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Could galcanezumab modulate inflammatory cytokines? A single-centre exploratory study
Get PDFIntroduction: Migraine is a highly disabling neurological disorder. The pathophysiological mechanisms underlying this condition are complex and not yet fully elucidated. While calcitonin gene-related peptide (CGRP) plays a pivotal role in the genesis of migraine, not all patients respond to CGRP-targeted therapeutic interventions, suggesting the involvement of alternative mechanisms such as neuroinflammation. In this context, cytokines may act as modulators of inflammatory responses associated with migraine. The objective of this study is to evaluate cytokine profiles in patients with episodic and chronic migraine in comparison with healthy controls and to investigate the modulatory effect of galcanezumab treating episodic migraine patients. Methods: in this prospective pilot study, 17 patients with high-frequency episodic migraine (EM), 18 with chronic migraine (CM), and 17 healthy controls (HC) were enrolled. Plasma cytokine levels (IFN-γ, IL-1β, IL-10, IL-6, TNF-α) were measured using multiplex immunoassay during the interictal phase. Blood samples of the EM group eligible for treatment with galcanezumab were additionally collected at three time points: baseline (T0) and 5 and 27 days after administration of galcanezumab (T5, corresponding to the maximum serum concentration (Cmax), and T27, drug half-life, respectively). Results: In comparison with patients diagnosed with CM and HC, EM patients demonstrated elevated interictal levels of IFN-γ, IL-1β, IL-6 and IL-10 (p < 0.001). In perspective analyses, a significant decrease in cytokine levels was observed in the galcanezumab-treated group at Cmax (T5) for IFN-γ, IL-1β, IL-10, and TNF-α, but not for IL-6 (p = 0.640). Discussion: This study highlights distinct cytokine profiles associated with chronic and episodic migraine. Treatment with galcanezumab was associated with a transient reduction in both pro- and anti-inflammatory cytokines during the first month of therapy. These findings support the hypothesis that CGRP could influence the inflammatory pathways in migraine pathophysiology
Interpersonal connections and career mobility in bureaucratic labor markets: evidence from Brazil
No full textInterpersonal networks are pervasive in state bureaucracies around the world. To what extent do they explain bureaucratic career trajectories? And are they driven more by political patronage and connections to influential bosses, or by information-sharing and trust-building among peers? We address these questions by constructing measures of the stock of interpersonal connections for the universe of over 440,000 Brazilian federal civil servants for the period 2000-18. Individuals’ networks strongly predict their future career mobility. Connections to higher-ranking officers or to members of the same political party have a strong effect, but the overall influence of individuals’ networks on their career trajectories is dominated by non-political connections to their peers, not connections to bosses or party colleagues. We show that these patterns are similar for politically appointed and career positions, and explore heterogeneity across various demographic groups. We discuss implications for theory and policy, as well as potential wider methodological applications
Updates about Roman mosaics in Oxfordshire, UK
Get PDFThere is a multitude of publications about Roman villas in the UK and some about the creation in mosaics the people of the Roman Empire produced upon their arrival in the British Isles. I focus here on mosaics found in Roman habitation within Oxfordshire, UK: the pavement at Stonefield discovered in 1712 and reproduced in textile during the eighteenth century, as well as the mosaic floor in room 30 at the North Leigh Roman Villa (fourth century AD). My paper does not reiterate substantially what other pieces of speciality literature say, but offers an update (up to January 2025) with respect to the two historical vestiges mentioned above
Social innovation in climate finance
No full textClimate change threatens low– and middle-income countries (LMICs), which face a multibillion-dollar climate financing gap. This chapter examines the Green Climate Fund (GCF), established under the 2015 Paris Agreement, as a social innovation model for mobilizing climate finance in LMICs. Using a social innovation lens, we analyze its evolution from 2009–2024. Since its inception, the GCF has allocated $15 billion across 270 projects, prioritizing country ownership and impact in vulnerable regions. While designed to balance mitigation and adaptation funding and strengthen local capacity, challenges persist. Three-quarters of funding remains controlled by international entities, and adaptation projects receive only a quarter of funds due to scalability barriers. The GCF's potential lies in building collaborative networks, yet reliance on traditional financiers and complex processes limits access. While it has improved process efficiency, gaps remain in outcome measurement and LMIC-driven projects. Overcoming barriers is essential to realizing its mandate for climate finance in LMICs
Perception and categorisation of vowels in German and English by Chinese university learners
Get PDFAccurate vowel perception is essential for effective communication and is a fundamental aspect of language learning. Vowels are important in any language because they carry important phonetic and phonological information that is essential for distinguishing between words and meanings. This research highlights the pivotal role of acoustic cues - particularly duration and formant cues - in the perception of vowels. It also explores how different factors, such as the learning environment and prior phonetic training, affect vowel perception. Understanding how learners perceive vowels and identifying the factors that influence them is crucial for improving communication skills and refining teaching methods. This dissertation examines the perceptual patterns of Chinese learners of German and/or English, focusing on their responses to English and German vowel categorisation and discrimination in three perceptual tasks. The study takes into account various background factors, including multilingualism, language proficiency, learning environment, and prior knowledge of phonetics and phonology, to explore possible correlations between learners' language learning backgrounds and their vowel perception abilities. The results of these tasks highlight the importance of both durational and formant cues in vowel perception. However, they also reveal a notable preference for durational cues among learners. The results also show that phonetic training and immersive language environments significantly increase learners' sensitivity to subtle variations in vowel duration and formant properties. Based on these insights, the dissertation argues for tailoring language teaching to learners' backgrounds. This approach involves exploiting strengths such as the processing of durational cues and incorporating explicit phonetic training and immersive learning experiences into language curricula. Such adaptations are proposed to optimise language learning and teaching by facilitating the more effective acquisition of the phonetic skills that are crucial for multilingual communication
Investigating strategies to degrade the inflammasome signalling adaptor ASC
No full textInflammation is a vital component of host defence, but its dysregulation can lead to chronic inflammation and pathological conditions. Central to inflammatory signalling are inflammasomes, large, multiprotein cytosolic complexes that facilitate the release of pro-inflammatory cytokines IL-1β and IL-18. In many diseases, multiple inflammasomes are activated. Most of them utilise the adaptor protein apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), which serves as a crucial site of signal amplification. This makes ASC an attractive target to control multiple inflammasomes at once. Here, we explore the best strategies one could use to degrade ASC and block inflammasome signalling.To accomplish this, we engineered a functional ASC-HaloTag (ASC-HT) fusion protein, enabling selective covalent labelling and manipulation via small-molecule Halo-reactive probes. We expressed ASC-HT in ASC-deficient bone marrow-derived macrophages or human HEK293T cells and explored the best strategy to degrade ASC by leveraging HaloTag-compatible degraders. Using a proteasome-dependent degrader (Halo-PROTAC), we achieved targeted degradation of ASC-HT in both HEK293T cells and in BMDMs, which then lowered the inflammasome assembly and downstream inflammatory cytokine secretion and lytic death in BMDMs. Autophagy-dependent degrader Halo-AUTAC was not found to degrade ASC, regardless of whether ASC was expressed as a monomer or a speck-forming oligomer.Our approach provides a framework to rapidly investigate the effective degradation strategies for ASC. It also highlights ASC degradation as a promising approach for modulation of inflammasome signalling
Implementation of OMOP and ConcePTION Common Data Models in CPRD GOLD: Risk of Bleeding and Cardiovascular Outcomes From Anticoagulant Use
Get PDFThe impact of the choice of common data model (CDM) approach on the study results in a real‐world evidence (RWE) study is unknown. We aimed to determine potential differences in the results of an RWE study when data were mapped to two different CDMs, ConcePTION and OMOP. With the same instance of CPRD GOLD, data were mapped to both CDMs. Using the same programming steps, we estimated the risk of direct oral anticoagulants (DOACs) vs. vitamin K antagonists (VKAs) on bleeding and cardiovascular (CVD) outcomes in patients with non‐valvular atrial fibrillation. Baseline characteristics, incidence rates, and Cox proportional hazards ratios were compared between the analyses. OMOP and ConcePTION mapped study populations included 80,701 (93,350 person‐years) and 76,726 exposed persons (100,135 person‐years), respectively. DOACs showed no differential risk of CVD compared to VKAs in ConcePTION mapped data (HR 0.99, 95% CI [0.91; 1.08]), but protective effects in OMOP (HR 0.82, 95% CI [0.74; 0.90]). DOACs had a similar increase in risk of stroke (ConcePTION HR 1.19, 95% CI [1.02; 1.37]; OMOP HR 1.10, 95% CI [0.96; 1.26]). No increased risk of major bleeding was identified (ConcePTION HR 0.97, 95% CI [0.84; 1.13]; OMOP HR 0.90, 95% CI [0.78; 1.04]). OMOP gave lower effect estimates for CVD and equivalent risks of stroke and bleeding associated with DOACs use. This study highlights the challenges in repeating the same analysis across the two data CDMs. Differences potentially stem from the cohort construction, the identification of phenotypes in the different CDMs, and the use of imputed variables defined during mapping processes, such as drug exposure duration
Visualizing the Odd-Parity Superconducting Order Parameter and Its Quasiparticle Surface Band in UTe 2
Get PDFA distinctive identifier of nodal intrinsic topological superconductivity (ITS) would the appearance of an Andreev bound state on crystal surfaces parallel to the nodal axis, in the form of a topological quasiparticle surface band (QSB) appearing only for
Sigscores: summary scores for molecular signatures in R
Get PDFSummary: The rapid expansion of multi-omics data has enabled the development of molecular signatures—coordinated patterns of molecular features that serve as powerful biomarkers for diagnosis, prognosis, and therapeutic decision-making. Despite their potential, many published signatures suffer from limited reproducibility and narrow applicability, partly due to challenges in summarizing complex, multi-feature profiles into a single, statistically sound and biologically meaningful score. Here, we introduce sigscores, an R package that streamlines the computation of summary scores for molecular signatures. Building on the quality control principles of our earlier tool, sigQC, sigscores supports an extensive array of scoring metrics—including measures of central tendency, dispersion, and aggregation. It incorporates a resampling framework to generate empirical null distributions for rigorous significance assessment and provides integrated visualization tools for diagnostic evaluation. Optimized for parallel execution on multi-core systems, sigscores is well-suited for both exploratory research and high-throughput large-scale applications. Availability and implementation: Source code freely available for download on GitHub at https://github.com/alebarberis/sigscores, implemented in R and supported on MacOS and MS Windows