Constitutive Components Research Articles

Recruitment of autophagy initiator TAX1BP1 advances aggrephagy from cargo collection to sequestration.

Autophagy mediates the degradation of harmful material within lysosomes. In aggrephagy, the pathway mediating the degradation of aggregated, ubiquitinated proteins, this cargo material is collected in larger condensates prior to its sequestration by autophagosomes. In this process, theautophagic cargo receptors SQSTM1/p62 and NBR1 drive cargo condensation, while TAX1BP1, which binds to NBR1, recruits the autophagy machinery to facilitate autophagosome biogenesis at the condensates. The mechanistic basis for the TAX1BP1-mediated switch from cargo collection to its sequestration is unclear. Here we show that TAX1BP1 is not a constitutive component of the condensates. Its recruitment correlates with the induction of autophagosome biogenesis. TAX1BP1 is sufficient to recruit the TBK1 kinase via the SINTBAD adapter. We define the NBR1-TAX1BP1-binding site, which is adjacent to the GABARAP/LC3 interaction site, and demonstrate that the recruitment of TAX1BP1 to cargo mimetics can be enhanced by an increased ubiquitin load. Our study suggests that autophagosome biogenesis is initiated once sufficient cargo is collected in the condensates.

An Infrastructural Brussels Effect: The translation of EU Law into the UK's digital borders

This article gives an account of the legal standards and safeguards that guide and constrain the current design of the UK's digital borders. Based on an empirical engagement with the development of Cerberus – an advanced risk-based analytics platform aimed at the detection of previously ‘unknown’ threats – the article presents a dual argument. On the one hand, it provides an account of the remaining salience and extraterritorial reach of EU law in setting standards for the collection, retention, processing and sharing of Passenger Name Records (PNR) data in the UK. This PNR data is a constitutive component of the digital border. Through the EU-UK Trade and Cooperation Agreement (TCA), the UK is now bound to comply with the rather stringent legal safeguards developed by the CJEU (in Opinion 1/15) on the retention and automated processing of PNR data. Our analysis shows the different channels through which EU law obtains this extraterritorial reach, how compliance can be monitored and enforced, and, crucially, how it has influenced and constrained the technical design of the UK's digital borders – a salient and unexplored phenomenon that we describe as an Infrastructural Brussels Effect. Yet, on the other hand, the article empirically shows that this is not merely a process of norm diffusion and extraterritoriality. Once legal standards become infrastructurally embedded in Cerberus, we witness normative translations and sociotechnical shifts with important legal and political consequences. Legal standards on ‘reasonable suspicion’ and the ‘objective evidence’ of ‘risk’, we argue, are given specific meaning through a logic of relational inference and algorithmic pattern detection (leading to forms of ‘concern by association’). By studying the entanglements between legal norms and material infrastructures – an approach we describe as infra-legalities – these normative effects become visible and contestable, providing a productive site for the sociolegal study of law and algorithmic governance.

First Comprehensive Evaluation of Genetic Variability for Bacterial Blight Resistance in Wild Punica granatum L. Populations from the North-Western Himalayas

Identifying and selecting disease-resistant sources from wild germplasm pools is pivotal due to their ecological benefits and cost-effectiveness. This study encompassed the survey and collection of wild pomegranate genotypes alongside commercial cultivars, followed by screening against native pathogens. Additionally, biochemical analyses were conducted to elucidate defense mechanisms in both resistant and susceptible genotypes. Cuttings from selected germplasm across four districts were obtained, grown for one year, and assessed for pathogenicity and biochemical responses. Microscopic and molecular analyses confirmed the pathogen as Xanthomonas axonopodis pv. punicae (Xap), identified by its distinctive morphology and a 1500 bp amplicon along with phylogeny analysis. Germplasm screening via detached and attached leaf assays identified genotypes with minimal disease severity, highlighting SH-14 and SH-16 as highly resistant in the attached leaf assay. Principal component analysis categorized genotypes based on disease parameters, with PC1 explaining approximately 75% of the variability. Agglomerative hierarchical clustering further grouped genotypes into ten clusters, emphasizing clusters IX and X for their significant resistance traits. Biochemical studies revealed that the resistant genotype SH-16 exhibited higher levels of constitutive defense components like chlorophyll and vitamin C, as well as induced defense components such as phenols, flavonoids, and antioxidants, compared to the susceptible cultivar Bhagwa. These findings underscore the critical roles of both constitutive and induced defense mechanisms in conferring pomegranate resistance to Xap. The study's comprehensive approach in evaluating genetic and biochemical resistance provides valuable insights for breeding disease-resistant pomegranate varieties, marking a significant advancement in exploring pomegranate wild relatives from the Himalayan region for their resistance to bacterial blight.

Arbor vitae cerebelli: Fractal properties and their quantitative assessment by novel “contour scaling” fractal analysis method (an anatomical study)

BackgroundArbor vitae cerebelli (tree-like branching white matter of the cerebellum) has a complex spatial configuration that is challenging to assess using conventional morphometric methods. This study proposes a fractal approach to describe and quantify the anatomy of Arbor vitae cerebelli. For this purpose, a new “contour scaling” method for fractal analysis of cerebellar white matter was developed. Material and methodsThe cerebella of 100 cadavers (50 male and 50 female) who died from causes unrelated to brain pathology, aged 20–95 years, were examined. Mid-sagittal sections of the cerebellar vermis were studied. The fractal dimension values of the cerebellar white matter were determined using both the developed fractal analysis method and the conventional “box counting” method, along with measurements of non-fractal parameters including cerebellar weight, area and perimeter of the vermis cross-section, perimeter-to-area ratio, and circularity. ResultsConsidering the cerebellar white matter as a tree-like fractal, it was found to have 7 or 8 primary branches, which subdivide into 10-18 second-iteration branches, 19–38 third-iteration branches, and 34–53 fourth-iteration branches. Females more often had 8 primary branches compared to males, while males had a greater number of branches in the second to fourth iterations. The mean fractal (Hausdorff) dimension was 1.697 (1.721 in males, 1.674 in females, P = 0.01). The fractal dimension correlated most strongly with the perimeter and area of the vermis cross-section and had no significant relationship with age. ConclusionThe fractal (Hausdorff) dimension, determined using the novel “contour scaling” method, quantitatively assesses the degree of branching of the cerebellar white matter. An increase in the absolute size of the cerebellum leads to a higher degree of branching of its white matter and an increase in the number of its constitutive components – white matter branches and folia.

PML is a constitutive component of chromatin domains enriched in repetitive elements and duplicated gene clusters in cancer cells

Heterochromatin is a pivotal element in the functional organization of genomes. In our study, we delve into the heterochromatin pattern of association by the PML (promyelocytic leukemia) protein. By using PML chromatin immunoprecipitation and sequencing data and comparing computational methodologies to depict PML chromatin association, we describe PML-associated domains or PADs as large heterochromatic regions that exhibit similar genomic features across cancer cell lines. We show that PADs are specifically enriched in non-coding genes, duplicated gene clusters, and repetitive DNA elements. Moreover, we find enriched binding motifs of KZFPs, which are involved in orchestrating epigenetic repression at repetitive DNA elements. Hence, our findings suggest that PML conservatively associates to heterochromatic domains enriched in repetitive DNA elements and duplicated gene clusters in cancer. These findings contribute to a broader understanding of the complex regulatory framework of genome organization by heterochromatin in cancer.

Non-voluntary BCI explantation: assessing possible neurorights violations in light of contrasting mental ontologies

In research involving patients with implantable brain–computer interfaces (BCIs), there is a regulatory gap concerning post-trial responsibilities and duties of sponsors and investigators towards implanted patients. In this article, we...

The translesion polymerase Pol Y1 is a constitutive component of the B. subtilis replication machinery.

Unrepaired DNA damage encountered by the cellular replication machinery can stall DNA replication, ultimately leading to cell death. In the DNA damage tolerance pathway translesion synthesis (TLS), replication stalling is alleviated by the recruitment of specialized polymerases to synthesize short stretches of DNA near a lesion. Although TLS promotes cell survival, most TLS polymerases are low-fidelity and must be tightly regulated to avoid harmful mutagenesis. The gram-negative bacterium Escherichia coli has served as the model organism for studies of the molecular mechanisms of bacterial TLS. However, it is poorly understood whether these same mechanisms apply to other bacteria. Here, we use in vivo single-molecule fluorescence microscopy to investigate the TLS polymerase Pol Y1 in the model gram-positive bacterium Bacillus subtilis. We find significant differences in the localization and dynamics of Pol Y1 in comparison to its E. coli homolog, Pol IV. Notably, Pol Y1 is constitutively enriched at or near sites of replication in the absence of DNA damage through interactions with the DnaN clamp; in contrast, Pol IV has been shown to be selectively enriched only upon replication stalling. These results suggest key differences in the roles and mechanisms of regulation of TLS polymerases across different bacterial species.

Replenishing IRAK-M expression in retinal pigment epithelium attenuates outer retinal degeneration.

Chronic inflammation is a constitutive component of many age-related diseases, including age-related macular degeneration (AMD). Here, we identified interleukin-1 receptor-associated kinase M (IRAK-M) as a key immunoregulator in retinal pigment epithelium (RPE) that declines during the aging process. Rare genetic variants of IRAK3, which encodes IRAK-M, were associated with an increased likelihood of developing AMD. In human samples and mouse models, IRAK-M abundance in the RPE declined with advancing age or exposure to oxidative stress and was further reduced in AMD. Irak3-knockout mice exhibited an increased incidence of outer retinal degeneration at earlier ages, which was further exacerbated by oxidative stressors. The absence of IRAK-M led to a disruption in RPE cell homeostasis, characterized by compromised mitochondrial function, cellular senescence, and aberrant cytokine production. IRAK-M overexpression protected RPE cells against oxidative or immune stressors. Subretinal delivery of adeno-associated virus (AAV)-expressing human IRAK3 rescued light-induced outer retinal degeneration in wild-type mice and attenuated age-related spontaneous retinal degeneration in Irak3-knockout mice. Our data show that replenishment of IRAK-M in the RPE may redress dysregulated pro-inflammatory processes in AMD, suggesting a potential treatment for retinal degeneration.

Altering the competitive environment of B cell epitopes significantly extends the duration of antibody production.

Persistent immunoglobulin G (IgG) production (PIP) provides long-term vaccine protection. While variations in the duration of protection have been observed with vaccines prepared from different pathogens, little is known about the factors that determine PIP. Here, we investigated the impact of three parameters on the duration of anti-peptide IgG production, namely amino acid sequences, protein carriers, and immunization programs. We show that anti-peptide IgG production can be transformed from transient IgG production (TIP) to PIP, by placing short peptides (Pi) containing linear B cell epitopes in different competitive environments using bovine serum albumin (BSA) conjugates instead of the original viral particles. When goats were immunized with the peste des petits ruminants (PPR) live-attenuated vaccine (containing Pi as the constitutive component) and BSA-Pi conjugate, anti-Pi IgG production exhibited TIP (duration < 60 days) and PIP (duration > 368 days), respectively. Further, this PIP was unaffected by subsequent immunization with the PPR live-attenuated vaccine in the same goat. When goats were coimmunized with PPR live-attenuated vaccine and BSA-Pi, the induced anti-Pi IgG production showed a slightly extended TIP (from ~60 days to ~100 days). This discovery provides new perspectives for studying the fate of plasma cells in humoral immune responses and developing peptide vaccines related to linear neutralizing epitopes from various viruses.

‘Botha Cake’ and ‘Belgian Onion Soup:’ Gendered Patriotism Through Three South African, First World War, Community Cookbooks

ABSTRACT This article considers three South African community cookbooks – including The Overseas Contingent Fund Recipe Book (Turffontein, 1915) and the Paarl Cookery Book in Aid of War Funds (Paarl, 1918) alongside Wartime Cookery (Cape Town, 1915) – as expressions of gendered patriotism. These community-created cookbooks enabled contributors to participate meaningfully in the First World War by drawing together two established gendered practices: philanthropic fundraising and food and household management. This ‘domesticity in action’ enabled participants to contribute to, and feel connected to, both local and trans-empire causes. These values of philanthropy, economy and patriotism are revealed in the constitutive components of the texts – the titles, aims, prefaces and even the recipes themselves. Apart from supporting specific funds, the call for economy in the cookbooks reflected both experiences and perceptions of wartime material hardship in South Africa. A further consideration of the contributors involved with the books’ compilations highlights the intersection of local and trans-empire networks, and wartime (white) identity politics within urban South Africa. The networks suggest locally-grounded loyalisms, many marked by personal connections to men serving, as well as friend and family networks with overseas reach. Lastly, the article is a reminder of the importance of cookbooks as neglected sources in the writing of history.

Rhodes Must Fall and the incongruence of academic freedom and decoloniality

ABSTRACT This study explores the rise of decolonial-styled politics within the University of Cape Town and the University of Oxford and the natural limitations of this form of politics within the ambit of academic freedom as understood by both universities. Leveraging the Rhodes Must Fall movement as a case study of translocal student activism which emerged at both institutions, the paper underscores the necessity of delineating the pursuit of decoloniality within the university into two constitutive components: decolonial thought and decolonial action. The paper argues that without this delineation, the decolonial projects within universities will remain inept.

Three-Pronged Resentment: How Status Insecurity, Relative Deprivation, and Powerlessness Mediate Between Social Positions and Populist Attitudes

Populist attitudes are frequently tied to a specific social position, namely the constituent’s status as a “loser of globalization.” Adding nuance to this explanatory framework, we investigate whether and how resentment mediates between social positions and populist attitudes. We distinguish three constitutive components of resentment—status insecurity, relative deprivation, and powerlessness—and analyze to what extent these sentiments explain the prevalence of two key populist attitudes: anti-elitism and demands for popular sovereignty. Using survey data from the Belgian National Election Study 2014, we show that although both populist attitudes are more likely among individuals of low socioeconomic status, this effect is mediated by a sense of group relative deprivation (anti-elitism and popular sovereignty) and feelings of powerlessness (anti-elitism). The effect of individual-level status insecurities on populist attitudes is, however, not significant. These results suggest that people do not simply adhere to antagonistic and people-centric views about politics because they experience economic precariousness; they embrace populist attitudes if their vulnerability is perceived in terms of a threatened sense of group position and understood as the outcome of an unjust society, wherein they feel powerless to alter their circumstances.

Modelling the Flow Behaviour of Al Alloy Sheets at Elevated Temperatures Using a Modified Zerilli-Armstrong Model and Phenomenological-Based Constitutive Models.

The flow behaviour of AA2060 Al alloy under warm/hot deformation conditions is complicated because of its dependency on strain rates (ε˙), strain (ε), and deformation modes. Thus, it is crucial to reveal and predict the flow behaviours of this alloy at a wide range of temperatures (T) and ε˙ using different constitutive models. Firstly, the isothermal tensile tests were carried out via a Gleeble-3800 thermomechanical simulator at a T range of 100, 200, 300, 400, and 500 °C and ε˙ range of 0.01, 0.1, 1, and 10 s-1 to reveal the warm/hot flow behaviours of AA2060 alloy sheet. Consequently, three phenomenological-based constitutive models (L-MJC, S1-MJC, S2-MJC) and a modified Zerilli-Armstrong (MZA) model representing physically based constitutive models were developed to precisely predict the flow behaviour of AA2060 alloy sheet under a wide range of T and ε˙. The predictability of the developed constitutive models was assessed and compared using various statistical parameters, including the correlation coefficient (R), average absolute relative error (AARE), and root mean square error (RMSE). By comparing the results determined from these models and those obtained from experimentations, and confirmed by R, AARE, and RMSE values, it is concluded that the predicted stresses determined from the S2-MJC model align closely with the experimental stresses, demonstrating a remarkable fit compared to the S1-MJC, L-MJC, and MZA models. This is because of the linking impact between softening, the strain rate, and strain hardening in the S2-MJC model. It is widely known that the dislocation process is affected by softening and strain rates. This is attributed to the interactions that occurred between ε and ε˙ from one side and between ε, ε˙, and T from the other side using an extensive set of constants correlating the constitutive components of dynamic recovery and softening mechanisms.

Creating the Multifaith Chapel, 1938–1955: Architecture and the Changing Understanding of “Religion”

Interfaith or multifaith chapels are so ubiquitous now in the United States—present in colleges and universities, hospitals, shopping malls, and airports—that their development as a distinct architectural form is often taken for granted. Yet that development in the mid-twentieth century was complex and even fraught. Taking a religious studies approach, this article examines the development of three early examples—the Chapel of the Four Chaplains, the Brandeis University chapels, and the MIT Chapel—to reveal the gradual movement, conceptual and architectural, toward a viable space serving many religions. While the former two examples proved unsuccessful in their goal of establishing a shared interfaith space due to their reliance on an understanding of religion as discrete traditions that resulted in exclusivist incompatibilities, the latter example moved beyond the emphasis on traditions to advance an unconventional, phenomenological understanding of religion as individual experience and spiritual life, and by doing so successfully achieved the goal of creating a space amenable to practitioners of many traditions, or none. Further, this article demonstrates how architecture functioned as a constitutive component in the developmental and popularization of this fresh understanding of religion and religious experience.

The splicing factor Prpf31 is required for hematopoietic stem and progenitor cell expansion during zebrafish embryogenesis

Pre-mRNA splicing is a precise regulated process, and is crucial for system development and homeostasis maintenance. Mutations in spliceosomal components have been found in various hematopoietic malignancies (HMs), and have been considered as oncogenic derivers of HMs. However, the role of spliceosomal components in normal and malignant hematopoiesis remain largely unknown. Pre-mRNA processing factor 31 (PRPF31) is a constitutive spliceosomal component, which mutations are associated with autosomal dominant retinitis pigmentosa. PRPF31 was found to be mutated in several HMs, but the function of PRPF31 in normal hematopoiesis has not been explored. In our previous study, we generated a prpf31 knockout zebrafish line, and reported that Prpf31 regulates the survival and differentiation of retinal progenitor cells (RPCs) by modulating the alternative splicing of genes involved in mitosis and DNA repair. In this study, by using the prpf31 knockout zebrafish line, we discovered that prpf31 knockout zebrafish exhibited severe defects in hematopoietic stem and progenitor cell (HSPC) expansion and its sequentially differentiated lineages. Immunofluorescence results showed that Prpf31 deficient HSPCs underwent malformed mitosis and M phase arrest during HSPC expansion. Transcriptome analysis and experimental validations revealed that Prpf31 deficiency extensively perturbed the alternative splicing of mitosis-related genes. Collectively, our findings elucidate a previously undescribed role for Prpf31 in HSPC expansion, through regulating the alternative splicing of mitosis-related genes.

Lignin and Cellulose Contents in Chinese Red Pine (Pinus tabuliformis Carr.) Plantations Varied in Stand Structure, Soil Property, and Regional Climate

The reserve of litter is expected to be reduced on the forest floors of pine plantations dually for the prevention of high risks of forest fires and with a more practical probability of reuse. Lignin and cellulose are the two key constitutive components in litter residues that account for the highest proportion of carbon but are the last to be fully decomposed. The existing trials started examining the mechanisms behind decomposing these two components in response to the combined driving forces of microclimatic factors, forest structure, and stand properties. However, the results were mostly limited to a local-scale ecosystem, and the evidence was reported to be highly scattered across varied conditions globally. Awareness about the combined effects of the driving forces behind the lignin and cellulose contents in the litter of plantations on a large scale is still scarce. In this study, a total of 60 Pinus tabuliformis Carr. plantations (40-year-old) were investigated for their litter quality, regional meteorological factors, soil properties, and stand structure in a provincial area across Liaoning, northeast China. High lignin (40%–43%) and cellulose contents (15%–20%) were found to be located mainly in stands around the biggest city of Shenyang. Rainfall was a key factor that determined the decomposition, but neither the forest structure nor soil nutrient content generated direct effects on the two litter components. The combined factors of low soil pH (~5.8) and high rainfall (~3.0 mm per day) together mainly accounted for the promotion of natural litter decomposition.

A qualitative study on the social representations of populism and democracy in Peru

The purpose of this paper is to describe and analyze the social representations of democracy, populism and the relationship between both concepts in a sample of citizens from different regions of Peru (n = 76). To this end, a qualitative research design was proposed, using in-depth interviews, which were analyzed from a discursive approach. The results show that democracy and populism are two closely related concepts in tension. On the one hand, the social representation of democracy is semantically poor, closely related to electoral behavior and is seen as a political system that, ideally, is positively valued. Populism, on the other hand, is seen as a political strategy based on the manipulation of citizens' needs in order to reach power using the democratic process of elections. The representation of populism in general is negative, and it is mentioned that it appears and acquires strength in the face of citizen dissatisfaction with democracy, when it cannot solve problems of poverty, corruption or exclusion. The representations of populism take up the constitutive components proposed by different authors on the topic (people, elites and democracy as a product of popular will), but the participants do not necessarily structure the relationships between these components as proposed in the academic literature. Finally, the results shows that respondents' experiences with democracy and populism in Peru act as important socializing forces that will frame how citizens relate to politics and the public.

Moral status – human status? Interrogating the connection between morality and dehumanisation during mass violence

Beginning with early studies in the 1970s, dehumanisation has become a key feature in attempts to grasp the fundamental dynamics and conditions under which mass atrocities emerge. One of the most long-standing, prominent and widely accepted conceptions sees the loss of moral status as a key constitutive component of processes of dehumanisation, suggesting that the victims’ exclusion from the moral universe of obligation breaks down moral barriers, enabling forms of persecution outside the established practices of violence among human communities. With reference to the paradigmatic case of the Holocaust, this article critically interrogates this so far unquestioned equation of a loss of moral standing with dehumanisation. Overall, it argues for a much more nuanced differentiation between normative and analytical uses of dehumanisation, the need for more detailed reflections on its empirical appearances and relevance, and a more critical engagement with its conceptual grounding. Doing so will lead dehumanisation research beyond its current state and would allow for a more intricate assessment of its uses, meanings and relevance in cases of mass violence.

Inflammatory recruitment of healthy hematopoietic stem and progenitor cells in the acute myeloid leukemia niche

Inflammation in the bone marrow (BM) microenvironment is a constitutive component of leukemogenesis in acute myeloid leukemia (AML). Current evidence suggests that both leukemic blasts and stroma secrete proinflammatory factors that actively suppress the function of healthy hematopoietic stem and progenitor cells (HSPCs). HSPCs are also cellular components of the innate immune system, and we reasoned that they may actively propagate the inflammation in the leukemic niche. In two separate congenic models of AML we confirm by evaluation of the BM plasma secretome and HSPC-selective single-cell RNA sequencing (scRNA-Seq) that multipotent progenitors and long-lived stem cells adopt inflammatory gene expression programs, even at low leukemic infiltration of the BM. In particular, we observe interferon gamma (IFN-γ) pathway activation, along with secretion of its chemokine target, CXCL10. We show that AML-derived nanometer-sized extracellular vesicles (EVAML) are sufficient to trigger this inflammatory HSPC response, both in vitro and in vivo. Altogether, our studies indicate that HSPCs are an unrecognized component of the inflammatory adaptation of the BM by leukemic cells. The pro-inflammatory conversion and long-lived presence of HSPCs in the BM along with their regenerative re-expansion during remission may impact clonal selection and disease evolution.

Remediation of toxic metal and metalloid pollution with plant symbiotic fungi.

Anthropogenic activities have dramatically accelerated the release of toxic metal(loid)s into soil and water, which can be subsequently accumulated in plants and animals, threatening biodiversity, human health, and food security. Compared to physical and chemical remediation, bioremediation of metal(loid)-polluted soil using plants and/or plant symbiotic fungi is usually low-cost and environmentally friendly. Mycorrhizal fungi and endophytic fungi are two major plant fungal symbionts. Mycorrhizal fungi can immobilize metal(loid)s via constitutive mechanisms, including intracellular sequestration with vacuoles and vesicles and extracellular immobilization by cell wall components and extracellular polymeric substances such as glomalin. Mycorrhizal fungi can improve the efficacy of phytoremediation by promoting plant symplast and apoplast pathways. Endophytic fungi also use constitutive cellular components to immobilize metal(loid)s and to reduce the accumulation of metal(loid)s in plants by modifying plant physiological status. However, a specific mechanism for the removal of methylmercury pollution was recently discovered in the endophytic fungi Metarhizium, which could be acquired from bacteria via horizontal gene transfer. In contrast to mycorrhizal fungi that are obligate biotrophs, some endophytic fungi, such as Metarhizium and Trichoderma, can be massively and cost-effectively produced, so they seem to be well-placed for remediation of metal(loid)-polluted soil on a large scale.