Distinct Dynamics Research Articles

A data-driven intravoxel mean diffusivities distribution approach for molecular classifications and MIB-1 prediction of gliomas.

Measuring non-parametric intravoxel mean diffusivity distributions (MDDs) using magnetic resonance imaging (MRI) is a sensitive method for detecting intracellular diffusivity changes during physiological alterations. Histological and molecular glioma classifications are essential for prognosis and treatment, with distinct water diffusion dynamics among subtypes. We developed a data-driven approach using a fully connected network (FCN) to enhance the speed and stability of calculating MDDs across varying SNRs, enable tumor microstructural mapping, and test its reliability in identifying MIB-1 labeling index (LI) levels and molecular status of gliomas. An FCN was trained to learn the mapping between the simulated diffusion decay curves and the ground truth MDDs. We performed 5 000 000 simulation curves with various diffusivity components and random SNR . Eighty percent of simulation curves were used for the FCN training, 10% for validation, and the others were external tests for the FCN performance evaluation. In vivo data were collected to evaluate its clinical reliability. One hundred one patients (44 years 14, 67 men) with gliomas and six healthy controls underwent a 3.0 T MRI examination with a spin echo-echo planar imaging (SE-EPI) diffusion-weighted imaging (DWI) sequence. The trained FCN was employed to calculate MDDs of each brain voxel by voxel. We used the Fuzzy C-means algorithm to cluster the MDDs of tumor voxels, facilitating the characterization of distinct glioma tissues. Quantitative assessments were conducted through sectional integrals of the MDDs, demarcated by six bands to derive signal fractions ( ) and diffusivities of the maximum peaks ( ). Cosine similarity scores (CSS) were used for MDD similarity. ANOVA and Mann-Whitney U test were used for difference analysis. Logistic regression and area under the receiver operator characteristic curve (AUC) were used for classification evaluation. The simulation results showed that the FCN-based MDD approach (FCN-MDD) achieved higher CSS than non-negative least squares-based MDD (NNLS-MDD). For in vivo data, the spectra of ET and NET obtained by FCN-MDD are more distinguishable than NNLS-MDD. Fraction maps delineate the characteristics of different tumor tissues (enhancing and non-enhancing tumor, edema, and necrosis). showed a positive and negative correlation with MIB-1 respectively ( , all ). The AUC of for predicting MIB-1 LI levels was 0.900 (95% CI, 0.826-0.974), versus 0.781 (0.677-0.886) of ADC. The highest AUC of isocitrate dehydrogenase (IDH) mutation status, assessed by a logistic regression model ( ) was 0.873 (95% CI, 0.802-0.944). The proposed FCN-MDD method was more robust to variations in SNR and less reliant on empirically set regularization values than the NNLS-MDD method. FCN-MDD also enabled qualitative and quantitative evaluation of the composition of gliomas.

African Popular Protest and Political Change

Abstract: In the twenty-first century, African countries have hosted more mass movements than any other region in the world. In the last decade, one in every three nonviolent revolutionary campaigns has taken place in Africa. The region also has the highest short-term success rate for people power. But is this success predicated on the mobilizational force of "protest democracy" to hold elites accountable? Or are African social movements' remarkable successes an environmental artefact, the result of ordinary protests in contexts of extraordinary instability? The evidence suggests that African social movements are uniquely effective and that political and military elites are increasingly trying to harness their power. Ordinary people—marshalled in massive demonstrations and persistent civil society organizing—have played a necessary, often decisive role in agitating for democracy. However, eliciting successful breakthroughs requires the alignment of protester demands with the abandonment of the status quo by elite blocs. Recent cascades of irregular power transfers in African politics illustrate these distinctive dynamics, where diverse domestic political contexts share an important common ingredient: the combination of mass movements pushing for change and military power players who are willing to help them.

Portfolio diversification opportunities in traditional energy and alternative/renewable energy ETF segments

"This study evaluates the diversification benefits of investing in traditional and alternative/renewable energy Exchange Traded Funds (ETFs) using the VAR-ADCC-GARCH model to analyze yields, correlations, and volatilities. The results demonstrate that alternative/renewable energy ETFs not only offer higher average returns but also significantly reduce portfolio risk compared to traditional energy ETFs. The research underscores the distinct investment dynamics between the two ETF segments, highlighting the advantages of incorporating renewable energy assets into diversified portfolios. These findings support the inclusion of environmentally-conscious investment strategies that effectively balance risk and return, emphasizing their importance for investors aiming to optimize their portfolios in line with sustainable practices. Keywords: portfolio diversification, ETFs, traditional energy, renewable energy, VAR-ADCC-GARCH Model JEL classification: G11, C58, A100, A110"

Perceptual coupling in human dyads: Kinematics does not affect interpersonal synchronization

The minimal, essential condition for individuals to interact is that they exchange information via at least one sensory channel. Once informational coupling is established, it enables basic forms of coordinated behavior to spontaneously emerge from the interaction. Our previous study revealed different coordination dynamics in dyads engaged in a joint finger-tapping task based on visual versus auditory coupling. This observation led us to propose the ‘modality-dependent hypothesis', which posits that coordination dynamics are influenced by the sensory modality mediating informational coupling. However, recognizing that different modalities have inherent differences in accessing spatiotemporal features of perceived movement, we formulated the alternative ‘kinematic hypothesis'. This hypothesis posits that differences in dynamics would vanish given equivalent kinematic information across modalities. The study involved forty (N = 40) participants, grouped into twenty (N = 20) dyads, who engaged in a joint finger-tapping task. This task was conducted under varying conditions of visual and auditory coupling, with manipulations in the access to kinematic information, categorized as discrete and continuous. Contrary to our initial predictions, the results strongly supported the ‘modality-dependent hypothesis'. We observed that visual and auditory coupling consistently yielded distinct attractor dynamics, regardless of the access to kinematic information. Furthermore, all conditions of auditory coupling resulted in higher levels of synchronization than their visual counterparts. These findings suggest that the differences in interpersonal synchronization are predominantly influenced by the sensory modality, rather than the continuity of kinematic information. Our study highlights the significance of sensorimotor interactions in interpersonal synchronization and addresses the potential of sonification strategies in supporting motor training and rehabilitation.

Slow and non-equilibrium dynamics due to electronic ferroelectricity in a strongly-correlated molecular conductor

Ferroelectricity, where electronic degrees of freedom determine the polar order—thereby enabling fast switching and phase control—is an important research field in current condensed-matter physics. Using a combination of resistance noise and dielectric spectroscopy we investigate the nature of relaxor-type electronic ferroelectricity in the organic conductor κ-(BETS)2Mn[N(CN)2]3, a system that represents a wider class of materials of correlated electron systems for which functionalities for organic spintronics recently have been discussed. The two complementary spectroscopies reveal a distinct low-frequency dynamics on different length scales, namely (i) an intrinsic relaxation that is typical for relaxor ferroelectrics which classifies the system as a possible new multiferroic, and (ii) two-level processes which we identify as fluctuating polar nanoregions (PNR), i.e., clusters of quantum electric dipoles that fluctuate collectively. The PNR preform above the metal insulator (MI) transition. Upon cooling through TMI, a drastic increase of the low-frequency 1/f-type fluctuations and slowing down of the charge carrier dynamics is accompanied by the onset of strong non-equilibrium dynamics indicating a glassy transition of interacting dipolar clusters. The freezing of PNR and non-equilibrium dynamics is suggested to be a common feature of organic relaxor-type electronic ferroelectrics.

Stuxnet vs WannaCry and Albania: Cyber-attribution on trial

The cyber-attribution problem poses a significant challenge to the effective application of international law in cyberspace. Rooted in unclear standards of proof, evidence disclosure requirements, and deficiencies within the legal framework of the attribution procedure, this issue reflects the limitations of some traditional legal concepts in addressing the unique nature of cyberspace. Notably, the effective control test, introduced by the ICJ in 1986 and reaffirmed in 2007 to attribute the actions of non-state actors, does not adequately account for the distinctive dynamics of cyberspace, allowing states to use proxies to evade responsibility.The legal impracticality and insufficiency of the attribution procedure not only give rise to the cyber-attribution problem but also compel states to develop new attribution tactics. This article explores the evolution of these cyber-attribution techniques to assess whether contemporary state practices align with the customary rules of attribution identified by the ICJ and codified by the ILC within ARSIWA, or whether new, cyber-specific rules might emerge. By analyzing two datasets on cyber incidents and three distinct cases – Stuxnet, WannaCry, and the 2022 cyberattacks against Albania – this article concludes that the effective control test cannot be conclusively identified as part of customary rules within cyberspace due to the insufficient support in state practice. Furthermore, it is apparent that the rules of attribution in the cyber-specific context are in a disarray, lacking consistent, widespread and representative practice to support a general custom. However, emerging state practice shows some degree of unification and development, suggesting the potential for the future establishment of cyber-specific rules of attribution.

A taxonomy of business models of digital care platforms in Spain

AbstractIn the last few years, the proliferation of digital labour platforms has led to the transformation of business models and labour relations in an increasing number of economic activities, including highly feminized and informal traditional sectors, such as care and domestic work. Drawing on an analysis of 37 digital care platforms in Spain, this research compares the distinctive features and structural power dynamics they engender, and it constructs a taxonomy of business models of these care platforms. By analysing the main features of their operational models, we are capable of distinguishing three main types of platforms: marketplace, on‐demand, and digital placement agencies. First, the paper argues that the distinctive features of each digital platform business model have differentiated impacts on working conditions in terms of access to tasks, remuneration, flexibility and means of control. This differentiation allows us to understand what is transformative and what is continuous in platforms' precarization or formalisation of care work and working conditions of carers, mainly women and migrants. Each business model has its differentiated outcomes in terms of labour control and reorganization of women's and migrants' reproductive work. Second, more broadly, while digital care platforms may have contributed to facilitating workers' access to jobs, reducing transaction costs and standardising processes, this has often been through the creation of more flexible and insecure forms of work and to increased market pressures. Therefore, this study contributes to existing research addressing the degree of formalization of labour relations in digital platform work through a nuanced analysis of their business models.

FlyVISTA, an Integrated Machine Learning Platform for Deep Phenotyping of Sleep in Drosophila.

Animal behavior depends on internal state. While subtle movements can signify significant changes in internal state, computational methods for analyzing these "microbehaviors" are lacking. Here, we present FlyVISTA, a machine-learning platform to characterize microbehaviors in freely-moving flies, which we use to perform deep phenotyping of sleep. This platform comprises a high-resolution closed-loop video imaging system, coupled with a deep-learning network to annotate 35 body parts, and a computational pipeline to extract behaviors from high-dimensional data. FlyVISTA reveals the distinct spatiotemporal dynamics of sleep-associated microbehaviors in flies. We further show that stimulation of dorsal fan-shaped body neurons induces micromovements, not sleep, whereas activating R5 ring neurons triggers rhythmic proboscis extension followed by persistent sleep. Importantly, we identify a novel microbehavior ("haltere switch") exclusively seen during quiescence that indicates a deeper sleep stage. These findings enable the rigorous analysis of sleep in Drosophila and set the stage for computational analyses of microbehaviors.

Complex Characterization of Nanofiber Biomaterials Based on Chitosan, Collagen and Fish Gelatine Produced by Electrospinning*

Electrospinning is an increasingly used technique for producing nanofibers from various types of polymers and biopolymers. These fibers are suitable for applications in tissue engineering, wound healing and drug delivery. In this study, we focused on biomaterials produced from raw marine fish collagen, fish gelatin and chitosan. Various collagen/chitosan and fish gelatin/chitosan in several ratios were dissolved in acetic acid. The formed solutions have concentrations in the range from 5 to 90% (g/ml). The effect of different molecular formats (native and denatured collagen) was studied. The prepared solutions were used in electrospinning experiments. The order degree of various phases of raw materials was established from x-ray diffraction (XRD) measurements. The raw materials, bio-polymeric solutions and finite nanofibers biomaterials were characterized using Fourier transform infrared (FT-IR) spectroscopy, scanning electron microscopy (SEM), low-field 1D NMR (nuclear magnetic resonance) relaxometry, 2D NMR T1-T2 COSY (correlation spectroscopy), T1-T2 EXSY (exchange spectroscopy) maps, and high field localized 1H NMR spectroscopy. The T 2-T 2 EXSY experiments showed that the number of components characterized by distinct dynamics is larger than those that can by estimated from 1D T 2-distributions due to molecular exchange. Moreover, the full complexity was also revealed by T 1-T 2 COSY maps. The study provides a better understanding of the nanofiber properties, demonstrates the potential of electrospinning for producing nanofibers, and highlights the importance of using multiple characterization methods for a better understanding of the properties of biological nanofibers.

Generational Differences in Urban Identity: Eskişehir

Cities are regarded as spaces of co-production of the social sphere, leaving diverse imprints on the memory and discourse of individuals within society. This study investigates these differences by categorizing them according to generations, focusing on the components of urban identity as perceived, lived, transformed, and interacted with by different generations within the city. The aim is to uncover the type of identity the city offers to various generations and the generation-oriented breakpoints in the production of collective memory. This research is intertwined with themes of urban politics, urban memory, and urban-public space, providing an opportunity to not only observe the generation gap but also to discern the distinct dynamics of the city. It underscores the importance of considering the generation gap in the city's collective accumulation and urban politics. The study draws on data from in-depth interviews with 12 participants, comprising three individuals from each of the X, Y, Z, and Baby Boomer generations, all of whom were born, raised, and currently reside in Eskişehir. Through an examination of factors such as age, upbringing, and life experiences, the research delves into how these elements shape individuals' senses of identity and attachment to the urban environment. Additionally, it explores how generational perspectives influence attitudes towards urban development, cultural identity, and community engagement in Eskişehir. By delving into these aspects, the study aims to provide deeper insights into how generational differences manifest within the context of urban identity in this specific city.

Octahedral Nanocrystals of Ru-Doped PtFeNiCuW/CNTs High-Entropy Alloy: High Performance Toward pH-Universal Hydrogen Evolution Reaction.

Integrating high-entropy philosophy and nanocrystal-specific orientation into a single catalyst represents a promising strategy in development of high-performance catalysts. Nonetheless, shape-controlled synthesis of high-entropy alloy (HEA) nanocrystals is challenging owing to the distinct redox potentials and growth dynamics of metal elements. Herein, a one-pot co-reduction method is developed to fabricate ruthenium (Ru)-doped PtFeNiCuW octahedral HEA nanocrystals onto carbon nanotubes (Ru-PtFeNiCuW/CNTs). It is demonstrated that Ru dopants and W(CO)6 promote the concurrent reduction and growth of other metal precursors to obtain higher yield and larger size of HEA nanocrystals, despite low Ru content in Ru-PtFeNiCuW/CNTs. As an electrocatalyst toward hydrogen evolution reaction (HER), Ru-PtFeNiCuW/CNTs exhibits low overpotentials of 9, 16, and 34mV at a current density of 10mA cm-2 and Tafel slopes of 19.2, 27.9, and 23.1mV dec-1 in acidic, alkaline, and neutral electrolytes, respectively. As a cathodic catalyst, Ru-PtFeNiCuW/CNTs operates for up to 1500 and 1200 h in acidic and alkaline electrolyte, respectively, at a current density of 50mA cm-2 in a two-electrode system for full water splitting. Theoretical calculations reveal accelerated kinetics of H2O dissociation on W sites and *H desorption on hollow Cu-Cu-Cu and Cu-Cu-Pt sites.

Unraveling RNA Conformation Dynamics in Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like Episode Syndrome with Solid-State Nanopores.

This study investigates transfer ribonucleic acid (tRNA) conformational dynamics in the context of MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) using solid-state silicon nitride (SiN) nanopore technology. SiN nanopores in thin membranes with specific dimensions exhibit high signal resolution, enabling real-time and single-molecule electronic detection of tRNA conformational changes. We focus on human mitochondrial tRNALeu(UAA) (mt-Leu(UAA)) that decodes Leu codons UUA/UUG (UUR) during protein synthesis on the mt-ribosome. The single A14G substitution in mt-Leu(UAA) is the major cause of MELAS disease. Measurements of current blockades and dwell times reveal distinct conformational dynamics of the wild-type (WT) and the A14G variant of mt-Leu(UAA) in response to the conserved post-transcriptional m1G9 methylation. While the m1G9-modified WT transcript adopts a more stable structure relative to the unmodified transcript, the m1G9-modified MELAS transcript adopts a less stable structure relative to the unmodified transcript. Notably, these differential features were observed at 0.4 M KCl, but not at 3 M KCl, highlighting the importance of experimental settings that are closer to physiological conditions. This work demonstrates the feasibility of the nanopore platform to discern tRNA molecules that differ by a single-nucleotide substitution or by a single methylation event, providing an important step forward to explore changes in the conformational dynamics of other RNA molecules in human diseases.

Systematic Analysis of Biological Processes Reveals Gene Co-expression Modules Driving Pathway Dysregulation in Alzheimer's Disease.

Alzheimer's disease (AD) manifests as a complex systems pathology with intricate interplay among various genes and biological processes. Traditional differential gene expression (DEG) analysis, while commonly employed to characterize AD-driven perturbations, does not sufficiently capture the full spectrum of underlying biological processes. Utilizing single-nucleus RNA-sequencing data from postmortem brain samples across key regions-middle temporal gyrus, superior frontal gyrus, and entorhinal cortex-we provide a comprehensive systematic analysis of disrupted processes in AD. We go beyond the DEG-centric analysis by integrating pathway activity analysis with weighted gene co-expression patterns to comprehensively map gene interconnectivity, identifying region- and cell-type-specific drivers of biological processes associated with AD. Our analysis reveals profound modular heterogeneity in neurons and glia as well as extensive AD-related functional disruptions. Co-expression networks highlighted the extended involvement of astrocytes and microglia in biological processes beyond neuroinflammation, such as calcium homeostasis, glutamate regulation, lipid metabolism, vesicle-mediated transport, and TOR signaling. We find limited representation of DEGs within dysregulated pathways across neurons and glial cells, suggesting that differential gene expression alone may not adequately represent the disease complexity. Further dissection of inferred gene modules revealed distinct dynamics of hub DEGs in neurons versus glia, suggesting that DEGs exert more impact on neurons compared to glial cells in driving modular dysregulations underlying perturbed biological processes. Interestingly, we observe an overall downregulation of astrocyte and microglia modules across all brain regions in AD, indicating a prevailing trend of functional repression in glial cells across these regions. Notable genes from the CALM and HSP90 families emerged as hub genes across neuronal modules in all brain regions, suggesting conserved roles as drivers of synaptic dysfunction in AD. Our findings demonstrate the importance of an integrated, systems-oriented approach combining pathway and network analysis to comprehensively understand the cell-type-specific roles of genes in AD-related biological processes.

Distinct dynamics of mRNA LNPs in mice and nonhuman primates revealed by in vivo imaging

The characterization of vaccine distribution to relevant tissues after in vivo administration is critical to understanding their mechanisms of action. Vaccines based on mRNA lipid nanoparticles (LNPs) are now being widely considered against infectious diseases and cancer. Here, we used in vivo imaging approaches to compare the trafficking of two LNP formulations encapsulating mRNA following intramuscular administration: DLin-MC3-DMA (MC3) and the recently developed DOG-IM4. The mRNA formulated in DOG-IM4 LNPs persisted at the injection site, whereas mRNA formulated in MC3 LNPs rapidly migrated to the draining lymph nodes. Furthermore, MC3 LNPs induced the fastest increase in blood neutrophil counts after injection and greater inflammation, as shown by IL-1RA, IL-15, CCL-1, and IL-6 concentrations in nonhuman primate sera. These observations highlight the influence of the nature of the LNP on mRNA vaccine distribution and early immune responses.

MHD nanofluid flow and heat transfer caused by a stretching sheet that is heated convectively: An approximate solution using ADM

The investigation detailed in this paper explores the behavior of a slippery nanofluid flowing over a permeable stretched sheet under the influence of magnetohydrodynamic forces, considering factors like thermal radiation, viscous dissipation, and convective boundary conditions. The analysis systematically establishes principles for conserving mass, heat, momentum, and nanoparticle concentration, deriving a set of nonlinear ordinary differential equations from the governing partial differential equations. To tackle these challenges, the Adomian decomposition approach is utilized as a central element of the solution methodology. Graphical representations are employed to depict the solutions across various physical parameters. Despite the significance of nanofluids in both industrial and scientific contexts, there exists a noticeable research gap concerning the combined impacts of thermal radiation, viscous dissipation, and convective boundary conditions on heat and mass transfer, especially when coupled with a permeable linear rough stretched sheet. This study aims to fill this void by offering quantitative insights into these intricate phenomena, thereby enhancing our understanding of nanofluid dynamics and their practical implications. The findings indicate that increasing slip velocity and magnetic parameters reduce the boundary layer thickness of the velocity profile but increase it for the temperature profile, suggesting a nuanced interplay between slip velocity and magnetic effects on velocity boundary layers, while the temperature boundary layer exhibits distinct thermal dynamics within the system.

Spin-State Control in Dysprosium(III) Metallacrown Magnets via Thioacetal Modification.

Integrating controllable spin states into single-molecule magnets (SMMs) enables precise manipulation of magnetic interactions at a molecular level, but remains a synthetic challenge. Herein, we developed a 3d-4f metallacrown (MC) magnet [DyNi5(quinha)5(Clsal)2(py)8](ClO4) ⋅ 4H2O (H2quinha=quinaldichydroxamic acid, HClsal=5-chlorosalicylaldehyde) wherein a square planar NiII is stabilized by chemical stacking. Thioacetal modification was employed via post-synthetic ligand substitutions and yielded [DyNi5(quinha)5(Clsaldt)2(py)8](ClO4) ⋅ 3H2O (HClsaldt=4-chloro-2-(1,3-dithiolan-2-yl)phenol). Thanks to the additional ligations of thioacetal onto the NiII site, coordination-induced spin state switching (CISSS) took place with spin state altering from low-spin S=0 to high-spin S=1. The synergy of CISSS effect and magnetic interactions results in distinct energy splitting and magnetic dynamics. Magnetic studies indicate prominent enhancement of reversal barrier from 57 cm-1 to 423 cm-1, along with hysteresis opening and an over 200-fold increment in coercive field at 2 K. Ab initio calculations provide deeper insights into the exchange models and rationalize the relaxation/tunnelling pathways. These results demonstrate here provide a fire-new perspective in modulating the magnetization relaxation via the incorporation of controllable spin states and magnetic interactions facilitated by the CISSS approach.

Spin‐State Control in Dysprosium(III) Metallacrown Magnets via Thioacetal Modification

AbstractIntegrating controllable spin states into single‐molecule magnets (SMMs) enables precise manipulation of magnetic interactions at a molecular level, but remains a synthetic challenge. Herein, we developed a 3d–4f metallacrown (MC) magnet [DyNi5(quinha)5(Clsal)2(py)8](ClO4) ⋅ 4H2O (H2quinha=quinaldichydroxamic acid, HClsal=5‐chlorosalicylaldehyde) wherein a square planar NiII is stabilized by chemical stacking. Thioacetal modification was employed via post‐synthetic ligand substitutions and yielded [DyNi5(quinha)5(Clsaldt)2(py)8](ClO4) ⋅ 3H2O (HClsaldt=4‐chloro‐2‐(1,3‐dithiolan‐2‐yl)phenol). Thanks to the additional ligations of thioacetal onto the NiII site, coordination‐induced spin state switching (CISSS) took place with spin state altering from low‐spin S=0 to high‐spin S=1. The synergy of CISSS effect and magnetic interactions results in distinct energy splitting and magnetic dynamics. Magnetic studies indicate prominent enhancement of reversal barrier from 57 cm−1 to 423 cm−1, along with hysteresis opening and an over 200‐fold increment in coercive field at 2 K. Ab initio calculations provide deeper insights into the exchange models and rationalize the relaxation/tunnelling pathways. These results demonstrate here provide a fire‐new perspective in modulating the magnetization relaxation via the incorporation of controllable spin states and magnetic interactions facilitated by the CISSS approach.

Overview and Lifecycle Management of Generic Pharmaceutical Drugs in Mexico, Guatemala and Brazil

Objective: The generic pharmaceutical markets in Mexico, Guatemala, and Brazil are influenced by distinct regulatory frameworks, production and distribution dynamics, and marketing strategies, which shape lifecycle management. Regulatory policies, market competition, and healthcare initiatives impact accessibility, affordability, and quality, presenting both challenges and opportunities for enhancement in these areas. Summary: This thesis offers an in-depth examination of lifecycle management strategies in the generic pharmaceutical markets of Mexico, Guatemala, and Brazil. Generic drugs are crucial for increasing access to affordable healthcare, especially in emerging economies. Through comparative analysis, this research explores the regulatory frameworks, market dynamics, and key challenges in the development, approval, marketing, and post-marketing surveillance of generic drugs in these three Latin American countries. The study starts with an overview of the regulatory landscape for generic pharmaceuticals in Mexico, Guatemala, and Brazil, highlighting similarities and differences in registration requirements, approval processes, and post-approval obligations. It investigates the roles of regulatory agencies like COFEPRIS, DIGEMID, and ANVISA in ensuring the quality, safety, and efficacy of generic drugs throughout their lifecycle. Additionally, the research delves into the strategies used by pharmaceutical companies for lifecycle management of generic drugs, including variations, biowaivers, and labeling changes. Real-world case studies illustrate post-approval changes and their regulatory implications in each country, providing insights into the complexities of managing generic drug portfolios in different regulatory environments. The thesis also examines the market dynamics affecting the availability, pricing, and accessibility of generic drugs in Mexico, Guatemala, and Brazil. Factors such as patent expirations, competition, healthcare policies, and public procurement practices are analysed to understand their impact on market entry, competition, and the affordability of generic drugs. Furthermore, the study addresses the challenges and opportunities in pharmacovigilance and post-marketing surveillance of generic drugs, emphasizing the need for robust systems to detect and manage adverse drug reactions and ensure patient safety. Conclusion: The key findings highlight regulatory frameworks, market dynamics, and lifecycle management strategies in the generic pharmaceutical markets, identifying challenges and opportunities. The study reflects on implications for stakeholders and suggests areas for future research to enhance accessibility, affordability, and quality.

A dual-color PAX7 and MYF5 in vivo reporter to investigate muscle stem cell heterogeneity in regeneration and aging

Increasing evidence suggests that the muscle stem cell (MuSC) pool is heterogeneous. In particular, a rare subset of PAX7-positive MuSCs that has never expressed the myogenic regulatory factor MYF5 displays unique self-renewal and engraftment characteristics. However, the scarcity and limited availability of protein markers make the characterization of these cells challenging. Here, we describe the generation of StemRep reporter mice enabling the monitoring of PAX7 and MYF5 proteins based on equimolar levels of dual nuclear fluorescence. High levels of PAX7 protein and low levels of MYF5 delineate a deeply quiescent MuSC subpopulation with an increased capacity for asymmetric division and distinct dynamics of activation, proliferation, and commitment. Aging primarily reduces the MYF5Low MuSCs and skews the stem cell pool toward MYF5High cells with lower quiescence and self-renewal potential. Altogether, we establish the StemRep model as a versatile tool to study MuSC heterogeneity and broaden our understanding of mechanisms regulating MuSC quiescence and self-renewal in homeostatic, regenerating, and aged muscles.

Geopolitics and global economic governance

Abstract This article analyses the relationship between geopolitics and global economic governance from an international relations perspective, laying stress on the long-term changes that have taken place in the character and dynamics of modern global international society. First, it unpacks what is involved in talk about the ‘the return of geopolitics’, arguing that the international political system needs to be understood in its own right and according to its distinctive logics and dynamics, separate from those of modern capitalism. The second section shifts the focus from the modern international to the modern global, arguing that the ‘we’ now involved in both geopolitics and global economic governance has changed in fundamental ways and that the diffusion of power and agency and the revolt against Western dominance are far broader than the rise of China. The final section looks at future pathways: the unlikely possibility of the restoration of US hegemony; the case for the primacy of political order over global governance and for refocusing attention on the primary or foundational institutions on which all more elaborate forms of global governance must depend; and the identification of some of the most important institutional pinch-points where geopolitics and global economic governance intersect and need to be managed, including sanctions, security-related trade measures, and industrial strategy.