perspectives while identifying tensions between the idea of neutrality and the idea of commitment, more or less conscious tensions at school (programs, knowledge and actors). A first direction looks at the history of the notion of neutrality in the Republican school and its resonance in « education for » more generally. These first readings will allow to update the debate on educational issues and the social project to be "committed" in this context. The second direction aims to study the scientific neutrality of its approach and its knowledge. Then, how the construction of knowledge in this specific framework can contribute to the development of critical thinking? The third direction is concerned with professional practices. How do teachers engage in teaching-learning these issues? Three directions, which connected, permit us to understand that the notion of neutrality invites further reflection on that of commitment. [ABSTRACT FROM AUTHOR]

SARS-CoV-2 pandemic required the establishment of total lockdown in France from March 17 to May 11, 2020. We analyzed the impact of this lockdown on the pediatric burn population consulting in our burn unit during this period compared to data from previous years in order to analyze our model of emergency care for children burned during this unprecedented situation. We carried out a retrospective single-center study by reviewing files concerning emergency consultations for children burns during the total lockdown in France in 2020 (COVID group) compared to the same weeks of 2018 and 2019 (no-COVID group). We find a significant decrease in the number of consultations (P = 0.02) during the confinement period. In the "COVID" group, we found a significant increase in burn to the hand (P = 0.03) and lower limbs (P = 0.03). The other criteria evaluated did not find any difference between the groups. Assessment of a possible rebound effect within 2 weeks of total lockdown found an increased incidence of the children burn consultation, an increased number of older children and mainly male. The decrease in the number of consultations alerts us to a potential increase in the functional sequelae of burns in these patients at risk. Longer-term follow-up will allow us to assess the consequences of this lockdown on this particularly at-risk population. [ABSTRACT FROM AUTHOR]

BACKGROUND: In recent years the global landscape of pharmaceutical development has evolved drastically in order to adapt to innovative products such as immunotherapy, regenerative medicines and cell and gene therapy, all offering the hope to cure numerous untreated diseases. The global COVID-19 pandemic also led competent authorities in charge of approval of new medicines to implement adapted regulatory pathways allowing early access to innovative treatments and vaccines. New challenges are to be overcome, it is the short development time, or the small patient populations, or again drug product features requiring complete new production, testing and distribution strategies. OBJECTIVE: This paper provides a short overview of the different adaptations required to allow the development of such innovative medicines. METHOD: Several drug development strategies for products under clinical development or recently approved were assessed. RESULTS: Fully integrated strategies encompassing research, non-clinical, clinical and product manufacturing development along with adapted regulatory pathways, anticipation of market access and supported by risk based are important. In such fast pace, the development of relevant manufacturing processes and test methods assessing quality, safety and efficacy of new drugs falls on the critical path and requires particular attention, anticipation and detailed planning as early as possible in order to ensure successful filing and approval. CONCLUSION: Insights within innovative products approved recently reveal the importance of defining a solid chemistry manufacturing and control strategy early on as part of clinical development. Interactions with agencies at key milestones of development are also essential to reduce risks, prioritize development to support safety and allow early access to patients. [ABSTRACT FROM AUTHOR]

We prove the generic Torelli theorem for hypersurfaces in $\mathbb {P}^{n}$ of degree $d$ dividing $n+1$ , for $d$ sufficiently large. Our proof involves the higher-order study of the variation of Hodge structure along particular one-parameter families of hypersurfaces that we call 'Schiffer variations.' We also analyze the case of degree $4$. Combined with Donagi's generic Torelli theorem and results of Cox and Green, this shows that the generic Torelli theorem for hypersurfaces holds with finitely many exceptions. [ABSTRACT FROM AUTHOR]

Observation of fast radio bursts (FRBs) are rising very quickly with the advent of specialized instruments and surveys, and it has recently been shown that some of them repeat quasi-periodically. In particular, evidence of a P = 16.35 d period has been reported for FRB 180916.J0158+65. We seek an explanation within the frame of our orbiting asteroid model, whereby FRBs are produced in the plasma wake of asteroids immersed in the wind of a pulsar or a magnetar. We used the data reported by the CHIME/FRB collaboration in order to infer the orbital characteristics of asteroid swarms, and performed parametric studies to explore the possible characteristics of the pulsar, its wind, and of the asteroids, under the constraint that the latter remain dynamically and thermally stable. We found a plausible configuration in which a young pulsar is orbited by a main ∼10−3 M⊙ companion with a period 3 P = 49 d, three times longer than the apparent periodicity P. Asteroids responsible for FRBs are located in three dynamical swarms near the L3, L4, and L5 Lagrange points, in a 2:3 orbital resonance akin to the Hildas class of asteroids in the Solar system. In addition, asteroids could be present in the Trojan swarms at the L4 and L5 Lagrange points. Together, these swarms form a carousel that explains the apparent P periodicity and dispersion. We estimated that the presence of at least a few thousand asteroids, of size ∼20 km, is necessary to produce the observed burst rate. We show how radius-to-frequency mapping in the wind and small perturbations by turbulence can suffice to explain downward-drifting sub-pulses, micro-structures, and narrow spectral occupancy. [ABSTRACT FROM AUTHOR]

Background: Primary malignant brain tumours account for more than one-third of all brain tumours and are associated with high morbidity and mortality. The purpose of this study was to estimate the incidence and prevalence of primary malignant central nervous system (CNS) tumours and trends in these rates in Canada from 1992 to 2017. Methods: We conducted an epidemiologic study using publicly available data from the Canadian Cancer Registry from 1992 to 2017 (1994 to 2015 for prevalence) for all of Canada except Quebec (1992 to 2011). We calculated the incidence and prevalence per 100 000 person-years and the age-standardized incidence and prevalence per 100 000 person-years of primary malignant CNS tumours and stratified them by sex and age (pediatric [≥ 19 yr], adult [20–64 yr] and older adult [> 64 yr]). Our analyses assessed average disease duration, survival differences between males and females, and trends over time. Results: During the study period, the average age-standardized incidence and prevalence rates of all primary malignant CNS tumours were 7.9 and 7.6 per 100 000 person-years, respectively. The incidence and prevalence increased by 37.5% and 40.5%, respectively, over the study period. Males accounted for more than half (26 085 [56.4%]) of all diagnoses and experienced decreased survival compared to females 1 year after diagnosis (p = 0.048). Children accounted for 4605 new diagnoses (10.0%), adults for 23 950 (51.7%), and older adults for 17 735 (38.3%). Age-standardized incidence and prevalence rates were highest among older adults. Interpretation: Overall, the incidence of primary malignant CNS tumours increased from 1992 to 2017, and males and older adults were disproportionately affected. Increased health care resources and awareness are needed to improve identification of these tumours and deliver evidence-based care that balances safety, efficacy and preservation of quality of life for affected patients. [ABSTRACT FROM AUTHOR]

The article discusses the use of Bessel beams in metal additive manufacturing, which provides better control over the spatiotemporal evolution of the melt pool compared to traditional Gaussian beams. Bessel beams reduce issues like porosity, keyhole formation, and spatter generation during the 3D printing process, resulting in 3D-printed structures with improved density, reduced surface roughness, and better mechanical properties.

The ALF transcription factor paralogs, AFF1 , AFF2 , AFF3 , and AFF4 , are components of the transcriptional super elongation complex that regulates expression of genes involved in neurogenesis and development. We describe an autosomal dominant disorder associated with de novo missense variants in the degron of AFF3, a nine amino acid sequence important for its binding to ubiquitin ligase, or with de novo deletions of this region. The sixteen affected individuals we identified, along with two previously reported individuals, present with a recognizable pattern of anomalies, which we named KINSSHIP syndrome (KI for horseshoe kidney, NS for Nievergelt/Savarirayan type of mesomelic dysplasia, S for seizures, H for hypertrichosis, I for intellectual disability, and P for pulmonary involvement), partially overlapping the AFF4- associated CHOPS syndrome. Whereas homozygous Aff3 knockout mice display skeletal anomalies, kidney defects, brain malformations, and neurological anomalies, knockin animals modeling one of the microdeletions and the most common of the missense variants identified in affected individuals presented with lower mesomelic limb deformities like KINSSHIP-affected individuals and early lethality, respectively. Overexpression of AFF3 in zebrafish resulted in body axis anomalies, providing some support for the pathological effect of increased amount of AFF3. The only partial phenotypic overlap of AFF3 - and AFF4 -associated syndromes and the previously published transcriptome analyses of ALF transcription factors suggest that these factors are not redundant and each contributes uniquely to proper development. [ABSTRACT FROM AUTHOR]

Acute and chronic itch are burdensome manifestations of skin pathologies including allergic skin diseases and atopic dermatitis, but the underlying molecular mechanisms are not well understood. Cysteinyl leukotrienes (CysLTs), comprising LTC4, LTD4, and LTE4, are produced by immune cells during type 2 inflammation. Here, we uncover a role for LTC4 and its signaling through the CysLT receptor 2 (CysLT2R) in itch. Cysltr2 transcript is highly expressed in dorsal root ganglia (DRG) neurons linked to itch in mice. We also detected CYSLTR2 in a broad population of human DRG neurons. Injection of leukotriene C4 (LTC4) or its nonhydrolyzable form NMLTC4, but neither LTD4 nor LTE4, induced dose-dependent itch but not pain behaviors in mice. LTC4-mediated itch differed in bout duration and kinetics from pruritogens histamine, compound 48/80, and chloroquine. NMLTC4-induced itch was abrogated in mice deficient for Cysltr2 or when deficiency was restricted to radioresistant cells. Itch was unaffected in mice deficient for Cysltr1, Trpv1, or mast cells (WSh mice). CysLT2R played a role in itch in the MC903 mouse model of chronic itch and dermatitis, but not in models of dry skin or compound 48/80- or Alternaria-induced itch. In MC903-treated mice, CysLT levels increased in skin over time, and Cysltr2-/- mice showed decreased itch in the chronic phase of inflammation. Collectively, our study reveals that LTC4 acts through CysLT2R as its physiological receptor to induce itch, and CysLT2R contributes to itch in a model of dermatitis. Therefore, targeting CysLT signaling may be a promising approach to treat inflammatory itch. [ABSTRACT FROM AUTHOR]

Atherosclerosis and obesity share pathological features including inflammation mediated by innate and adaptive immune cells. LXRα plays a central role in the transcription of inflammatory and metabolic genes. LXRα is modulated by phosphorylation at serine 196 (LXRα pS196), however, the consequences of LXRα pS196 in hematopoietic cell precursors in atherosclerosis and obesity have not been investigated. To assess the importance of LXRα phosphorylation, bone marrow from LXRα WT and S196A mice was transplanted into Ldlr−/− mice, which were fed a western diet prior to evaluation of atherosclerosis and obesity. Plaques from S196A mice showed reduced inflammatory monocyte recruitment, lipid accumulation, and macrophage proliferation. Expression profiling of CD68+ and T cells from S196A mouse plaques revealed downregulation of pro-inflammatory genes and in the case of CD68+ upregulation of mitochondrial genes characteristic of anti-inflammatory macrophages. Furthermore, S196A mice had lower body weight and less visceral adipose tissue; this was associated with transcriptional reprograming of the adipose tissue macrophages and T cells, and resolution of inflammation resulting in less fat accumulation within adipocytes. Thus, reducing LXRα pS196 in hematopoietic cells attenuates atherosclerosis and obesity by reprogramming the transcriptional activity of LXRα in macrophages and T cells to promote an anti-inflammatory phenotype. Voisin et al. show that reducing phosphorylation at serine 196 of LXRα (LXRα pS196) in hematopoietic cells attenuates atherosclerosis and obesity of mice fed a high-fat diet. They find that the transcriptional activity of LXRα is reprogrammed in macrophages and T cells to promote an anti-inflammatory phenotype, thus identifying a functional role of LXRα pS196 in immune cells. [ABSTRACT FROM AUTHOR]

This review summarised robust and consistent genetic variants associated with aerobic-related and resistance-related phenotypes. In total we highlight 12 SNPs and 7 SNPs that are robustly associated with variance in aerobic-related and resistance-related phenotypes respectively. To date, there is very little literature ascribed to understanding the interplay between genes and environmental factors and the development of physiological traits. We discuss future directions, including large-scale exercise studies to elucidate the functional relevance of the discovered genomic markers. This approach will allow more rigour and reproducible research in the field of exercise genomics. [ABSTRACT FROM AUTHOR]

Spider pulsars are binary systems containing an energetic millisecond pulsar that intensely irradiates a closely orbiting low-mass companion. Modelling their companion's optical light curves is essential to the study of the orbital properties of the binary, including the determination of the pulsar mass, characterizing the pulsar wind, and the star itself. We aim to generalize the traditional direct heating model of irradiation, whereby energy deposited by the pulsar wind into the stellar envelope is locally re-emitted, by introducing heat redistribution via diffusion and convection within the outer stellar envelope. We approximate the irradiated stellar envelope as a 2D shell. This allows us to propose an effective equation of energy conservation that can be solved at a reduced computational cost. We then implement this model in the icarus software and use evidence sampling to determine the most likely convection and diffusion laws for the light curve of the redback companion of PSR J2215+5135. Redistribution effects concentrate near the terminator line of pulsar irradiation, and can create apparent hot and cold spots. Among the models tested for PSR J2215+5135, we find that all models with heat redistribution are more likely than symmetric direct heating. The best-fitting redistribution model involves diffusion together with a uniformly rotating envelope. However, we caution that all models still present serious systematic effects, and that prior knowledge from pulsar timing, spectroscopy, and distance are key to determine with certainty the most accurate redistribution law. We propose an extension of the direct heating framework that allows for exploring a variety of heat redistribution effects. Future work is necessary to determine the relevant laws from first principles and empirically using complementary observations. [ABSTRACT FROM AUTHOR]

Neurodegenerative diseases (ND) have been linked to the critical process in aging—cellular senescence. However, the temporal dynamics of cellular senescence in ND conditions is unresolved. Here, we show senescence features develop in human Huntington's disease (HD) neural stem cells (NSCs) and medium spiny neurons (MSNs), including the increase of p16INK4a, a key inducer of cellular senescence. We found that HD NSCs reprogram the transcriptional targets of FOXO3, a major cell survival factor able to repress cell senescence, antagonizing p16INK4a expression via the FOXO3 repression of the transcriptional modulator ETS2. Additionally, p16INK4a promotes cellular senescence features in human HD NSCs and MSNs. These findings suggest that cellular senescence may develop during neuronal differentiation in HD and that the FOXO3‐ETS2‐p16INK4a axis may be part of molecular responses aimed at mitigating this phenomenon. Our studies identify neuronal differentiation with accelerated aging of neural progenitors and neurons as an alteration that could be linked to NDs. [ABSTRACT FROM AUTHOR]

Background: The Multidomain Alzheimer Preventive Trial (MAPT) was designed to assess the efficacy of omega-3 fatty acid supplementation, multidomain intervention (MI), or a combination of both on cognition. Although the MAPT study was negative, an effect of MI in maintaining cognitive functions compared to placebo group was showed in positive amyloid subjects. A FDG PET study (MAPT-NI) was implemented to test the impact of MI on brain glucose metabolism. Methods: MAPT-NI was a randomized, controlled parallel-group single-center study, exploring the effect of MI on brain glucose metabolism. Participants were non-demented and had memory complaints, limitation in one instrumental activity of daily living, or slow gait. Participants were randomly assigned (1:1) to "MI group" or "No MI group." The MI consisted of group sessions focusing on 3 domains: cognitive stimulation, physical activity, nutrition, and a preventive consultation. [18F]FDG PET scans were performed at baseline, 6 months, and 12 months, and cerebral magnetic resonance imaging scans at baseline. The primary objective was to evaluate the MI effect on brain glucose metabolism assessed by [18F]FDG PET imaging at 6 months. The primary outcome was the quantification of regional metabolism rate for glucose in cerebral regions involved early in Alzheimer disease by relative semi-quantitative SUVr (FDG-based AD biomarker). An exploratory voxel-wise analysis was performed to assess the effect of MI on brain glucose metabolism without anatomical hypothesis. Results: The intention-to-treat population included 67 subjects (34 in the MI group and 33 in the No MI group. No significant MI effect was observed on primary outcome at 6 months. In the exploratory voxel-wise analysis, we observed a difference in favor of MI group on the change of cerebral glucose metabolism in limbic lobe (right hippocampus, right posterior cingulate, left posterior parahippocampal gyrus) at 6 months. Conclusions: MI failed to show an effect on metabolism in FDG-based AD biomarker, but exploratory analysis suggested positive effect on limbic system metabolism. This finding could suggest a delay effect of MI on AD progression. Trial registration: ClinicalTrials.gov Identifier, NCT01513252. [ABSTRACT FROM AUTHOR]

Minority youth, because of structural, ecological, and societal inequalities, are at heightened risk of reporting depression and experiencing negative sanctions associated with delinquency. Sociological theories suggest that greater exposure to ecological risk factors at the peer, family, school and community levels are associated with elevated rates of youth depression and delinquency. Desensitization theory posits that repeated exposures to ongoing stressors result in a numbing of psychological and behavioral responses. Thus, it remains unclear whether racial/ethnic differences exist with regards to how contextual stressors correlate with depression and delinquency. Using a sample of 616 Black, 687 Latinx, and 1,318 White youth, this study explores racial/ethnic differences across four ecological risk factors of risky peers, low family warmth, poor school engagement, and community violence as they relate to youth delinquency and depression. Data were collected through in-school survey of youth from 16 public schools surrounding a major city in the Midwest. Significant racial/ethnic differences provided partial support for the desensitization theory. Among Black youth, the magnitude of relationships between ecological risk factors and delinquency was significantly weaker for three of the four predictors and for all four predictors of depression in comparison to White youth. Among Latinx youth, the magnitude of relationships between ecological risk factors was significantly weaker for depression, but not delinquency, in comparison to White youth. Results indicate that ecological risk factors may have differential associations to youth depression and delinquency, which may call for culturally tailored intervention approaches. Highlights: Because of structural stressors inequalities minority youth report more depression and delinquency rates. Desensitization theory posits that repeated exposures to ongoing structural stressors result in a numbing of psychological and behavioral responses. Black versus white youth reported lower depression rates related to structural stressors. Latinx versus white youth reported lower depression rates but not delinquency related to structural stressors. [ABSTRACT FROM AUTHOR]

Lipid droplets are ubiquitous organelles in eukaryotes that act as storage sites for neutral lipids. Under normal growth conditions, they are not required in the yeast Saccharomyces cerevisiae. However, recent works have shown that lipid droplets are required for autophagy to proceed in response to nitrogen starvation and that they play an essential role in maintaining ER homeostasis. Autophagy is a major catabolic pathway that helps degradation and recycling of potentially harmful proteins and organelles. It can be pharmacologically induced by rapamycin even in the absence of lipid droplets. Here, we show that amino acid starvation is responsible for autophagy failure in lipid droplet-deficient yeast. It not only fails to induce autophagy but also inhibits rapamycin-induced autophagy. The general amino acid control pathway is not involved in this paradoxical effect of amino acid shortage. We correlate the autophagy failure with mitochondria aggregation and we show that amino acid starvation-induced autophagy is restored in lipid droplet-deficient yeast by increasing mitochondrial biomass physiologically (respiration) or genetically (REG1 deletion). Our results establish a new functional link between lipid droplets, ER and mitochondria during nitrogen starvation-induced autophagy. [ABSTRACT FROM AUTHOR]

Context: Palonosetron (PALO) is one of the two active components of NEPA, the fixed-combination antiemetic comprising netupitant (oral)/fosnetupitant (IV) and PALO. To increase the convenience of NEPA administration, especially for patients with swallowing difficulties, an IV NEPA formulation has been developed, where PALO is administered as a 30-minute infusion instead of the approved 30-second bolus.Objectives: To determine the efficacy and safety of the PALO component used in IV NEPA.Methods: Noninferiority, double-blind, and randomized Phase 3 trial in chemotherapy-naive adult patients with cancer requiring highly emetogenic chemotherapy. Patients were randomized to receive a single dose of PALO 0.25 mg administered IV either as a 30-minute infusion or as a 30-second bolus before highly emetogenic chemotherapy. The primary objective was to demonstrate noninferiority of the 30-minute infusion vs. 30-second bolus in terms of complete response (CR; no emesis and no rescue medication) in the acute phase. Secondary efficacy endpoints were CR in the delayed and overall phases and no emesis and no rescue medication in all phases. Safety was a secondary endpoint.Results: Overall, 440 patients received study treatment. In the infusion group, 186 (82.7%) patients reported CR in the acute phase vs. 186 (86.5%) patients in the bolus group, demonstrating the noninferiority of PALO infusion vs. bolus (P < 0.001). Secondary endpoints showed similar results between the two treatment groups.Conclusion: PALO 0.25-mg 30-minute IV infusion was noninferior to 30-second IV bolus in terms of CR rate in the acute phase. These results support the use of PALO 0.25 mg as a component of IV NEPA. [ABSTRACT FROM AUTHOR]

Mitochondria supply intracellular energy requirements during exercise. Specific mitochondrial haplogroups and mitochondrial genetic variants have been associated with athletic performance, and exercise responses. However, these associations were discovered using underpowered, candidate gene approaches, and consequently have not been replicated. Here, we used whole-mitochondrial genome sequencing, in conjunction with high-throughput genotyping arrays, to discover novel genetic variants associated with exercise responses in the Gene SMART (Skeletal Muscle Adaptive Response to Training) cohort (n = 62 completed). We performed a Principal Component Analysis of cohort aerobic fitness measures to build composite traits and test for variants associated with exercise outcomes. None of the mitochondrial genetic variants but eight nuclear encoded variants in seven separate genes were found to be associated with exercise responses (FDR < 0.05) (rs11061368: DIABLO, rs113400963: FAM185A, rs6062129 and rs6121949: MTG2, rs7231304: AFG3L2, rs2041840: NDUFAF7, rs7085433: TIMM23, rs1063271: SPTLC2). Additionally, we outline potential mechanisms by which these variants may be contributing to exercise phenotypes. Our data suggest novel nuclear-encoded SNPs and mitochondrial pathways associated with exercise response phenotypes. Future studies should focus on validating these variants across different cohorts and ethnicities. [ABSTRACT FROM AUTHOR]

Background: Little is known about how genetics and epigenetics interplay in depression. Evidence suggests that genetic variants may change vulnerability to depression by modulating DNA methylation (DNAm) and non-coding RNA (ncRNA) levels. Therefore, the aim of the study was to investigate the effect of the genetic variation, previously identified in the largest genome-wide association study for depression, on proximal DNAm and ncRNA levels. Results: We performed DNAm quantitative trait locus (meQTL) analysis in two independent cohorts (total n = 435 healthy individuals), testing associations between 102 single-nucleotide polymorphisms (SNPs) and DNAm levels in whole blood. We identified and replicated 64 SNP-CpG pairs (padj. < 0.05) with meQTL effect. Lower DNAm at cg02098413 located in the HACE1 promoter conferred by the risk allele (C allele) at rs1933802 was associated with higher risk for depression (praw = 0.014, DNAm = 2.3%). In 1202 CD14+ cells sorted from blood, DNAm at cg02088412 positively correlated with HACE1 mRNA expression. Investigation in postmortem brain tissue of adults diagnosed with major depressive disorder (MDD) indicated 1% higher DNAm at cg02098413 in neurons and lower HACE1 mRNA expression in CA1 hippocampus of MDD patients compared with healthy controls (p = 0.008 and 0.012, respectively). Expression QTL analysis in blood of 74 adolescent revealed that hsa-miR-3664-5p was associated with rs7117514 (SHANK2) (padj. = 0.015, mRNA difference = 5.2%). Gene ontology analysis of the miRNA target genes highlighted implication in neuronal processes. Conclusions: Collectively, our findings from a multi-tissue (blood and brain) and multi-layered (genetic, epigenetic, transcriptomic) approach suggest that genetic factors may influence depression by modulating DNAm and miRNA levels. Alterations at HACE1 and SHANK2 loci imply potential mechanisms, such as oxidative stress in the brain, underlying depression. Our results deepened the knowledge of molecular mechanisms in depression and suggest new epigenetic targets that should be further evaluated. [ABSTRACT FROM AUTHOR]

Br vs. TsO chemoselective pallado‐catalyzed Suzuki–Miyaura reaction has been developed from the 5‐bromo‐2‐tosyloxynicotinaldehyde for the preparation of polysubstituted pyridines. This methodology has been applied for the preparation of a terpyridine aldehyde, as a versatile precursor of potential Mcl‐1 (Induced myeloid leukemia cell differentiation protein) inhibitors. The synthesis of pyridoclax, our lead compound which demonstrated efficacy for the treatment of chemoresistant ovarian cancer, has also been achieved via the palladium‐catalyzed cross‐coupling reaction in 5 steps from 3,5‐dibromo‐2‐hydroxypyridine with 50 % overall yield. [ABSTRACT FROM AUTHOR]