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Since the 1980s, most advanced economies have massively 'flexibilized' their labour markets by reducing the protection against layoffs and introducing temporary and flexible contracts. Concurrently, a well-established economic stylized fact – the stability of the wage share of income – has been challenged as empirical evidence reveals a substantial decline in labour share across numerous countries. In this study, we aim to empirically investigate the causal link between these two phenomena by examining the impact of changes in the regulation of fixed-term contracts, as measured by variation over time in the temporary contracts EPL index, on the functional distribution of income. We employ Jordà's local projection method for a panel of 18 advanced countries over the period 1985–2019 and show that reforms that deregulate fixed-term contracts consistently reduce the wage share. • The wage share has declined in many countries in recent decades. • The study investigates the impact of fixed-term contract protection reforms on functional income distribution. • Local projections are applied to EPL variations for a sample of 18 advanced economies over the period 1985–2019. • A nonlinear analysis is conducted to explore the effects of flexibilization and tightening reforms. • The results indicate that deregulating fixed-term contracts leads to a significant reduction in the wage share. [ABSTRACT FROM AUTHOR]

Street theater is historically a form of political performance art used to foster social change and is characterized by unscheduled performances in public spaces, interactive audience participation, and short performances often repeated in the same spot for passersby. Long used as a creative tool within social movements, street skits not only entertain but are used to educate and build awareness on pressing issues. It is an art form for the people, by the people, making theater available for all ("on the streets") rather than solely for those who can afford it. Street theater also has its uses in public health education and organizing and has been used globally as an effective method of health promotion, especially in rural and low-literacy areas. This paper looks at a street theater project that university students at Clark University in Worcester, MA participated in as part of a "Health Rights: Advocacy and Action" course. Students were tasked with developing a street theater skit that educates on a public health issue and publicly perform the skit on campus. Three skits were produced: (1) "Deadly Derailment": raised awareness on industry deregulation and the 2023 toxic chemical spill in East Palestine, OH; (2) "Harm Reduction Saves Lives": addressed humane and non-victim blaming ways to address substance use; and (3) "End the STIgma": educated on sexual health on a college campus. Teaching street theater as part of public health pedagogy is a creative approach to inspire students to use their voices and link health promotion and activism. [ABSTRACT FROM AUTHOR]

Background: Myotonic Dystrophy type I (DM1) is the most common muscular dystrophy in adults. Previous reports have highlighted that neuromuscular junctions (NMJs) deteriorate in skeletal muscle from DM1 patients and mouse models thereof. However, the underlying pathomechanisms and their contribution to muscle dysfunction remain unknown. Methods: We compared changes in NMJs and activity-dependent signalling pathways in HSALR and Mbnl1ΔE3/ΔE3 mice, two established mouse models of DM1. Results: Muscle from DM1 mouse models showed major deregulation of calcium/calmodulin-dependent protein kinases II (CaMKIIs), which are key activity sensors regulating synaptic gene expression and acetylcholine receptor (AChR) recycling at the NMJ. Both mouse models exhibited increased fragmentation of the endplate, which preceded muscle degeneration. Endplate fragmentation was not accompanied by changes in AChR turnover at the NMJ. However, the expression of synaptic genes was up-regulated in mutant innervated muscle, together with an abnormal accumulation of histone deacetylase 4 (HDAC4), a known target of CaMKII. Interestingly, denervation-induced increase in synaptic gene expression and AChR turnover was hampered in DM1 muscle. Importantly, CaMKIIβ/βM overexpression normalized endplate fragmentation and synaptic gene expression in innervated Mbnl1ΔE3/ΔE3 muscle, but it did not restore denervation-induced synaptic gene up-regulation. Conclusions: Our results indicate that CaMKIIβ-dependent and -independent mechanisms perturb synaptic gene regulation and muscle response to denervation in DM1 mouse models. Changes in these signalling pathways may contribute to NMJ destabilization and muscle dysfunction in DM1 patients. [ABSTRACT FROM AUTHOR]

Since 2013, Permitted Development Rights (PDR) in England have allowed commercial-to-residential conversions in locations once deemed suitable only for non-residential land-use. This deregulation of planning control has been justified as a way of encouraging more home-building in areas experiencing 'housing crisis', but its overall consequences remain unclear. This paper hence compiles quantitative evidence on a city-wide scale on the price, size, build and location of these conversions in London 2013–2021. It finds that homes produced through this route are generally smaller than the London average and are over-concentrated in neighbourhoods with fewer accessible green spaces and higher-than-average levels of air pollution. Here, larger conversion schemes (of more than 10 units) appear particularly problematic, potentially subjecting residents to forms of 'slow violence' that could have long-term consequences for their physical and mental health. The paper also finds that, on average, PDR conversions are marginally more affordable than other new developments in the capital, but are also more expensive per square metre, suggesting deregulation is allowing developers to 'extract' maximum value from these schemes rather than providing affordable homes per se. The implications of this are discussed in relation to the politics of housing in London and the wider forms of planning deregulation allowing developers to accrue increased profits from housing in an era of intense financialisation. [ABSTRACT FROM AUTHOR]

Indonesian rural youth face challenges accessing farmland and sustaining an agricultural livelihood while their labour is not necessarily absorbed by other sectors. In that context, the Omnibus Law on Job Creation (Law 11/2020) promises to liberalise trade and investment across multiple sectors, including agriculture and food security. Combining legal research and political economy approaches to youth and agrarian challenges, we identify amendments to legislation that reduce safeguards for the environment, workers' and farmers' rights and their livelihoods. If fully implemented, the legislative amendments could further narrow youth's options both for secure formal work and futures in farming by accelerating the expansion of infrastructure, industrial plantations and extractive industries that utilise low‐wage labour and huge areas of land. This exposes inconsistencies in the government's approach to increase future food security by promoting intensification of agriculture and attracting youth to farming, while enabling agro‐ and resource extraction that absorbs land yet offers limited and precarious employment prospects. [ABSTRACT FROM AUTHOR]

In Turkey, as in many Mediterranean countries, the Covid‐19 pandemic enhanced the mobility of the country's affluent classes to coastal towns. Many decided to settle there permanently, either by making their second homes their main residences, or by purchasing or renting new property. This has created severe social, infrastructural and environmental problems in these towns because of transformed demographics, a largely unregulated construction boom, increased renovation activities and an unprecedented rise in real‐estate and consumer‐goods prices. In this article we contextualize these problems in relation to the Justice and Development Party's neoliberal policies of urban governance and rescaling in the past 15 years. The government, having given the construction sector the main role in Turkey's economic development, subsequently granted it new spatial opportunities through the authoritarian and centralized allocation of urban and rural land. Coastal towns have been the target of unregulated urban growth and predatory construction in this process and have thus provided new spatial development prospects. Local governmental reform in 2012, which introduced radical urban rescaling and weakened district municipalities' planning and regulation capacities, further intensified the process. These factors have had a severe impact on coastal towns and their middle‐income residents, who face new mobility pressures. [ABSTRACT FROM AUTHOR]

The Perception of Anomie Scale (PAS) is a measure used to evaluate the state of society and whether it is disintegrated and deregulated. Although widely used, the psychometric properties of reliability, validity, and measurement invariance according to sex have not been studied in the Chilean university population. To explore these properties, a cross-sectional study was carried out with 383 students from public (45.7%) and private (54.3%) universities, with a mean age of 21.5 years (SD = 3.3). A CFA and ESEM were performed, which confirmed the two-factor correlated structure, achieving better goodness-of-fit indices by eliminating five items (RMSEA = 0.09; CFI = 0.98; TLI = 0.95). This also provided evidence of reliability and measurement invariance according to sex. This study provides evidence of the psychometric quality of the PAS scale, thus allowing its use in the Chilean university context. [ABSTRACT FROM AUTHOR]

This research turns the spotlight to the deregulation of once publicly funded affordable housing. Through a microsimulation that follows the conversion from affordable to market-rate units on Roosevelt Island New York, we estimate the expected demographic changes each year between 1976 and 2070. The simulation combines information from the American Community Survey, the island's masterplan, the privatization agreements, and interviews with residents, to produce interactive graphs at three urban scales: the neighborhood, the project, and the building. We found that while the households of market-rate units are gradually becoming younger and more affluent, the households of affordable units are becoming older and more impoverished. Despite an individual agreement for each building, the demographic changes are similar, and that, those changes will affect low-income buildings first. Moreover, upon expiration, 30 percent of the existing protected tenants will be over 65 and at risk of being displaced. The simulation is available at http://ridigitaltwin.pythonanywhere.com/. [ABSTRACT FROM AUTHOR]

Families in the United States suffer from a removal epidemic. The child welfare framework allows unnecessary and harmful intervention into family and parenting matters, traditionally left to the discretion of the parent. Many states allow Child Protective Services ("CPS") to investigate, intervene, and permanently separate a child from their parents for innocuous activities such as letting the child play outside unattended. This especially affects low-income and minority families. To prevent CPS from unnecessarily intervening in a family's decision to let their children engage in independent, unsupervised activities, Utah passed a "free-range" parenting act ("Act") in 2018. The Act explicitly excludes independent, age-appropriate activities from the definition of neglect. This Act has remained largely unexamined: whether the passage of the free-range parenting law has resulted in a decrease of non-supervision cases referred to and substantiated by CPS is unclear. It is also unclear whether free-range parenting laws are a viable solution to the issue of unnecessary and harmful state intervention, in general. This Note explores whether the free-range parenting law passed in Utah in 2018 has led to any discernible reduction in non-supervision cases and removals. Since the statistical analysis has significant limitations, the Note then takes a more general approach in examining whether these laws address the causes of unnecessary state intervention. The Note finds that many free-range parenting laws fail to address larger issues in the child welfare system and tend to mainly benefit middle-class and high-income families. A solution will likely require a concerted effort by all three branches of the government. It is imperative that efforts to pass free-range parenting laws are not abandoned but rather utilized for bigger and more equitable change. [ABSTRACT FROM AUTHOR]

Simple Summary: UGT enzymes metabolize and detoxify numerous small molecules that are important in cancer, including carcinogens, endogenous growth regulators, and anticancer drugs. Alternatively spliced UGT transcripts can encode truncated proteins that inhibit canonical UGTs, thus reducing detoxification activity. We assessed the expression of specific variant transcripts, designated as UGT1A_v2 and _v3, in six different cancers using RNA-seq datasets with large cohorts of paired normal and tumor tissues. Our results show high interindividual variation in v2 and v3 transcript abundance, as well as tissue- and tumor-specific expression patterns. These findings suggest that the variants have tissue-specific impacts on glucuronidation and may have a more significant role in tumors than in normal tissues. The high interindividual variability is likely relevant to differing personalized drug metabolisms through the UGT conjugation pathway. Finally, our discovery of novel UGT1A variant transcripts further highlights the diversity of the UGT1A transcriptome and proteome. The UGT1A locus generates over 60 different alternatively spliced transcripts and 30 circular RNAs. To date, v2 and v3 transcripts are the only variant UGT1A transcripts that have been functionally characterized. Both v2 and v3 transcripts encode the same inactive variant UGT1A proteins (i2s) that can negatively regulate glucuronidation activity and influence cancer cell metabolism. However, the abundance and interindividual variability in the expression of v2 and v3 transcripts in human tissues and their potential deregulation in cancers have not been comprehensively assessed. To address this knowledge gap, we quantified the expression levels of v1, v2, and v3 transcripts using RNA-seq datasets with large cohorts of normal tissues and paired normal and tumor tissues from patients with six different cancer types (liver, kidney, colon, stomach, esophagus, and bladder cancer). We found that v2 and v3 abundance varied significantly between different tissue types, and that interindividual variation was also high within the same tissue type. Moreover, the ratio of v2 to v3 variants varied between tissues, implying their differential regulation. Our results showed higher v2 abundance in gastrointestinal tissues than liver and kidney tissues, suggesting a more significant negative regulation of glucuronidation by i2 proteins in gastrointestinal tissues than in liver and kidney tissues. We further showed differential deregulation of wildtype (v1) and variant transcripts (v2, v3) in cancers that generally increased the v2/v1 and/or v3/v1 expression ratios in tumors compared to normal tissues, indicating a more significant role of the variants in tumors. Finally, we report ten novel UGT1A transcripts with novel 3′ terminal exons, most of which encode variant proteins with a similar structure to UGT1A_i2 proteins. These findings further emphasize the diversity of the UGT1A transcriptome and proteome. [ABSTRACT FROM AUTHOR]

Several states have enacted specialized limited liability company legislation in an attempt to attract decentralized autonomous organizations. In this way, the regulatory competition debate surrounding states such as Wyoming, Tennessee, and Vermont, attempting to dethrone Delaware, has found a new battleground. According to Professor Lynn LoPucki, this will entail a regulatory race to the bottom, that is, a race to "laxity." I disagree. In fact, deregulation has already been achieved in the traditional limited liability company form. The decentralized autonomous organization limited liability company is no laxer or more attractive to investors, who willlikely prefer the traditional limited liability company or even other entity forms, given the diversity of investors' needs and aims. Moreover, some decentralized autonomous organization organizers may wish not to incorporate at all, hoping to avoid the law altogether. While increasingly risky, this strategy rests on the belief in the alegality liability shield, further diminishing the impact of the /ex specialis approach. After analyzing the statutory developments and the scholarly and industrial commentary, I conclude that in decentralized autonomous organizations, as elsewhere, the regulatory race to the bottom is a fad. [ABSTRACT FROM AUTHOR]

In order to solve the problem of power exchange between areas of multi-area power systems under the power market, this paper designs a power trading contract based on the generation participation matrix, so as to simulate the specific process of power change in each area. With the integration of wind power into the large-scale power system, it is difficult to model the multi-area power system. For this situation, this paper designs a data-driven model-free adaptive load frequency control algorithm based on collecting input and output data, which gets rid of the dependence of the power system on the model. Along with the frequent transmission of input and output data in each area, the communication load of the power system also increases. Aiming at saving communication resources, this paper designs an event-triggered mechanism to reduce the communication bandwidth. The stability of the control algorithm is demonstrated theoretically. Finally, a three-area power system with wind penetration is used as an example to simulate and verify the effectiveness of the proposed algorithm in this paper. [ABSTRACT FROM AUTHOR]

In 2016, the City of Toronto legalised the ridehail giant Uber under a particularly Uber‐friendly regulatory regime. Rather than understanding this interim outcome along the lines of now widespread narratives of corporate "disruption", in this article I take up Manuel B. Aalbers' notion of "regulated deregulation" in order to foreground the state's role as a manically prolific facilitator of early Uberisation. Based on ethnographic research in Toronto, I argue that the three longer‐standing state spatial strategies of (1) the common‐sense neoliberal state, (2) the labour‐averse competition state, and (3) the tech‐infatuated smart state were paramount in creating those "on‐the‐ground" conditions—social, legal, spatial, and other—on which Uber has been able to thrive in many cities across the North American continent. [ABSTRACT FROM AUTHOR]

Since 15 November 2012, the South Korean government amended the law to make some medicines available at 24-hour convenient stores that had previously been sold at pharmacies only. The aim of this study was to evaluate the impact of this legislation on drug poisoning in youth patients, who may be affected by increased access. This study retrospectively analyzed data registered in the Emergency Department-based Injury In-depth Surveillance (EDIIS) database from January 2007 to December 2018. Patients aged 15 to 24 years old were selected to analyze the incidence and outcomes of acetaminophen (AAP) poisoning in youth patientsBefore the deregulation of over-thecounter (OTC) medication sales, 1994 youth patients visited the emergency department (ED) from 2007-2012. By contrast, 5440 youth visited the ED from 2013-2018 after deregulation. In particular, there were 263 (13.2%) and 820 (15.1%) cases of AAP poisoning intentionally before and after deregulation, respectively, which was not significantly different (p = 0.085). However, the number of patients who were admitted to the general ward (GW) due to AAP poisoning significantly increased from 93 (35.4%) to 339 (41.3%) (p = 0.041). Furthermore, the number of patients who were admitted to the intensive care unit (ICU) after ingesting AAP significantly increased from 9 (3.4%) to 93 (11.3%) (p<0.001). There was no significant difference in intentional AAP poisoning ratios following the deregulation of OTC drug sales; however, GW and ICU admission rates significantly increased. This study demonstrated that there is positive relationship between intentional AAP poisoning and severity in youth patients after the deregulation legislation. [ABSTRACT FROM AUTHOR]

The Developmental Origins of Health and Disease (DOHaD) concept has provided the framework to assess how early life experiences can shape health and disease throughout the life course. While maternal malnutrition has been proposed as a risk factor for the developmental programming of prostate cancer (PCa), the molecular mechanisms remain poorly understood. Using RNA-seq data, we demonstrated deregulation of miR-206-Plasminogen (PLG) network in the ventral prostate (VP) of young maternally malnourished offspring. RT-qPCR confirmed the deregulation of the miR-206-PLG network in the VP of young and old offspring rats. Considering the key role of estrogenic signaling pathways in prostate carcinogenesis, in vitro miRNA mimic studies also revealed a negative correlation between miR-206 and estrogen receptor α (ESR1) expression in PNT2 cells. Together, we demonstrate that early life estrogenization associated with the deregulation of miR-206 networks can contribute to the developmental origins of PCa in maternally malnourished offspring. Understanding the molecular mechanisms by which early life malnutrition affects offspring health can encourage the adoption of a governmental policy for the prevention of non-communicable chronic diseases related to the DOHaD concept. [ABSTRACT FROM AUTHOR]

This study focused on the privatization and commercialization policy in the telecommunication industry in Nigeria, within the period 2012-2020. The objective of the study was to evaluate the impact of the privatization and telecommunication industry on the nation's economy. The paper utilized the secondary source of data and desk analysis in discussing the paper. The paper highlighted some challenges facing the Nigerian telecommunication industry in its new era which amongst others include, inadequate power supply, and transmission infrastructural challenges. In a cross examination of the policy under review, the paper discovered amongst others that, privatization and commercialization in Nigerian telecommunication industry have affected the economy positively. Also, the paper revealed that the deregulation of the telecommunication industry has provided a huge boost in the growth of the industry. In terms of employment opportunities, the study revealed that, the privatization and commercialization of the telecommunication has improved the employment rate in Nigeria. The paper therefore concluded that privatization and commercialization of the telecommunication industry has opened up new frontiers for communication and expanded the economic base of the economy. The paper recommended amongst others that the government should continue to create a conducive environment for the telecommunication industry to flourish. [ABSTRACT FROM AUTHOR]

Hopes for the Paris targets to limit warming to 1.5 degrees are receding as catastrophic consequences of climate deregulation are building up and causing harm to human lives and livelihoods. Several natural tipping points are now at risk of irreversible change. The results of the Dubai climate summit will not change that. Michael Gross reports. Hopes for the Paris targets to limit warming to 1.5 degrees are receding as catastrophic consequences of climate deregulation are building up and causing harm to human lives and livelihoods. Several natural tipping points are now at risk of irreversible change. The results of the Dubai climate summit will not change that. [ABSTRACT FROM AUTHOR]

Profit maximization is critical in the control of power system networks for both power providers and users. Electrical energy is freely accessible in the electrical grid during off-peak hours, with storage units helping to store excess energy and assist the electrical grid during high-demand situations. Such techniques promote grid stability and ensure safe operation. Because renewable resources are intermittent, energy storage technologies are especially significant in renewable-associated power systems. Vehicle-to-grid (V2G) technology has recently acquired popularity in preserving power grid stability in the presence of renewable resources.V2G technology employs automobiles as mobile storage devices and focuses on the efficient utilization of extra power available during off-peak hours. The goal of this work is to improve the functioning of a V2G system in a power network to reduce energy production costs while increasing system profitability. This study for deregulated power environments also depicts the influence of V2G mixing on system voltage profile and locational marginal pricing (LMP), as well as the performance of the Unified Power Flow Controller (UPFC) on system economics. The MiPower simulation program is used in the study to find the best placement of the power storage unit for the modified IEEE 14-bus system. [ABSTRACT FROM AUTHOR]

Intrapulmonary arteries located in the proximal lung differ from those in the distal lung in size, cellular composition, and the surrounding microenvironment. However, whether these structural variations lead to region-specific regulation of vasoreactivity in homeostasis and following injury is unknown. Herein, we employ a two-step method of precision-cut lung slice (PCLS) preparation, which maintains almost intact intrapulmonary arteries, to assess contractile and relaxation responses of proximal preacinar arteries (PaAs) and distal intraacinar arteries (IaAs) in mice. We found that PaAs exhibited robust vasoconstriction in response to contractile agonists and significant nitric oxide (NO)-induced vasodilation. In comparison, IaAs were less contractile and displayed a greater relaxation response to NO. Furthermore, in a mouse model of pulmonary arterial hypertension (PAH) induced by chronic exposure to ovalbumin (OVA) allergen and hypoxia (OVA-HX), IaAs demonstrated a reduced vasocontraction despite vascular wall thickening with the emergence of new αSMA+ cells coexpressing markers of pericytes. In contrast, PaAs became hypercontractile and less responsive to NO. The reduction in relaxation of PaAs was associated with decreased expression of protein kinase G, a key component of the NO pathway, following chronic OVA-HX exposure. Taken together, the PCLS prepared using the modified preparation method enables functional evaluation of pulmonary arteries in different anatomical locations and reveals region-specific mechanisms underlying the pathophysiology of PAH in a mouse model. [ABSTRACT FROM AUTHOR]

The Electricity Demand Prediction (EDP) and Generation Expansion Planning (GEP) make a real-world planning problem more optimal. In this study, the EDP problem has been solved using the optimization techniques such as Differential Evolution (DE), Genetic Algorithm (GA) and Artificial Immune System (AIS) for Tamil Nadu state, India. The electricity demand has been predicted and validated in terms of Mean Absolute Percentage Error (MAPE). The results reveal that DE outperformed other algorithms in solving the EDP problem. Continually, the GEP problem under partial deregulated environmental has been solved using the DE. In the GEP model, utilities and Independent Power Producer (IPP) have acted as the generating sources where IPP sells the power to utilities and utilities sell the power to the consumers. The utilities have been modeled to ensure the profit of all IPP, fuel mix ratio, system security, reliability, etc. The problem has been solved for the 6-year (till 2024) and 12-year (till 2030) planning horizons by considering three different scenarios, such as (i) without budget constraint of utilities, (ii) with budget constraint of utilities and (iii) penetration of huge Renewable Energy Source (RES) with budget constraint of utilities. The expansion capacities of each power plants were estimated over the planning horizon by maximizing the profit to the generating sources. The values of reliability indices and CO2 emission have been obtained. [ABSTRACT FROM AUTHOR]

Although much of the U.S. electricity system moved to deregulated markets in the late 1990s, states in the southeastern United States—home to the nation's largest, most valuable, and most polluting utilities—chose to retain regulated monopolies. In this article, we draw on interviews with regulators, environmental organizations, lobbyists, and utility executives to examine how utilities in the southeastern United States have maintained their position as monopolies in the face of calls for competition in the 1990s and again in the 2020s. We ground our inquiry in geographical political economy, with attention to the role that law plays in balancing monopoly and competition in electricity provision and capitalism more broadly. Our research suggests that the cultural political economy of energy regulation in the Southeast has played a central role in enabling electric utilities to maintain their monopoly position, with utilities using their relationships with regulators to parlay their monopoly preference into narratives of monopoly-as-consumer-protection. We therefore offer insights regarding long-debated mechanisms of regulatory capture, highlighting how the structure of public utility law creates opportunities for political and personal relationships to overpower general ideological commitments to competition. These findings demonstrate how law is deployed as a mediating tool of capitalist relations. [ABSTRACT FROM AUTHOR]

The aim of this paper is to analyse institutional change in the Spanish labour market in from a historical perspective, particularly regarding two main areas: labour regulation and collective bargaining. The main thesis is that it is possible to identify four main stages. Firstly, there was an institutional structure unfavourable to workers, which was overcome by the agency of the labour movement in the period of the so-called desarrollismo (1960-1975). Secondly, the years of transition from dictatorship to democracy (1976-1983) were a period of labour market regulation. Thirdly, there was a period of labour market dualism (1984-1996) based on the application of flexibility at the margin in the face of veto power. This was followed by deregulation (1997-2019), which was a consequence of the weakening of power resources resulting from the previous labour market segmentation. [ABSTRACT FROM AUTHOR]

In-situ upgrading of informal settlements has emerged as a key planning policy to provide durable housing that respects human rights and is financially viable. Slum upgrading policies usually focus on tenure legalisation and infrastructure improvements. However, we argue that such interventions miss a significant aspect by which informal settlements can be prevented from developing slum conditions – the application of building regulation. In conventional upgrading approaches, the application of building regulation has been conceived as a singular approach, in which city-wide, state-initiated building codes are adapted to the settlement. We broaden the debate on regulating informal settlement by incorporating regulation 'from within', which acknowledges that informal settlements are formed by sociospatial logics which are amenable to regulation by the dwellers themselves. This viewpoint discusses why urban regulation is needed in informal settlement upgrading, presents two of the broad critiques on the application of planning regulation to informal settlement, and suggests three approaches to regulating, namely 'lowering standards', 'relational rules', and 'neighbourly consent'. This article was published open access under a CC BY licence: https://creativecommons.org/licences/by/4.0. [ABSTRACT FROM AUTHOR]

Hailey‐Hailey disease (HHD) is a rare autosomal dominantly inherited disorder caused by mutations in the ATP2C1 gene that encodes an adenosine triphosphate (ATP)‐powered calcium channel pump. HHD is characterized by impaired epidermal cell‐to‐cell adhesion and defective keratinocyte growth/differentiation. The mechanism by which mutant ATP2C1 causes HHD is unknown and current treatments for affected individuals do not address the underlying defects and are ineffective. Notch signalling is a direct determinant of keratinocyte growth and differentiation. We found that loss of ATP2C1 leads to impaired Notch1 signalling, thus deregulation of the Notch signalling response is therefore likely to contribute to HHD manifestation. NOTCH1 is a transmembrane receptor and upon ligand binding, the intracellular domain (NICD) translocates to the nucleus activating its target genes. In the context of HHD, we found that loss of ATP2C1 function promotes upregulation of the active NOTCH1 protein (NICD‐Val1744). Here, deeply exploring this aspect, we observed that NOTCH1 activation is not associated with the transcriptional enhancement of its targets. Moreover, in agreement with these results, we found a cytoplasmic localization of NICD‐Val1744. We have also observed that ATP2C1‐loss is associated with the degradation of NICD‐Val1744 through the lysosomal/proteasome pathway. These results show that ATP2C1‐loss could promote a mechanism by which NOTCH1 is endocytosed and degraded by the cell membrane. The deregulation of this phenomenon, finely regulated in physiological conditions, could in HHD lead to the deregulation of NOTCH1 with alteration of skin homeostasis and disease manifestation. [ABSTRACT FROM AUTHOR]

As a contribution to the debate on deregulation of spatial planning and lean regional plans, this paper presents the first long-term study for Germany analysing the regulatory intensity of all regional plans legally valid in 2017 on the topics of settlement and open space development over time. As a final result, the assumption of a general deregulation and streamlining of regional plans cannot be confirmed. In contrast, changes in the legal basis, such as the priority of inner over outer urban development, have led to a continuous increase in the regulatory intensity over time, particularly in the case of positive growth management policies with an active role of regional planning. At the same time, there is evidence of streamlining tendencies in some states, which can partly be interpreted as deregulation tendencies. To date, however, they are merely an expression of state-specific ways of shaping regional planning and not a sign of an accelerated deregulation competition. [ABSTRACT FROM AUTHOR]

Modern power systems include a large amount of renewable energy generation and power converter components, which in turn have an effect on the system's inertia. It becomes a major challenge in load frequency control (LFC) of an interconnected system. As a means of overcoming the challenges associated with LFC, this article analyzed the effects of virtual inertia control (VIC) on a three-area interconnected system that incorporates renewable power generators within the deregulated market. Virtual damping and a cascade controller combination of the proportional-integral and tilted-integral controller (PI–TI) have been proposed in the VIC technique to lessen the inertia problem associated with the power system. The controller gains are optimized using a novel algorithm named the mine blast algorithm. In addition to evaluating the effectiveness of the proposed VIC method, it is also studied using AC/DC tie line interconnected systems, and phase locked loops. Under all aspects, the obtained results demonstrate that the proposed VIC technique leads to increase system dynamic performances in different deregulated environments by reducing oscillations and deviations in frequency, tie power, and settling time. The reliability of the proposed control method is also verified by performing stability and robustness analyses. The considered power system was simulated using the OPAL-RT digital simulator under various scenarios. [ABSTRACT FROM AUTHOR]

In a deregulated power system, with a limited power system framework, alleviation in power transfer has been one of the most crucial problems. This alleviation of bulk power transmission came with congestion, where a transmission line transmits power very near the constrained thermal limits. Congestion has to be mitigated for reliable, economical, and stable operation of the power system. Congestion can be mitigated by applying several methods which may be cost-free or non-cost-free. This article presents a cost-free method employing TCSC as a FACTS device. FACTS devices are very costly. To make the TCSC operation economic, LUF and DLUF are used here to optimally locate the device. TCSC is used here as a variable impedance device. A novel hybrid heuristic optimization technique where Grey Wolf optimizer is merged with Particle Swarm Optimizer to optimize the size of TCSC. The proposed method is implemented to regulate the line reactance for congestion mitigation. The power loss and voltage deviation of the system are reduced by the proposed method to relieve the system congestion. The system security margin is enhanced significantly to make the system more reliable. The proposed algorithm is validated on IEEE 30 bus system and is also validated by comparing the results with parent algorithms. The results reveal that the proposed methodology successfully minimized the objectives for mitigating congestion. [ABSTRACT FROM AUTHOR]

The article focuses on disappointing aviation system of American West future growth of the U.S. commercial air travel and the nation's economy. It mentions congressional investment into American automobile infrastructure was the Federal Highway Act of 1956 and initial focus on automobile development coupled with the deregulation of air travel had lasting effects on aircraft infrastructure. It also mentions increasing the total passenger volume per flight for ancillary service.

Tandem of P domains in a weak inwardly rectifying K+ channel (TWIK)-related acid sensitive K+-1 channel (TASK-1) is activated under extracellular alkaline conditions (pH 7.2–8.2), which are upregulated in astrocytes (particularly in the CA1 region) of the hippocampi of patients with temporal lobe epilepsy and chronic epilepsy rats. Perampanel (PER) is a non-competitive α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor (AMPAR) antagonist used for the treatment of focal seizures and primary generalized tonic–clonic seizures. Since AMPAR activation leads to extracellular alkaline shifts, it is likely that the responsiveness to PER in the epileptic hippocampus may be relevant to astroglial TASK-1 regulation, which has been unreported. In the present study, we found that PER ameliorated astroglial TASK-1 upregulation in responders (whose seizure activities were responsive to PER), but not non-responders (whose seizure activities were not responsive to PER), in chronic epilepsy rats. ML365 (a selective TASK-1 inhibitor) diminished astroglial TASK-1 expression and seizure duration in non-responders to PER. ML365 co-treatment with PER decreased spontaneous seizure activities in non-responders to PER. These findings suggest that deregulation of astroglial TASK-1 upregulation may participate in the responsiveness to PER, and that this may be a potential target to improve the efficacies of PER. [ABSTRACT FROM AUTHOR]

A cell cycle is a series of events that takes place in a cell as it grows and divides. At the G1 phase of cell cycle, cells monitor their cumulative exposure to specific signals and make the critical decision to pass through the restriction (R)-point. The R-point decision-making machinery is fundamental to normal differentiation, apoptosis, and G1–S transition. Deregulation of this machinery is markedly associated with tumorigenesis. Therefore, identification of the molecular mechanisms that govern the R-point decision is one of the fundamental issues in tumor biology. RUNX3 is one of the genes frequently inactivated in tumors by epigenetic alterations. In particular, RUNX3 is downregulated in most K-RAS-activated human and mouse lung adenocarcinomas (ADCs). Targeted inactivation of Runx3 in the mouse lung induces adenomas (ADs), and markedly shortens the latency of ADC formation induced by oncogenic K-Ras. RUNX3 participates in the transient formation of R-point-associated activator (RPA-RX3-AC) complexes, which measure the duration of RAS signals and thereby protect cells against oncogenic RAS. This review focuses on the molecular mechanism by which the R-point participates in oncogenic surveillance. [ABSTRACT FROM AUTHOR]

A variety of agricultural conservation trends have gained and lost favour throughout the years, with farm bills in the United States often influencing which conservation practices are implemented. This paper explores the consequences of a set of conservation techniques loosely defined as "no‐till agriculture," focusing on their implementation and adoption since 1985, at which point such approaches began to be explicitly encouraged under US Farm Bill soil conservation mandates. We begin by noting a core contradiction that has characterized these approaches in the Fifteenmile Watershed of Wasco County, Oregon, where despite high rates of farmer enrollment in no‐till programs, both no‐till agriculture and sustained tillage have led to the increased use of herbicides and sustained sediment runoff. Using a critical physical geography framework that integrates intensive physical field data collection, spatial analysis, social surveys, and interviews, we address the biophysical and social factors collectively driving changes in herbicide use and variable erosion estimates. We draw particular attention to how farm bill support for no‐till has enrolled farmers in a vaguely defined and underregulated conservation practice that may ultimately undermine environmental quality. Key Messages: No‐till has been broadly used to describe many conservation tillage practices, which has led to inaccurate erosion estimates.Variations in no‐till practices have coincided with unprecedented increases of herbicide.Processes of neoliberalization have influenced the sustainability of no‐till. [ABSTRACT FROM AUTHOR]

This study investigates whether deregulation has affected bank efficiency in the 'cross-strait' relationship between China and Taiwan. I measure bank efficiency across three periods – after Taiwan and China joined the World Trade Organization, the global financial crisis, and the signing of the Economic Cooperation Framework Agreement (ECFA) – and show that Taiwanese banks were significantly more efficient than their Chinese counterparts. These results show that the ECFA platform has not improved bank efficiency and thus has failed to function effectively. This finding suggests that China and Taiwan should continue negotiating within the ECFA context to enhance cross-strait financial cooperation. [ABSTRACT FROM AUTHOR]

This article introduces grasshopper optimization algorithm (GOA) for getting an optimum and effective solution of an automatic generation control (AGC) problem in hybrid power systems under a deregulated scenario using a 3-degree freedom of proportional integral and derivative (3DOF-PID) controller. Initially, two-area thermal-hydro-gas-wind system is considered. To compensate the load disturbances and to stabilize the area frequency oscillations, dynamic power flow control with PID and 3DOF-PID controllers have been studied. The performances of PID and 3DOF-PID controllers are evaluated with high voltage direct current (HVDC) link. The present investigation reveals that GOA-optimized 3DOF-PID controller is better than any other conventional technique, such as moth swarm algorithm (MSA) optimization technique. Afterward, a two-area AGC system is considered, where in one area wind power plant is incorporated with a thermal hydro plant and in the other area solar thermal power-plant (STPP) is incorporated with the same combination. Additionally, the effectiveness of different flexible AC transmission system (FACTS) devices e.g. unified power flow controller (UPFC) and super conducting magnetic energy storage device (SMES) along with 3DOF-PID controller-based AGC is compared with PID controller-based AGC. Moreover, to make the AGC problem more realistic, initially generation rate constraints (GRC) and governor with dead band (GDB) and finally boiler dynamics (BD) are included in thermal unit, and performance of the proposed controller using proposed algorithm is evaluated under deregulated environment. Finally, the proposed technique is applied under random load variation. [ABSTRACT FROM AUTHOR]

The modern power system has reached its present state after wading a long path facing several changes in strategies and the implementation of several reforms. Economic and geographical constraints led to reforms and deregulations in the power system to utilize resources optimally within the existing framework. The major hindrance in the efficient operation of the deregulated power system (DPS) is congestion, which is the result of the participation of private players under deregulation policies. This paper reviews different setbacks introduced by congestion and the methods applied/proposed to mitigate it. Technical and non-technical methods are reviewed and detailed. Major optimization techniques proposed to achieve congestion alleviation are presented comprehensively. This paper combines major publications in the field of congestion management and presents their contribution towards the alleviation of congestion. [ABSTRACT FROM AUTHOR]

For an uninterrupted power supply, renewable energy promises to be a suitable alternative compared to the conventional sources. System delays or communication delays may cause significant synchronization imbalances between various components in big electrical grids. Since the properties of solar and wind generation constantly change with climatic circumstances, engineers encounter many difficulties when substituting sustainable power with conventional electricity. The computation delay margin may be leveraged to handle a time-delayed automatic generation control (AGC) system. In order to regulate a distributed hybrid renewable energy system in a three-area AGC configuration, this paper investigates the influence of the fractional integral order on the stable system's delay parameter region. By changing the fractional order range, the delay margin can be increased, potentially broadening the time-delayed system's stability region. The controller's stability region has dependency on the order of fraction and the time delay. For this purpose, the asymptotic Bode diagram of the time-delayed fractional proportional-integral controller is determined. The gain and phase margins are used to calculate the delay margin for the application in discussion. The Honey Badger algorithm helps to adjust the controller parameters. It is also confirmed that the suggested controller is resilient to random load perturbations, nonlinearities, and parameter variations. [ABSTRACT FROM AUTHOR]

Background: The African aviation liberalisation process began in 1988, following the liberalisation processes in Europe and the United States (US). However, by 2023, Intra-Africa air services are still reliant on the Bilateral Air Services Agreement (BASA) by which international traffic rights are exchanged in terms of the 1944 Chicago Convention, a multilateral treaty. These impose restrictions on intra-African connectivity and are obstacles to liberalisation. African multilateral initiatives, such as the Yamoussoukro Declaration, have varying levels of implementation by African states. While liberalisation efforts have major impacts on airlines, thus far these have been led by government structures. Objective: The main objectives of the study are to determine the involvement of airlines in African liberalisation development and the likely impact of the liberalisation initiatives on airline operations. Method: Semi-structured interviews were conducted with 12 intra-Africa airline executives from four Regional Economic Communities (REC), which would be impacted by liberalisation. Results: The study finds that airlines do not fully participate in the development of liberalisation initiatives. Although sometimes consulted, their associations are usually only granted observer status at deliberations and negotiations. The likely impacts of the initiatives to airlines include direct connectivity, and harmonised African air transport access. Conclusion: The lack of airline participation may be a key reason for the slow progress towards liberalisation and full deregulation in Africa. Contribution: This study contributes to the body of knowledge, by being the first study to consider the role of airlines in the development of liberalisation initiatives. [ABSTRACT FROM AUTHOR]

With commercial participants now undertaking an ever-expanding role within the development and supply-chains of China's space industry post Document No. 60, the resulting legal challenges relating to this emerging industry status-quo has garnered much academic discussion. Specifically, while China's space industry has grown at a rapid pace within the past few decades, China's legislative framework has remained largely silent over matters relating to space. Instead, China continues to remain as the only major space-faring nation without a national space law and regime. This substantive legislative gap over China's space related activities has negatively impacted the industry's current deregulation process. While it has been the academic community's primary solution to address the industry's current substantive legislative gap through coordinated rulemaking activities, this paper aims to advance the current academic discussion by taking an alternative approach and arguing that the fundamental legislative challenge and solution to China's emerging commercial space industry, is not substantive, but rather procedural by nature. Importantly, by reconceptualizing the industry's substantive gap from one that is determined by the number of missing legal instruments, to one determined by the rate of legislative activity i.e., the pace of law-making activities vis-à-vis commercial expansion, this paper argues that only through the implementation of legal procedural rulemaking mechanisms will China's space law regime be able to sufficiently address the current substantive legislative gap at a pace matching commercial expansion. • The deregulation of China's space industry. • Regulatory structure and legal challenges of China's space industry. • A procedural argument to resolve China's substantive space law gap. [ABSTRACT FROM AUTHOR]

DGCR8 emerged recently as miRNAs biogenesis pathway protein with a highlighted role in thyroid disease. This study aimed to characterize this miRNA biogenesis component, in particular the p.(E518K) mutation and DGCR8 expression in a series of thyroid lesions. The series of thyroid lesions was genotyped for the c.1552G>A p.(E518K) mutation. When frozen tissue was available, DGCR8 mRNA expression was analysed by qPCR. Formalin-fixed paraffin-embedded tissues were studied for DGCR8 immunoexpression. We present for the first time the p.(E518K) mutation in a case of poorly differentiated thyroid carcinoma and present the deregulation of DGCR8 expression at mRNA level in follicular-patterned tumours. The obtained data solidify DGCR8 as another important player of miRNA-related gene mutations in thyroid tumorigenesis, particularly in follicular-patterned thyroid tumours. [ABSTRACT FROM AUTHOR]

Post-traumatic stress disorder (PTSD) is a psychopathological disorder that affects emotional regulation, cognition, and behavior. Moreover, deregulation in different memory processes has been related to a persistent PTSD prognosis. In a way, the traumatic memory presents itself as timeless, since it functions as a rigid frame that keeps the personal history locked in the past, at the time of the traumatic event. Thus, this essay reflects on the memory processes involved in PTSD, and the place of testimony in the process of reframing the traumatic experience, for it is through the stories we tell ourselves and others about who we are that we can build an autobiographical history and a sense of personal reality. [ABSTRACT FROM AUTHOR]

This is the first study to integrate structural and non-structural approaches into the evaluation of competitive conditions for banks in Taiwan. It is found that the results of structural and non-structural approaches are compatible. This study finds that market share may not have a significant impact on banks' efficiency but may significantly impact profitability. This implies that banks are willing to sacrifice something to expand their market share, such as not enforcing minimum cost targets and wasting resources to raise an already unrealistic market share target. Furthermore, it is essential to pay attention to the observation that the degrees of competition deteriorated after the Global Financial Crisis (GFC). This argues that the transmission mechanism from market structure to performance occurring through product differentiation is able to exercise market power in banks products and earn supernormal profit, which is normally associated with dominant banks and not with collusive behaviour. [ABSTRACT FROM AUTHOR]

Football fanzines once stood at the vanguard of fan activism. Historically, they have served as the voice of supporters, largely independent of the clubs they are associated with. Indeed, a recurring characteristic of these fanzines is that they often challenge and question authority. In the halcyon days of past decades, they proliferated and often acted as a powerful vector of change within football. Increasingly though, they have been pushed to the margins, for a number of reasons, ranging from the increasing digitalisation of media to the growing distance between fans and club owners as a consequence of the money that's now in the game. Football's inexorable drift towards deregulation means that fanzines alone can no longer act as agents of change and challenge. They need to work in synch with supporters' groups in order to make their voices heard. More than that, this needs to happen not just at a local, but a national level, so that supporters from top to bottom of English football's shaky pyramid are seen to speak with one voice. Perhaps above all, there is a need for independent regulation of the game's governance. [ABSTRACT FROM AUTHOR]

At one time, the legal profession largely regulated itself. However, based on the economic notion that increased competition would benefit consumers, jurisdictions have deregulated their legal markets by easing rules relating to attorney advertising, fees, and, most recently, nonlawyer ownership of law firms. Yet, despite reformers' high expectations, legal markets today resemble those of previous decades, and most legal services continue to be delivered by traditional law firms. How to account for this seeming inertia? We argue that the competition paradigm is theoretically flawed because it fails to fully account for market failures relating to asymmetric information, imperfect information, and negative externalities. In addition, the regulatory costs imposed on sophisticated consumers such as corporate purchasers of legal services differ radically from those imposed on ordinary consumers who use legal services infrequently. Merely increasing the number and types of legal services providers cannot make legal markets more efficient. We illustrate our theoretical account with evidence from the United Kingdom, Europe, and Asia. For legal markets to better serve the public, regulators must tailor solutions by segment. Regulators should seek to minimize negative externalities associated with the delivery of legal services to the corporate segment and confront information asymmetries that lead to the maldistribution of legal services in the consumer segment. Deregulation alone is insufficient and may in fact exacerbate existing market failures. [ABSTRACT FROM AUTHOR]

The prime objective of the proposed research work is to study the frequency response of a wind plant integrated two area power system under sudden load disturbances when considered under deregulated market environment. The thermal power system has been modelled with suitable generation constraint and governor dead bands. Erratic behaviour of wind power makes the power system very sensitive to frequency deviations and proper frequency control is needed for stability. A new tilted integral derivative controller (TID) with type II fuzzy controller is considered as secondary controller for minimizing frequency fluctuations. The gains of the controller are set at an optimal value with the help of newly designed hybrid Dragonfly algorithm–Whale optimization algorithm for proper control action. System dynamic performance with and without renewable penetration is studied and robustness of the proposed controller is established under various market conditions and varying renewable power integration. [ABSTRACT FROM AUTHOR]

This study examines health regulation under conditions of geographical constraint in two strikingly different settings, one on a remote island in Bangladesh and the other in an impoverished rural region in Australia. Both suffer from an absence of medically qualified professionals, which means that in the resultant vacuum, patients access alternative healthcare. The concept of regulation (or lack of regulation) is explored in terms of unconventional new responses to rural health deficits. The two cases show unexpected commonality, with policymakers facing shared challenges beyond physical remoteness. The difference in the degree of enforcement of regulation offers the greatest point of difference. This comparative study revealed a weak health regulatory system in the remote Bangladesh area of Bhola Island where 'alternatives' to formal clinical approaches have become the default choice. Brazen stop‐gap servicing is commonplace on Bhola Island, but in The Gemfields such practices only occur in the shadows or as a last resort. Each isolated location, one in a developing country and the other in a developed setting, exemplifies how geographical remoteness can present an opportunity for innovations in supply to emerge. Surprisingly, it is the developing world case that better leverages a regulatory void to respond to local healthcare needs. [ABSTRACT FROM AUTHOR]

In Japan, the Goal of Carbon Neutral in 2050 was declared by Prime Minister in October, 2020. In order to achieve the goal, the Japanese government positioned Renewable Energy Source (RES) such as PV and wind power as 'main power supply resource' and is expanding its introduction by taking various types of countermeasures to solve the problems induced by massive integration of the RES into the grid. In recent years, the power system was damaged many times by a lot of natural disaster such as strong earthquakes, typhoons and heavy rains. The situation of the Japanese power system is drastically changing due to low demand growth, massive introduction of the RES as well as evolution of the power system reform that is introduction of power markets such as energy spot market, capacity market and balancing market. In this paper, our activities toward deregulated, smart and resilient power systems are presented. © 2022 Institute of Electrical Engineers of Japan. Published by Wiley Periodicals LLC. [ABSTRACT FROM AUTHOR]

Wnt1 is the first mammalian Wnt gene, which is discovered as proto-oncogene and in human the gene is located on the chromosome 12q13. Mutations in Wnt1 are reported to be associated with various cancers and other human diseases. The structural and functional consequences of most of the non-synonymous SNPs (nsSNPs), present in the human Wnt1 gene, are not known. In the present work, extensive bioinformatics analyses are used to screen 292 nsSNPs of Wnt1 for predicting pathogenic and harmless polymorphisms. We have identified 10 highly deleterious nsSNPs among which 7 are located within the highly conserved areas. These 10 nsSNPs are also predicted to affect the post-translational modifications of Wnt1. Further, structure based stability analyses of these 10 highly deleterious nsSNPs revealed 8 variants as highly destabilizing. These 8 highly destabilizing variants were shown to have high BC score and high RMSIP score from normal mode analyses. Based on the deformation energies, obtained from the normal mode analyses, variants like G169A, G169S, G331R and G331S were found to be unstable. Molecular Dynamics (MD) simulations revealed structural stability and fluctuation of WT Wnt1 and its prioritized variants. RMSD remained fluctuating mostly between 4 and 5 Å and occasionally between 3.5 and 5.5 Å ranges. RMSF in the CTD region (residues 330–360) of the binding pocket were lower compared to that of WT. Studying the impacts of nsSNPs on the binding interface of Wnt1 and seven Frizzled receptors have predicted substitutions which can stabilize or destabilize the binding interface. We have found that Wnt1 and FZD8-CRD is the best docked complex in our study. MD simulation based analyses of wild type Wnt1-FZD8-CRD complex and the 8 prioritized variants revealed that RMSF was higher in the unstructured regions and RMSD remained fluctuating in the region of 5 Å ± 1 Å. We have also observed differential Wnt1 gene expression pattern in normal, tumor and metastatic conditions across different tissues. Wnt1 gene expression was significantly higher in metastatic tissues of lungs, colon and skin; and was significantly lower in metastatic tissues of breast, esophagus and kidney. We have also found that Wnt1 deregulation is associated with survival outcome in patients with gastric and breast cancer. Furthermore, these computationally screened highly deleterious nsSNPs of Wnt1 can be analyzed in population based genetic studies and may help understand the Wnt1 associated diseases. [ABSTRACT FROM AUTHOR]

This study sought to establish the corporal deregulation that is seen in the bodies of students using digital devices like Instagram. The methodology used was comprised of a visual analysis, literary review and thematic interviews. The conclusions revealed the joining of human and non-human bodies in an organized regime, a governmentality, in which techniques and stereotypes of gender and race circulate, from which bodies are molded and reproduced through the digital device; a government without governing bodies in the context of the social distancing of the Covid-19 pandemic and the crisis of bodily touch. [ABSTRACT FROM AUTHOR]

While mitochondrial bioenergetic deregulation has long been implicated in cellular senescence, its mechanistic involvement remains unclear. By leveraging diverse mitochondria-related gene expression profiles derived from two different cellular senescence models of human diploid fibroblasts, we found that the expression of mitoribosomal proteins (MRPs) was generally decreased during the early-to-middle transition prior to the exhibition of noticeable SA-β-gal activity. Suppressed expression patterns of the identified senescence-associated MRP signatures (SA-MRPs) were validated in aged human cells and rat and mouse skin tissues and in aging mouse fibroblasts at single-cell resolution. TIN2- and POT1-interaction protein (TPP1) was concurrently suppressed, which induced senescence, accompanied by telomere DNA damage. Lastly, we show that SA-MRP deregulation could be a potential upstream regulator of TPP1 suppression. Our results indicate that mitoribosomal deregulation could represent an early event initiating mitochondrial dysfunction and serve as a primary driver of cellular senescence and an upstream regulator of shelterin-mediated telomere deprotection. [ABSTRACT FROM AUTHOR]

Glutamate excitotoxicity contributes to many neurodegenerative diseases. Excessive glutamate receptor-mediated calcium entry causes delayed calcium deregulation (DCD) that coincides with abrupt mitochondrial depolarization. We developed cA-TAT, a live-cell protease activity reporter based on a vimentin calpain cleavage site, to test whether glutamate increases protease activity in neuronal cell bodies prior to DCD. Treatment of rat cortical neurons with excitotoxic (100 µM) glutamate increased the low baseline rate of intracellular cA-TAT proteolysis by approximately three-fold prior to DCD and by approximately seven-fold upon calcium deregulation. The glutamate-induced rate enhancement prior to DCD was suppressed by glutamate receptor antagonists, but not by calpain or proteasome inhibitors, whereas DCD-stimulated proteolysis was partly attenuated by the proteasome inhibitor MG132. Further suggesting that cA-TAT cleavage is calpain-independent, cA-TAT fluorescence was observed in immortalized Capn4 knockout fibroblasts lacking the regulatory calpain subunit. About half of the neurons lost calcium homeostasis within two hours of a transient, 20 min glutamate receptor stimulation. These neurons had a significantly (49%) higher mean baseline cA-TAT proteolysis rate than those maintaining calcium homeostasis, suggesting that the unknown protease(s) cleaving cA-TAT may influence DCD susceptibility. Overall, the results indicate that excitotoxic glutamate triggers the activation of calpain-independent neuronal protease activity prior to the simultaneous loss of calcium homeostasis and mitochondrial bioenergetic function. [ABSTRACT FROM AUTHOR]