Active State Research Articles

Evaluation of South Korea’s Growing Activities in the Changing Arctic: An Essay in Honor of Ted L. McDorman

South Korea, though not an Arctic state itself, has emerged as a significant player in Arctic affairs. This article explores South Korea’s multifaceted engagement in the region, including scientific research, economic endeavors, and international cooperation. South Korea aims to become a leading state in Arctic-related activities, with its Arctic policy focused on this goal. To achieve this, the country prioritizes strengthening scientific research in the Arctic, expanding economic activities, and fostering global cooperation. These objectives and activities in the Arctic are part of South Korea’s broader effort to establish itself as a pivotal player on the global stage. Additionally, South Korea has developed unique Arctic initiatives, such as the North Pacific Arctic Conference, which has grown into a leading academic forum hosted by a non-Arctic state; the Arctic Academy, where Arctic students are invited to South Korea to learn alongside Korean students; and Arctic Partnership Week, which brings together experts from the Arctic region to discuss a wide range of Arctic-related topics. These distinctive Arctic activities of South Korea have also played a significant role in diversifying Arctic Ocean governance by bridging the gap between Arctic and non-Arctic states.

Changes In Motivation States For Physical Activity With Maximal Exercise Vary By Aerobic Fitness Level

Changes In Motivation States For Physical Activity With Maximal Exercise Vary By Aerobic Fitness Level

German And Spanish Adaptations Of The Crave Scale For Motivation States For Physical Activity

German And Spanish Adaptations Of The Crave Scale For Motivation States For Physical Activity

A temperature-inducible protein module for control of mammalian cell fate.

Inducible protein switches allow on-demand control of proteins in response to inputs including chemicals or light. However, these inputs either cannot be controlled with precision in space and time or cannot be applied in optically dense settings, limiting their application in tissues and organisms. Here we introduce a protein module whose active state can be reversibly toggled with a small change in temperature, a stimulus that is both penetrant and dynamic. This protein, called Melt (Membrane localization through temperature), exists as a monomer in the cytoplasm at elevated temperatures but both oligomerizes and translocates to the plasma membrane when temperature is lowered. The original Melt variant switched states between 28-32°C, and state changes could be observed within minutes of temperature change. Melt was highly modular, permitting thermal control over diverse processes including signaling, proteolysis, nuclear shuttling, cytoskeletal rearrangements, and cell death, all through straightforward end-to-end fusions. Melt was also highly tunable, giving rise to a library of variants with switch point temperatures ranging from 30-40°C. The variants with higher switch points allowed control of molecular circuits between 37°C-41°C, a well-tolerated range for mammalian cells. Finally, Melt permitted thermal control of cell death in a mouse model of human cancer, demonstrating its potential for use in animals. Thus Melt represents a versatile thermogenetic module for straightforward, non-invasive, spatiotemporally-defined control of mammalian cells with broad potential for biotechnology and biomedicine.

PP2A phosphatase regulatory subunit PPP2R3C is a new positive regulator of the hedgehog signaling pathway

Cellular signaling pathways rely on posttranslational modifications (PTMs) to finely regulate protein functions, particularly transcription factors. The Hedgehog (Hh) signaling cascade, crucial for embryonic development and tissue homeostasis, is susceptible to aberrations that lead to developmental anomalies and various cancers. At the core of Hh signaling are Gli proteins, whose dynamic balance between activator (GliA) and repressor (GliR) states shapes cellular outcomes. Phosphorylation, orchestrated by multiple kinases, is pivotal in regulating Gli activity. While kinases in this context have been extensively studied, the role of protein phosphatases, particularly Protein Phosphatase 2A (PP2A), remains less explored.This study unveils a novel role for the B″gamma subunit of PP2A, PPP2R3C, in Hh signaling regulation. PPP2R3C interacts with Gli proteins, and its disruption reduces Hedgehog pathway activity as measured by reduced expression of Gli1/2 and Hh target genes upon Hh signaling activation, and reduced growth of a Hh signaling-dependent medulloblastoma cell line. Moreover, we establish an antagonistic connection between PPP2R3C and MEKK1 kinase in Gli protein phosphorylation, underscoring the intricate interplay between kinases and phosphatases in Hh signaling pathway. This study sheds light on the previously understudied role of protein phosphatases in Hh signaling and provides insights into their significance in cellular regulation.

State participation in investment agreements (international investment activity): issues of immunity and jurisdiction

It is indicated that international private-law relations nowadays are expanding significantly primarily in connection with the internationalization of economic life. The modern world is characterized by the economic interdependence of states, the expansion of not only traditional forms of foreign economic relations, but also relatively new forms such as leasing operations, concessions, franchising, and others. The article examines the current trends in the development of state immunity in international private law relations, in particular, in investment relations. The author defines the scope of these relations and gives their general characteristics, as well as identifies the peculiarities of the State’s participation in these relations as a subject of private international law. The author examines the content, types of international investment relations, development trends and peculiarities of legal regulation. The author pays special attention to the jurisdictional issues of investment dispute resolution involving states. The author analyzes legal acts and shows the role of judicial practice in this area. The author substantiates the need to apply functional (limited) immunity in international private law relations. Expansion of the range of international private legal relations over time due to the development of foreign economic activity, integration processes, and interdependence of States in the second half of the twentieth century contributed to the expansion of State participation in civil (private) relations, which objectively led to the establishment of the concept of functional (limited) immunity in the legislative, judicial and contractual practice of different countries. The concept of limited immunity is becoming increasingly popular in the world, which is explained by the development of economic relations between different countries and the increasing involvement of states in commercial activities, which on their own behalf enter into various foreign trade agreements, obtain loans from foreign banks, use maritime transport for commercial purposes, i.e. by their actions they seem to put themselves in the position of a merchant, trader, private person, which then allows the courts to consider them as ordinary participants in the process. The current policy vector of most continental law states on immunity issues is shifting towards the use of limited immunity of states.

Activismos digitales. Nuevas formas de lucha mediadas por plataformas en la era del capitalismo de la vigilancia

The academic concern for the role that activisms assume in the face of social problems in a troubled world maintains a pre-eminent relevance. Revolutionary waves are being registered as phenomena that express social demands. Understanding transmedia activism implies observing the reality beyond the struggles and polarizations of hashtags. In this context, what is understood by digital activism? How does the power dispute unfold in the digital territory? What is understood by performances? How is digital activism projected in the era of heightened Surveillance Capitalism? This paper aims to analyze academic productions that conceptualize, problematize and study digital activism. In addition, to characterize and understand their main features and identify trends and challenges that they present in the framework of Surveillance Capitalism. The methodological strategy was elaborated on the state of the art regarding digital activism. In order to analyze the current state of digital activism and its future evolution, search, selection, and bibliographic organization were included. Among the main findings, are the identification of studies that analyze the digital territory as a field of power dispute and the characterization of digital activism from social movements and collective political action and other forms of online participation, such as slacktivism.

Unified bursting strategies in ectopic and endogenous even-skipped expression patterns.

Transcription often occurs in bursts as gene promoters switch stochastically between active and inactive states. Enhancers can dictate transcriptional activity in animal development through the modulation of burst frequency, duration, or amplitude. Previous studies observed that different enhancers can achieve a wide range of transcriptional outputs through the same strategies of bursting control. For example, despite responding to different transcription factors, all even-skipped enhancers increase transcription by upregulating burst frequency and amplitude while burst duration remains largely constant. These shared bursting strategies suggest that a unified molecular mechanism constraints how enhancers modulate transcriptional output. Alternatively, different enhancers could have converged on the same bursting control strategy because of natural selection favoring one of these particular strategies. To distinguish between these two scenarios, we compared transcriptional bursting between endogenous and ectopic gene expression patterns. Because enhancers act under different regulatory inputs in ectopic patterns, dissimilar bursting control strategies between endogenous and ectopic patterns would suggest that enhancers adapted their bursting strategies to their trans-regulatory environment. Here, we generated ectopic even-skipped transcription patterns in fruit fly embryos and discovered that bursting strategies remain consistent in endogenous and ectopic even-skipped expression. These results provide evidence for a unified molecular mechanism shaping even-skipped bursting strategies and serve as a starting point to uncover the realm of strategies employed by other enhancers.

NASP gene contributes to autism by epigenetic dysregulation of neural and immune pathways

BackgroundEpigenetics makes substantial contribution to the aetiology of autism spectrum disorder (ASD) and may harbour a unique opportunity to prevent the development of ASD. We aimed to identify novel epigenetic...

Molecular characterisation of lupus low disease activity state (LLDAS) and DORIS remission by whole-blood transcriptome-based pathways in a pan-European systemic lupus erythematosus cohort

ObjectivesTo unveil biological milieus underlying low disease activity (LDA) and remission versus active systemic lupus erythematosus (SLE).MethodsWe determined differentially expressed pathways (DEPs) in SLE patients from the PRECISESADS project (NTC02890121)...

Co-existence of synaptic plasticity and metastable dynamics in a spiking model of cortical circuits.

Evidence for metastable dynamics and its role in brain function is emerging at a fast pace and is changing our understanding of neural coding by putting an emphasis on hidden states of transient activity. Clustered networks of spiking neurons have enhanced synaptic connections among groups of neurons forming structures called cell assemblies; such networks are capable of producing metastable dynamics that is in agreement with many experimental results. However, it is unclear how a clustered network structure producing metastable dynamics may emerge from a fully local plasticity rule, i.e., a plasticity rule where each synapse has only access to the activity of the neurons it connects (as opposed to the activity of other neurons or other synapses). Here, we propose a local plasticity rule producing ongoing metastable dynamics in a deterministic, recurrent network of spiking neurons. The metastable dynamics co-exists with ongoing plasticity and is the consequence of a self-tuning mechanism that keeps the synaptic weights close to the instability line where memories are spontaneously reactivated. In turn, the synaptic structure is stable to ongoing dynamics and random perturbations, yet it remains sufficiently plastic to remap sensory representations to encode new sets of stimuli. Both the plasticity rule and the metastable dynamics scale well with network size, with synaptic stability increasing with the number of neurons. Overall, our results show that it is possible to generate metastable dynamics over meaningful hidden states using a simple but biologically plausible plasticity rule which co-exists with ongoing neural dynamics.

A General Mechanism for the General Stress Response in Bacteria.

The General Stress Response promotes survival of bacteria in adverse conditions, but how sensor proteins transduce species-specific signals to initiate the response is not known. The serine/threonine phosphatase RsbU initiates the General Stress Response in B. subtilis upon binding a partner protein (RsbT) that is released from sequestration by environmental stresses. We report that RsbT activates RsbU by inducing otherwise flexible linkers of RsbU to form a short coiled-coil that dimerizes and activates the phosphatase domains. Importantly, we present evidence that related coiled-coil linkers and phosphatase dimers transduce signals from diverse sensor domains to control the General Stress Response and other signaling across bacterial phyla. These results additionally resolve the mystery of how shared sensory domains control serine/threonine phosphatases, diguanylate cyclases and histidine kinases, revealing a common coiled-coil linker transduction mechanism. We propose that this provides bacteria with a modularly exchangeable toolkit for the evolution of diverse signaling pathways.

An Ethical Evaluation of Savings and Cooperative Societies in Ukum and Katsina-Ala Local Government Areas of Benue State

There a number of thrifts cooperative societies in Ukum and Katsina-Ala Local Government Areas which provides informal savings and investment avenues for the rural dwellers. However, there are a number of factors that affect the effectiveness of these thrifts and cooperatives such as poor and non-repayment of loans and misappropriation of funds. These challenges border on lack of ethical principles in business. Thus, one of the basic problems confronting business practice among the people of Ukum and Katsina-Ala Local Government is poor ethical principles in business practice. This paper therefore evaluates the ethics of savings and investment of selected thrifts and cooperative societies in Ukum and Katsina-Ala Local Government Area of Benue State. The paper adopts both primary and secondary sources of data collection and employed the descriptive and analytic methods of data analysis. Two thrifts and cooperative societies in Ukum and Katsina-Ala LGAs were sampled for the study. The analysis revealed that thrifts and cooperative societies have positive impact on business practice among the people. It is evident that cooperative societies exist in Ukum and Katsina-Ala LGAs where people save and invest monies in different businesses including farming, trading, purchase of commercial vehicles, motorcycles and in meeting other household needs. However, it was found that there are ethical challenges in managing thrifts and cooperative in Ukum and Katsina-Ala LGAs. These challenges are a result of poor ethical principles which are shown in the conduct of those who take loans without paying back and financial misappropriation on the part of those who own and manage such thrifts and cooperatives. The paper recommends among others that there is need to strengthen the ethical principles of integrity, financial accountability and transparency in Ukum and Katsina-Ala LGAs of Benue State for more effective business activities in the area. People borrowing money should do that with good reason and in a manner that they can repay the loans. Traditional and religious leaders should encourage people in the area to join thrifts and cooperatives, bams and adashi as ways of raising capital to start new businesses in the area.

The relationship between rehabilitation motivation and upper limb motor function in stroke patients.

Insufficient motivation among post-stroke survivors may be an important factor affecting their motor function recovery. This study seeks to investigate the relationship between motivation and functional recovery in stroke patients undergoing rehabilitation training. 103 stroke patients with upper limb impairments were studied during their hospital stays. Assessments were done before and after rehabilitation training to measure motivation, emotional state, motor function, and independence in daily activities. Data analysis was conducted to examine the distribution of these factors among the participants. Pearson and Spearman correlation analyses were used to study the relationships between motivation, emotional state, and motor function. Patients were divided into high and low motivation groups based on the Rehabilitation Motivation Scale (RMS), and chi-square and rank-sum tests were used to compare functional differences before and after treatment among patients with varying levels of motivation. 66 participants were found to have low motivation in the initial assessment of the RMS (64.08%). Consistency in motivation levels was observed among patients with high motivation (r = 0.648, P<0.001). Apathy was identified as the main factor affecting motivation in patients with low motivation (p = 0.027), while depression and anxiety were not significantly correlated. Motivation was strongly linked to improvements in upper limb motor function, daily living activities, and self-exercise duration (p < 0.001) for stroke patients undergoing rehabilitation. Post-training, there was a notable increase in motivation, motor function, and independence in daily activities (p < 0.001). Increased rehabilitation motivation was linked to better upper limb motor function and daily independence in patients, particularly those with low motivation. This correlation was significant for both the FMA-UE and FIM scores. Old patients with poor upper limb motor function often have low motivation, which hinders their recovery. Using strategies to boost motivation in stroke patients with impaired upper limb function could greatly improve their rehabilitation and motor skills. It is crucial to prioritize these intervention strategies. Enhancing rehabilitation motivation in stroke patients with low motivation and upper limb motor impairments can foster the restoration of their functional capabilities.

Curvature in the very-high energy gamma-ray spectrum of M 87

The radio galaxy M 87 is a variable very-high energy (VHE) gamma-ray source, exhibiting three major flares, which were reported in 2005, 2008, and 2010. Despite extensive studies, the origin of the VHE gamma-ray emission is not yet fully understood. In this study, we investigate the VHE gamma-ray spectrum of M 87 during states of high gamma-ray activity, utilizing 20.2 h of H.E.S.S. observations. Our findings indicate a preference for a curved spectrum, characterized by a log-parabola model with extra-galactic background light (EBL) model above 0.3 TeV at the 4σ level, compared to a power-law spectrum with EBL. We investigate the degeneracy between the absorption feature and the EBL normalization and derive upper limits on EBL models that are mainly sensitive in the wavelength range of 12.4 μm–40 μm.

Hand LightWeightNet: an optimized hand pose estimation for interactive mobile interfaces

In this paper, a hand pose estimation method is introduced that combines MobileNetV3 and CrossInfoNet into a single pipeline. The proposed approach is tailored for mobile phone processors through optimizations, modifications, and enhancements made to both architectures, resulting in a lightweight solution. MobileNetV3 provides the bottleneck for feature extraction and refinements while CrossInfoNet benefits the proposed system through a multitask information sharing mechanism. In the feature extraction stage, we utilized an inverted residual block that achieves a balance between accuracy and efficiency in limited parameters. Additionally, in the feature refinement stage, we incorporated a new best-performing activation function called “activate or not” ACON, which demonstrated stability and superior performance in learning linearly and non-linearly gates of the whole activation area of the network by setting hyperparameters to switch between active and inactive states. As a result, our network operated with 65% reduced parameters, but improved speed by 39% which is suitable for running in a mobile device processor. During experiment, we conducted test evaluation on three hand pose datasets to assess the generalization capacity of our system. On all the tested datasets, the proposed approach demonstrates consistently higher performance while using significantly fewer parameters than existing methods. This indicates that the proposed system has the potential to enable new hand pose estimation applications such as virtual reality, augmented reality and sign language recognition on mobile devices.

Abstract 6444: Assessing cytotoxic T cell responses to immune checkpoint inhibitors in murine and human tumor samples using metabolic imaging

Abstract Background Immune checkpoint inhibitors (ICI) have revolutionized cancer treatment. Unfortunately, existing FDA approved biomarkers do not accurately predict which patients will respond. The Elephas Cybrid™ platform aims to improve ICI response prediction by imaging a patient’s biopsy treated with ICI ex vivo. Multiphoton microscopy (MPM) is a powerful imaging technique to interrogate the biological changes in live tumor fragments (LTFs) following ICI treatment. MPM allows rapid visualization of biological processes in 3D living tissues in a non-destructive fashion allowing for longitudinal assessment of a sample. We and others have used label-free metabolic imaging to demonstrate that changes in T cell metabolism and activation status are correlated. Using MPM imaging we successfully demonstrated T cell activation and T cell mediated cytotoxicity in response to ICI in LTFs and tumor biopsies. Methods Tumors were cut into LTFs, sorted, and cultured using the Cybrid platform. LTF structure and metabolic status were assessed using intrinsically fluorescent NAD(P)H and FAD. Anti-CD8 nanobodies and cleaved caspase 3/7 dye were used to characterize T cell cytotoxicity. Multi-channel fluorescence intensity and lifetime were obtained over 48 hours using MPM. Results Murine CT26 LTFs generated with the Cybrid platform were treated with ICI and cytotoxicity was assessed in the intact LTFs by monitoring caspase 3/7 activity using MPM over 48 hours. We found that ICI treatment resulted in a significant increase in caspase 3/7 activity compared to control treated LTFs. By blocking the interaction of T cells with tumor cells through antibody blockade, we demonstrated that the cytotoxicity observed was T cell mediated. As additional confirmation, we measured changes in cytotoxicity in the ICI resistant LLC1 tumor model. As expected, we did not observe an increase in cytotoxicity in LLC1 LTFs treated with ICI. MPM allows for the tracking of labeled T cells and characterization of their metabolism as a means of assessing changes in their activation state. We used a CD8 nanobody to label T cells in CT26 LTFs and then characterized the shift in metabolism following ICI treatment. Finally, we applied the Cybrid platform to human biopsies treated with ICI and characterized the cytotoxicity and shifts in T cell metabolism in living tissue. These data show that the Cybrid platform can measure changes in T cell metabolism and T cell cytotoxicity in response to ICI in 3D living tissue. Conclusions The methods presented herein will advance the field of cancer diagnostics by progressing from fixed tissue imaging and genetic characterization to the assessment of clinically relevant ICI-treated biopsies. Understanding the response of biopsies to immunotherapies will allow clinicians to make more informed treatment decisions and improve the lives of those with cancer. Citation Format: Jonathan Ouellette, Janey Degnan, Anna Kellner, Evan Flietner, Lindsay Doebert, Zachary Swider, Eric Wait, Victoria Pope, Laura Hrycyniak, Sean Caenepeel, Kevin Eliceiri, T S. Ramasubramanian, Michael J. Korrer. Assessing cytotoxic T cell responses to immune checkpoint inhibitors in murine and human tumor samples using metabolic imaging [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6444.

Allosterically activating SHP2 by oleanolic acid inhibits STAT3–Th17 axis for ameliorating colitis

Src homology 2 domain-containing tyrosine phosphatase 2 (SHP2) is an essential tyrosine phosphatase that is pivotal in regulating various cellular signaling pathways such as cell growth, differentiation, and survival. The activation of SHP2 has been shown to have a therapeutic effect in colitis and Parkinson's disease. Thus, the identification of SHP2 activators and a complete understanding of their mechanism is required. We used a two-step screening assay to determine a novel allosteric activator of SHP2 that stabilizes it in an open conformation. Oleanolic acid was identified as a suitable candidate. By binding to R362, K364, and K366 in the active center of the PTP domain, oleanolic acid maintained the active open state of SHP2, which facilitated the binding between SHP2 and its substrate. This oleanolic acid-activated SHP2 hindered Th17 differentiation by disturbing the interaction between STAT3 and IL-6Rα and inhibiting the activation of STAT3. Furthermore, via the activation of SHP2 and subsequent attenuation of the STAT3–Th17 axis, oleanolic acid effectively mitigated colitis in mice. This protective effect was abrogated by SHP2 knockout or administration of the SHP2 inhibitor SHP099. These findings underscore the potential of oleanolic acid as a promising therapeutic agent for treating inflammatory bowel diseases.

Plasma metabolomic profile is near-normal in people with HIV on long-term suppressive antiretroviral therapy.

Combination antiretroviral therapy (ART) has transformed human immunodeficiency virus (HIV) infection in people with HIV (PWH). However, a chronic state of immune activation and inflammation is maintained despite achieving HIV suppression and satisfactory immunological recovery. We aimed to determine whether the plasma metabolomic profile of PWH on long-term suppressive ART and immunologically recovered approximates the normality by comparison with healthy controls with similar age and gender. We carried out a cross-sectional study in 17 PWH on long-term ART (HIV-RNA <50 copies/mL, CD4+ ≥500 cells/mm3, and CD4+/CD8+ ≥1) and 19 healthy controls with similar age and gender. Metabolomics analysis was performed by gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS). The statistical association analysis was performed by principal component analysis (PCA), partial least squares discriminant analysis (PLS-DA), and Generalized Linear Models (GLM) with a gamma distribution (log-link). Significance levels (p-value) were corrected for multiple testing (q-value). PCA and PLS-DA analyses found no relevant differences between groups. Adjusted GLM showed 14 significant features (q-value<0.20), of which only three could be identified: lysophosphatidylcholine (LysoPC) (22:6) (q-value=0.148), lysophosphatidylethanolamine (LysoPE) (22:6) (q-value=0.050) and hydroperoxy-octadecatrienoic acid (HpOTrE)/dihydroperoxy-octadecatrienoic acid (DiHOTrE)/epoxy-octadecadienoic acid (EpODE) (q-value=0.136). These significant identified metabolites were directly correlated to plasma inflammatory biomarkers in PWH and negatively correlated in healthy controls. PWH on long-term ART have a metabolomic profile that is almost normal compared to healthy controls. Nevertheless, residual metabolic alterations linked to inflammatory biomarkers persist, which could favor the development of age-related comorbidities among this population.

Transcriptional control of neural stem cell activity.

In the adult brain, neural stem cells (NSCs) are under the control of various molecular mechanisms to produce an appropriate number of neurons that are essential for specific brain functions. Usually, the majority of adult NSCs stay in a non-proliferative and undifferentiated state known as quiescence, occasionally transitioning to an active state to produce newborn neurons. This transition between the quiescent and active states is crucial for the activity of NSCs. Another significant state of adult NSCs is senescence, in which quiescent cells become more dormant and less reactive, ceasing the production of newborn neurons. Although many genes involved in the regulation of NSCs have been identified using genetic manipulation and omics analyses, the entire regulatory network is complicated and ambiguous. In this review, we focus on transcription factors, whose importance has been elucidated in NSCs by knockout or overexpression studies. We mainly discuss the transcription factors with roles in the active, quiescent, and rejuvenation states of adult NSCs.