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Temporary collective relocation of former combatants in cantonments plays a vital role in Disarmament, Demobilisation, and Reintegration (DDR) programmes. Existing research emphasizes the necessity of implementing limited-duration cantonments to mitigate potential security dilemmas. The 2016 Peace Agreement between the Colombian government and the Revolutionary Armed Forces of Colombia (FARC-EP) provides a unique experience, deviating from conventional practices by maintaining cantonments over an extended period, with some evolving into permanent settlements. What are the effects of this strategy on community-based reintegration? Drawing upon original data from interviews, ethnographic observation, and surveys conducted in conflict-affected communities, this paper compares two cases: a cantonment successfully transformed into a permanent settlement and another initially promising cantonment that ultimately failed to achieve permanence. This study argues that long-term cantonments contribute to community-based reintegration benefiting former combatants and receiving communities by maintaining internal cohesion, supporting the local economy, and rebuilding the social fabric in conflict-affected territories. However, specific conditions, particularly land ownership and security, are crucial for such a development. Without these conditions, long-term cantonments face the risk of being closed or relocated, threatening peacebuilding outcomes. The displacement of ex-combatants to other territories hinders community access to the benefits offered by the collective reintegration process. [ABSTRACT FROM AUTHOR]

In this article I argue that the resurge of political violence by Renamo combatants in central Mozambique in the period 2013–2016 should not be merely understood in terms of a remobilisation of former combatants. Rather, the trajectories of Renamo's combatants are better understood when considered in relation to the continuation of Renamo as a political party, an armed movement, and a social and economic network, all at the same time, over the course of war and peace. Based on ethnographic research in the district of Maringue in central Mozambique, I show how Renamo maintained its armed wing from 1992 onwards; how former combatants remained part of so-called 'Renamo networks' in multiple ways; how the wider social context of Maringue was intertwined with Renamo during the war and how in post-war Maringue people, places, and institutions became politically divided between the Frelimo state and Renamo. Considering Renamo in terms of an armed political party within wider social and economic networks, offers new outlooks on the more recent armed conflict and the position of combatants. Conceptually this process is not easy to capture in terms of demobilisation and remobilisation (hence the title – renamobilised). Theoretically, this analysis of the trajectories of former combatants in Mozambique contributes to literature on the continuation of wartime networks and details the manifold ways by which these are intertwined with social life after war's end. [ABSTRACT FROM AUTHOR]

Lung cancer is one of the most common malignant tumors. Despite decades of research, the treatment of lung cancer remains challenging. Non-small cell lung cancer (NSCLC) is the primary type of lung cancer and is a significant focus of research in lung cancer treatment. The deubiquitinase ubiquitin-specific protease 28 (USP28) plays a role in the progression of various tumors and serves as a potential therapeutic target. This study aims to determine the role of USP28 in the progression of NSCLC. We examined the impact of the USP28 inhibitor AZ1 on the cell cycle, apoptosis, DNA damage response, and cellular immunogenicity in non-small cell lung cancer. We observed that AZ1 and siUSP28 induce DNA damage, leading to the activation of Noxa-mediated mitochondrial apoptosis. The dsDNA and mtDNA released from DNA damage and mitochondrial apoptosis activate tumor cell immunogenicity through the cGAS-STING signaling pathway. Simultaneously, targeting USP28 promotes the degradation of c-MYC, resulting in cell cycle arrest and inhibition of DNA repair. This further promotes DNA damage-induced cell apoptosis mediated by the Noxa protein, thereby enhancing tumor cell immunogenicity mediated by dsDNA and mtDNA. Moreover, we found that the combination of AZ1 and cisplatin (DDP) can enhance therapeutic efficacy, thereby providing a new strategy to overcome cisplatin resistance in NSCLC. These findings suggest that targeting USP28 and combining it with cisplatin are feasible strategies for treating NSCLC. [ABSTRACT FROM AUTHOR]

Radical Islamic insurgency and violent extremism have claimed over 5,250 lives and forcibly displaced at least 734,000 people in Cabo Delgado, northern Mozambique over the past six and a half years. Counter-insurgency efforts of the government to date have mainly focused on a military- and security-based response, paying less attention to the structural drivers of extremist violence, such as socio-economic inequalities, poor gov-ernance, historic ideological, ethnic and religious oppositions, and an incomplete peace-building and reconciliation process from the post-civil war period. The paper examines how Mozambique can learn from its past peace-building and Disarmament, Demobilisation and Reintegration (DDR) experience, build on the achievements while also correct the shortcomings, which have equally contributed to the rise of violence. It also analyses ways to implement a tailored, inclusive, and effective strategy of Countering and Pre-venting Violent Extremism (C/PVE), building on the past but linking it to present needs and future challenges. Addressing long-standing root causes, focusing on youth and their communities, and furthering reconciliation are just a few areas, among others, to focus on to ensure that a heavy military response does not undermine the prospects of long-term peace. [ABSTRACT FROM AUTHOR]

Genotoxic stress activates the DNA‐damage response (DDR) signalling cascades responsible for maintaining genome integrity. Downstream DNA repair pathways include the tyrosyl‐DNA phosphodiesterase 1 (TDP1) enzyme that hydrolyses the phosphodiester bond between the tyrosine of topoisomerase I (TopI) and 3′‐phosphate of DNA. The plant TDP1 subfamily contains the canonical TDP1α gene and the TDP1β gene whose functions are not fully elucidated. The current study proposes to investigate the involvement of TDP1 genes in DDR‐related processes by using Arabidopsis thaliana mutants treated with genotoxic agents. The phenotypic and molecular characterization of tdp1α, tdp1β and tdp1α/β mutants treated with cisplatin (CIS), curcumin (CUR), NSC120686 (NSC), zeocin (ZEO), and camptothecin (CPT), evidenced that while tdp1β was highly sensitive to CIS and CPT, tdp1α was more sensitive to NSC. Gene expression analyses showing upregulation of the TDP2 gene in the double mutant indicate the presence of compensatory mechanisms. The downregulation of POL2A gene in the tdp1β mutant along with the upregulation of the TDP1β gene in pol2a mutants, together with its sensitivity to replication inhibitors (CIS, CTP), point towards a function of this gene in the response to replication stress. Therefore, this study brings novel information relative to the activity of TDP1 genes in plants. Summary Statement: The function of the plant TDP1 genes and their roles in DDR are far from being elucidated. By using Arabidopsis thaliana single and double mutants, our study indicates that TDP1β may play relevant functions related to the presence of double‐strand breaks and replication stress, thus providing novel data regarding its role in DNA repair. [ABSTRACT FROM AUTHOR]

Cells have evolved a robust and highly regulated DNA damage response to preserve their genomic integrity. Although increasing evidence highlights the relevance of RNA regulation, our understanding of its impact on a fully efficient DNA damage response remains limited. Here, through a targeted CRISPR-knockout screen, we identify RNA-binding proteins and modifiers that participate in the p53 response. Among the top hits, we find the m6A reader YTHDC1 as a master regulator of p53 expression. YTHDC1 binds to the transcription start sites of TP53 and other genes involved in the DNA damage response, promoting their transcriptional elongation. YTHDC1 deficiency also causes the retention of introns and therefore aberrant protein production of key DNA damage factors. While YTHDC1-mediated intron retention requires m6A, TP53 transcriptional pause-release is promoted by YTHDC1 independently of m6A. Depletion of YTHDC1 causes genomic instability and aberrant cancer cell proliferation mediated by genes regulated by YTHDC1. Our results uncover YTHDC1 as an orchestrator of the DNA damage response through distinct mechanisms of co-transcriptional mRNA regulation. Synopsis: The DNA damage response (DDR) is critical to preserve genomic integrity, and p53 plays a central role in this process. Here, we show that YTHDC1 controls the correct expression of TP53 mRNA as well as splicing of key DDR factors in a m6A-independent and -dependent manner, respectively. CRISPR knockout screening focused on RNA regulators identifies YTHDC1 as required for p53-dependent reporter gene activation. YTHDC1 directly controls TP53 expression through promoter-proximal RNAPII pause-release in a m6A-independent mechanism. In addition, YTHDC1 directly regulates the efficient splicing of ATR, BIRC6 and SETX transcripts in a m6A-dependent manner. Depletion of YTHDC1 results in accumulated DNA damage, reduced proliferation and tumorigenicity of lung cancer cells, caused by deregulation of DDR factors. m6A reader YTHDC1 contributes to genome integrity by promoting p53 expression and controling pre-mRNA splicing of key DNA damage response regulators. [ABSTRACT FROM AUTHOR]

Background: Cervical cancer (CC) stands as a significant health threat to women globally, with high-risk human papillomaviruses as major etiologic agents. The DNA damage repair (DDR) protein topoisomerase I (TOP1) has been linked to various cancers, yet its distinct roles and mechanisms in CC are not fully elucidated. Methods: We investigated TOP1 expression in cervical intraepithelial neoplasia (CIN) and CC tissues utilizing qRT-PCR and IHC, correlating findings with patient prognosis. Subsequent knockdown studies were performed in vitro and in vivo to evaluate the influence of TOP1 on tumor growth, DNA repair, and inflammatory responses. Results: TOP1 was highly expressed in CIN and CC, negatively correlating with patient prognosis. Inhibition of TOP1 impeded CC cell growth and disrupted DNA repair. TOP1 was shown to regulate tumor-promoting inflammation and programmed death-ligand 1 (PD-L1) production in a cGAS-dependent manner. HPV oncoproteins E6 and E7 upregulated TOP1 and activated the cGAS-PD-L1 pathway. Conclusions: TOP1 acts as a DNA repair mediator, promoting CC development and immune evasion. Targeting the TOP1-cGAS-PD-L1 axis could be a potential therapeutic strategy for CC. [ABSTRACT FROM AUTHOR]

This narrative review explores the pathophysiology of obesity, cellular senescence, and exosome release. When exposed to excessive nutrients, adipocytes develop mitochondrial dysfunction and generate reactive oxygen species with DNA damage. This triggers adipocyte hypertrophy and hypoxia, inhibition of adiponectin secretion and adipogenesis, increased endoplasmic reticulum stress and maladaptive unfolded protein response, metaflammation, and polarization of macrophages. Such feed-forward cycles are not resolved by antioxidant systems, heat shock response pathways, or DNA repair mechanisms, resulting in transmissible cellular senescence via autocrine, paracrine, and endocrine signaling. Senescence can thus affect preadipocytes, mature adipocytes, tissue macrophages and lymphocytes, hepatocytes, vascular endothelium, pancreatic β cells, myocytes, hypothalamic nuclei, and renal podocytes. The senescence-associated secretory phenotype is closely related to visceral adipose tissue expansion and metaflammation; inhibition of SIRT-1, adiponectin, and autophagy; and increased release of exosomes, exosomal micro-RNAs, pro-inflammatory adipokines, and saturated free fatty acids. The resulting hypernefemia, insulin resistance, and diminished fatty acid β-oxidation lead to lipotoxicity and progressive obesity, metabolic syndrome, and physical and cognitive functional decline. Weight cycling is related to continuing immunosenescence and exposure to palmitate. Cellular senescence, exosome release, and the transmissible senescence-associated secretory phenotype contribute to obesity and metabolic syndrome. Targeted therapies have interrelated and synergistic effects on cellular senescence, obesity, and premature aging. [ABSTRACT FROM AUTHOR]

Neurons in the brain are continuously exposed to various sources of DNA damage. Although the mechanisms of DNA damage repair in mitotic cells have been extensively characterized, the repair pathways in post-mitotic neurons are still largely elusive. Moreover, inaccurate repair can result in deleterious mutations, including deletions, insertions, and chromosomal translocations, ultimately compromising genomic stability. Since neurons are terminally differentiated cells, they cannot employ homologous recombination (HR) for double-strand break (DSB) repair, suggesting the existence of neuron-specific repair mechanisms. Our research has centered on the microtubule-associated protein tau (MAPT), a crucial pathological protein implicated in neurodegenerative diseases, and its interplay with neurons' DNA damage response (DDR). This review aims to provide an updated synthesis of the current understanding of the complex interplay between DDR and cytoskeletal proteins in neurons, with a particular focus on the role of tau in neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

This article examines the temporal approaches that the Nigerian government adopted in the aftermath of the Nigerian-Biafra War (1967–1970). First, the central government pursued speedy implementation of the demilitarisation of Igbo ex-combatants, often identifying them as a security threat. Second, the provision of social support for ex-combatants' social reintegration was delayed and progressed slowly, especially in relation to Igbo soldiers. Third, the government refused to fairly acknowledge the economic and social legacy of the activities conducted by Igbos both before and during the civil war, identifying the post-war period as a new era disconnected from the past. Due to these arrangements, the Igbos (both ex-combatants and civilians) were subject to systematic suppression during the post-war DDR (demilitarisation, demobilisation and re-integration of ex-combatants) process and their resilience and capacity to settle into the civilian life were substantially diminished. Based on these findings, this study will argue that such temporal features of DDR were set by the Nigerian government to perpetuate hierarchies and exclusion against Igbos in post-hostility Nigeria. [ABSTRACT FROM AUTHOR]

Youth as a category that informs international interventions in conflict-affected settings has gained currency in the past decade. This article traces the rising rhetoric of youth in UN Disarmament, Demobilization and Reintegration (DDR) discourse and demonstrates how changes in its dominant representations have implications beyond the matter of semantics. Drawing on post-structuralist traditions, the article highlights how the DDR discourse delineates problems through particular framings that call forth certain solutions, which in turn reinforce the very (mis)understandings that underlie the interventions. A case study from the Central African Republic illustrates how the hegemonic representation of youth-as-troublemakers in UN documents, together with a compelling narrative that naturalized the link between youth, unemployment and violence, made possible and conferred legitimacy to the proliferation of projects with an overwhelming economic focus. The article discusses how the resource landscape, such as opportunities to unlock earmarked funding, incentivizes the reproduction of certain constructions of youth that align with today's policy panic around violent extremism. In so doing, it puts into question the instrumental approach towards discourse by pointing to surprising ways in which discourses become appropriated by both international peacebuilders and the 'subjects' of these interventions. [ABSTRACT FROM AUTHOR]

Der vorliegende Beitrag setzt sich mit der Kafka Rezeption in der DDR auseinander, mit besonderem Augenmerk auf die ästhetisch-politischen Debatten, die das Werk Kafkas Anfang der 1960er Jahre in der DDR — und darüber hinaus — entfacht hat. Ausgehend von den zahlreichen Aufzeichnungen und Korrespondenzen aus dem Alfred Kurella-Archiv (Akademie der Künste), besonders zwischen Alfred Kurella und Roger Garaudy, Jean-Paul Sartre, Louis Aragon, Carlo Salinari und Ernst Fischer, sollen die unterschiedlichen ästhetischen Positionen in Bezug auf den Realismus Begriff beleuchtet werden. Vor dem Hintergrund der ersten wissenschaftlichen Publikationen zu Kafka in der DDR, besonders in der Zeitschrift Sinn und Form, der Forschung von Klaus Hermsdorf, sowie der Kafka-Konferenz in Liblice im Mai 1963, der Person von Eduard Goldstücker und dem Prager Frühling 1968, sollen die ästhetischen, historischen und politischen Zusammenhänge rekonstruiert werden. [ABSTRACT FROM AUTHOR]

The Design and Development Research (DDR) approach is an increasingly employed research method by education researchers, as it aims to produce a product through specific stages. Therefore, this study aims to explain and detail the design and development aspects of an Arabic language camp called the Academic Arabic Language Camp (KeMBAA), which utilizes the Design and Development Research approach (DDR). This language camp targets the participation of new postgraduate students in the religious studies department at the Faculty of Islamic Studies, National University of Malaysia. Developing and implementing KeMBAA is an effort to design, develop, and execute a product that incorporates DDR elements such as multidisciplinary and interdisciplinary approaches, mixed methodologies, cycles, and various other components. KeMBAA aims to provide an Arabic language learning experience in an interactive and enjoyable environment for students who are accustomed to traditional Arabic language teaching methods, which require a new touch through more impactful innovation. This study employs the DDR approach, executed through three main phases: the needs analysis phase, the design and development phase, and concluding with the assessment phase. The study's findings present the key features of KeMBAA, alongside the foundational design principles, as an innovation in Arabic language learning for Islamic Studies students. The framework for developing KeMBAA is expected to serve as a reference for Arabic language teaching innovation, particularly for researchers in Arabic and foreign languages. [ABSTRACT FROM AUTHOR]

In November 2018, the State of Cameroon announced the creation of the National Committee for Disarmament, Demobilisation and Reintegration (NCDDR) to organise, supervise and manage the disarmament, demobilisation and reintegration of former Boko Haram fighters and armed groups in the English-speaking North-West and South-West regions. The need arose as communities had been hosting successive waves of former Boko Haram associates. This research focuses on those communities where reintegration routes are either off or upstream the institutional framework set by the government. Based on a field survey and available literature on the current security crisis in the Far-North region of Cameroon, the study describes the profiles of these ex-hostages and ex-combatants that are grouped under the term of ex-associates. Reception conditions as well as the ordalic reintegration mechanisms put in place by the communities' leaders are also analysed. The challenge of identifying and counting those ex-associates exhaustively and the delay in implementing a coherent national reintegration strategy make it quite illusory to envisage a credible alternative to that still existing community model. [ABSTRACT FROM AUTHOR]

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This article investigates the distinct pathways and roles played by former rebel leaders in conditions of conflict transformation. Focusing on southern Syria, it offers a comparative analysis of the mediation undertaken by remobilised and demobilised rebel leaders to articulate the concerns and demands of local communities to state officials in the aftermath of insurgency. Drawing on multiple waves of fieldwork conducted in southern Syria between June 2018 and December 2023, it illustrates how factors such as legitimacy and effectiveness have shaped civilian preferences to engage with external powers through intermediaries. Furthermore, it reveals the underlying factors that shaped the diverse state approaches to rebels-turned-intermediaries, ranging from pragmatic collaboration to outright marginalisation. [ABSTRACT FROM AUTHOR]

Teachers play a crucial role in disseminating knowledge in educational settings, typically adhering to a credulist-testimonial approach outlined in pedagogical literature. Consequently, students often acquire knowledge through this method, potentially leading to discrepancies between their conceptual understanding and the intended educational objectives. This study investigates the phenomenon of learning obstacles encountered by junior high school students, with a particular emphasis on mathematics education. It is part of a series of Didactical Design Research (DDR) projects aimed at developing effective instructional materials. Employing an interpretive paradigm within the DDR framework, the study adopts a qualitative approach utilizing hermeneutic phenomenology design. Various research tools such as diagnostic assessments, interview guidelines, observation sheets, and audio recordings are employed. Data analysis is conducted using the Constant Comparative Method (CCM). The findings highlight ontogenic, didactic, and epistemological obstacles students face, stemming from factors such as a lack of interest in mathematics, ineffective material presentation, and misconceptions regarding set concepts. These results underscore the importance of educators employing effective teaching strategies to help students overcome these obstacles and succeed in their mathematics education.

Abstract Backgrounds Ampullary adenocarcinoma (AMPAC) is a rare malignancy, treated as pancreatic or intestinal cancer based on its histologic subtype. Little is known about the genomic features of Chinese patients with AMPAC. Materials and methods We enrolled 145 Chinese AMPAC patients in our local cohort and performed a compressive somatic and germline genetic testing using a 156 gene panel. Expression of PD-L1 (clone 28 − 8) was also assessed in tumor specimens from 64 patients. Results The frequency of genetic alterations (GAs) in Chinese patients with AMPAC was found to be distinctive, with TP53, KRAS, SMAD4, APC, CTNNB1, ARID1A, and CDKN2A emerged as the most frequently mutated genes. Comparing with Western patients, significant differences were observed in the prevalence of PIK3CA and ARID2. Furthermore, the incidence of MSI-H was lower in the Chinese cohort, with only two patients identified as MSI-H. Conversely, 11 patients (8.27%) had pathogenic/likely pathogenic germline alterations, all of which were in the DNA damage response (DDR) pathway. In our cohort, 34.48% (22/64) of patients exhibited positive PD-L1 expression in tumor cells, and this expression was associated with GAs in CTNNB1 and BLM. Importantly, over three-fourths of Chinese AMPAC patients in our study had at least one actionable GA, with more than one-fifth of them having actionable GAs classified as Level 3. These actionable GAs were primarily involved in the DDR and PI3K pathways. Notably, GAs in the DDR pathway were detected in both Chinese and Western patients, and regardless of their functional impact, these alterations demonstrated enhanced overall survival rates and higher tumor mutational burden (TMB) levels. Conclusion These findings underscore the distinct genomic landscape of Chinese AMPAC patients and highlight the potential for targeted therapies based on the identified GAs.

Breast cancer risk have been discussed to be associated with polymorphisms in genes as well as abnormal DNA damage repair function. This study aims to assess the relationship between genes single nucleotide polymorphisms (SNPs) related to DNA damage repair and female breast cancer risk in Chinese population. A case–control study containing 400 patients and 400 healthy controls was conducted. Genotype was identified using the sequence MassARRAY method and expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER-2) in tumor tissues was analyzed by immunohistochemistry assay. The results revealed that ATR rs13091637 decreased breast cancer risk influenced by ER, PR (CT/TT vs. CC: adjusted odds ratio [OR] = 1.54, 95% confidence interval [CI]: 1.04–2.27, p = 0.032; CT/TT vs. CC: adjusted OR = 1.63, 95%CI: 1.14–2.35, p = 0.008) expression. Stratified analysis revealed that PALB2 rs16940342 increased breast cancer risk in response to menstrual status (AG/GG vs. AA: adjusted OR = 1.72, 95%CI: 1.13–2.62, p = 0.011) and age of menarche (AG/GG vs. AA: adjusted OR = 1.54, 95%CI: 1.03–2.31, p = 0.037), whereas ATM rs611646 and Ku70 rs132793 were associated with reduced breast cancer risk influenced by menarche (GA/AA vs. GG: adjusted OR = 0.50, 95%CI: 0.30–0.95, p = 0.033). In a summary, PALB2 rs16940342, ATR rs13091637, ATM rs611646, and Ku70 rs132793 were associated with breast cancer risk. [ABSTRACT FROM AUTHOR]

Child soldier disarmament, demobilization and reintegration (DDR) practice has a strong normative commitment to protect children from harm and violence. However, there exist policy and research knowledge gaps in comprehending the translation of such norms in meeting the social and protective needs of children. In Sri Lanka from 2009, 594 former child soldiers from the Liberation Tamil Tigers of Elam (LTTE) underwent a national rehabilitation programme. National engagement with international child protection norms could not materialize from a militarized governance framework implemented at the end of the civil war. This article provides a primary source of data based on 45 semi-structured interviews with former boy and girl child soldiers from the LTTE. The Sri Lankan case-study demonstrates that the DDR programme resulted in the re-calibration of social and political control over child and adult participants. Former child soldiers' social and protective needs therefore remain complex and unresolved because of state generated structural violence related to poverty and militarization. The article advances a framework to account for a generational power dynamic of adult–child relations, and the politics of institutionalized protection to account for children's formal rehabilitation and return experiences. [ABSTRACT FROM AUTHOR]

Primary malignant melanoma of the esophagus (PMME) is an extremely rare but highly aggressive malignancy with a poor prognosis. Due to the scarcity of driver gene alterations, there is a need for more clinical data to comprehensively depict its molecular alterations. This study reviewed 26 PMME cases from three medical centers. Hybrid capture‐based targeted sequencing of 295 and 1021 genes was performed in 14 and 12 cases, respectively. We found that PMME patients had a relatively low tumor mutation burden (median, 2.88 mutations per Mb) and were simultaneously accompanied by mutations in genes such as KIT (6/26, 23%), TP53 (6/26, 23%), SF3B1 (4/26, 15%), and NRAS (3/26, 12%). KIT, NRAS, and BRAF were mutually exclusive, and SF3B1 co‐occurred with KIT mutation and amplification. The most common pathways affected were the mitogen‐activated protein kinases and DNA damage response (DDR) pathways. Stage IV was a risk factor for both progression‐free survival (hazard ratio [HR] = 5.14, 95% confidence interval [CI] = 1.32–19.91) and overall survival (OS), HR = 4.33, 95% CI = 1.22–15.30). Treatment with immune‐checkpoint inhibitors (ICIs) was an independent factor for favorable OS (HR = 0.10, 95% CI = 0.01–0.91). Overall, PMME is a complex malignancy with diverse gene alterations, especially with harboring DDR alterations for potentially response from ICIs. [ABSTRACT FROM AUTHOR]

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In 2018, armed groups opposing the incumbent in Ethiopia, agreed to desert the violent means and participate in Disarmament, Demobilization and Reintegration (DDR). Like many DDR processes, it faced discrepant combatant data, lack of clear strategy, poor coordination and delays; these were challenges that emerged from absence of clear DDR planning and elaborated peace agreements between the Ethiopian government and the armed groups. While these technical and political challenges are understood in relation to DDR around the world, analysis tends to acknowledge but fail to properly theorize regional contexts such as the reality where armed groups are hosted by neighbouring countries, the relationship between adjacent countries, proxy wars, insecure borders and the regional dimension of proliferation of arms, which are particular challenges in the Horn of Africa. We argue that these regional realities shaped DDR in post-2018 Ethiopia; groups that were arguably sustained by the very nature of the region itself. Drawing from extensive interviews with armed group leaders and members, civil society and government stakeholders, we contribute towards the understanding of DDR's regional dimensions; in 2018 the promise of regional stability through the Ethiopian-Eritrean reproachment was central to the armed groups participation in the DDR processes and its management. [ABSTRACT FROM AUTHOR]

Copyright of Psychosozial is the property of Psychosozial-Verlag GmbH & Co. KG and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Psychosozial is the property of Psychosozial-Verlag GmbH & Co. KG and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Psychosozial is the property of Psychosozial-Verlag GmbH & Co. KG and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Backgrounds: Ampullary adenocarcinoma (AMPAC) is a rare malignancy, treated as pancreatic or intestinal cancer based on its histologic subtype. Little is known about the genomic features of Chinese patients with AMPAC. Materials and methods: We enrolled 145 Chinese AMPAC patients in our local cohort and performed a compressive somatic and germline genetic testing using a 156 gene panel. Expression of PD-L1 (clone 28 − 8) was also assessed in tumor specimens from 64 patients. Results: The frequency of genetic alterations (GAs) in Chinese patients with AMPAC was found to be distinctive, with TP53, KRAS, SMAD4, APC, CTNNB1, ARID1A, and CDKN2A emerged as the most frequently mutated genes. Comparing with Western patients, significant differences were observed in the prevalence of PIK3CA and ARID2. Furthermore, the incidence of MSI-H was lower in the Chinese cohort, with only two patients identified as MSI-H. Conversely, 11 patients (8.27%) had pathogenic/likely pathogenic germline alterations, all of which were in the DNA damage response (DDR) pathway. In our cohort, 34.48% (22/64) of patients exhibited positive PD-L1 expression in tumor cells, and this expression was associated with GAs in CTNNB1 and BLM. Importantly, over three-fourths of Chinese AMPAC patients in our study had at least one actionable GA, with more than one-fifth of them having actionable GAs classified as Level 3. These actionable GAs were primarily involved in the DDR and PI3K pathways. Notably, GAs in the DDR pathway were detected in both Chinese and Western patients, and regardless of their functional impact, these alterations demonstrated enhanced overall survival rates and higher tumor mutational burden (TMB) levels. Conclusion: These findings underscore the distinct genomic landscape of Chinese AMPAC patients and highlight the potential for targeted therapies based on the identified GAs. [ABSTRACT FROM AUTHOR]

What explains the divergent strategies of middle commanders after negotiated peace? After Colombia's peace process with the insurgent group Revolutionary Armed Forces of Colombia, former FARC midlevel commanders deployed a variety of strategies, from leading reintegration projects to build peace, to rearming splinter groups to spoil peace. Most other studies approach leading and spoiling separately, thus failing to account for both outcomes. Responding to this limitation, this article proposes an integrated theory explaining middle commander strategies after armed conflict. It argues that former commanders seek to maximise personal security and influence, and they choose strategies that respond to variations in local security and community embeddedness. Former commanders in secure areas with community embeddedness will build peace, while former commanders in dangerous areas with community embeddedness will spoil peace. This argument is evaluated with a qualitative analysis using primary data collected during field work in Colombia, including 59 interviews with former FARC members. [ABSTRACT FROM AUTHOR]

Ricezione

Mobile applications are now being used for 21st-century learning, including alphabet learning. There are numerous mobile application products for online learning, particularly those relating to the alphabet ABC. It was revealed that previous mobile applications did not provide interactive activities that suited preschool students. Therefore, this study aims to develop Hooray! Hooray! ABC for learning the alphabet. This study employed Design and Development Research (DDR) as the research design, which is divided into three phases: Phase I - the needs of the application; Phase II - the design and development; and Phase III - the evaluation. ADDIE model is used as the instructional design to design and develop the mobile application. Two experts were chosen to validate the application. It was tested for usability and student performance on 35 preschool students. The results reveal that Hooray! Hooray! ABC can be used for learning the alphabet based on experts' agreement in terms of usefulness (96%), ease of use (97%), ease of learning (94%), and satisfaction (100%). In addition, the result shows that Hooray! Hooray! ABC can increase students' performance (t = 13.271, p = 0.00) in learning the alphabet, making it beneficial for preschool students, teachers, and schools. This study also acknowledged the limitations and future suggestions of this study.

Simple Summary: Metastatic prostate cancer is traditionally treated with androgen deprivation therapy. The introduction of second-generation antiandrogens into clinical practice elicits prolonged responses but also gives rise to mechanisms of resistance that do not rely on androgens. The emergent phenotype of androgen-indifferent prostate cancer is associated with an aggressive, atypical clinical course. The term "aggressive variant prostate cancer" (AVPC) has been coined in order to separate this phenotype from hormone-responsive tumors. Unfortunately, morphology alone cannot reliably predict virulent behavior. The development of prognostic and predictive biomarkers is therefore crucial. In line with this, research has been focusing on unraveling the biological identity of AVPC. Drawing from the current knowledge about AVPC molecular pathogenesis and evolution, we attempt to identify candidate tissue-based AVPC biomarkers. Prostate cancer (PC) is a common malignancy among elderly men, characterized by great heterogeneity in its clinical course, ranging from an indolent to a highly aggressive disease. The aggressive variant of prostate cancer (AVPC) clinically shows an atypical pattern of disease progression, similar to that of small cell PC (SCPC), and also shares the chemo-responsiveness of SCPC. The term AVPC does not describe a specific histologic subtype of PC but rather the group of tumors that, irrespective of morphology, show an aggressive clinical course, dictated by androgen receptor (AR) indifference. AR indifference represents an adaptive response to androgen deprivation therapy (ADT), driven by epithelial plasticity, an inherent ability of tumor cells to adapt to their environment by changing their phenotypic characteristics in a bi-directional way. The molecular profile of AVPC entails combined alterations in the tumor suppressor genes retinoblastoma protein 1 (RB1), tumor protein 53 (TP53), and phosphatase and tensin homolog (PTEN). The understanding of the biologic heterogeneity of castration-resistant PC (CRPC) and the need to identify the subset of patients that would potentially benefit from specific therapies necessitate the development of prognostic and predictive biomarkers. This review aims to discuss the possible pathophysiologic mechanisms of AVPC development and the potential use of emerging tissue-based biomarkers in clinical practice. [ABSTRACT FROM AUTHOR]

Introduction: Astrocytes are the glial cells responsible for brain homeostasis, but if injured, they could damage neural cells even deadly. Genetic damage, DNA damage response (DDR), and its downstream cascades are dramatic events poorly studied in astrocytes. Hypothesis and methods: We propose that 1 h of 400 mmol/L ethanol and/or 1 μmol/L corticosterone exposure of cultured hippocampal astrocytes damages DNA, activating the DDR and eliciting functional changes. Immunolabeling against γH2AX (chromatin DNA damage sites), cyclin D1 (cell cycle control), nuclear (base excision repair, BER), and cytoplasmic (anti-inflammatory functions) APE1, ribosomal nucleolus proteins together with GFAP and S100β plus scanning electron microscopy studies of the astrocyte surface were carried out. Results: Data obtained indicate significant DNA damage, immediate cell cycle arrest, and BER activation. Changes in the cytoplasmic signals of cyclin D1 and APE1, nucleolus number, and membrane-attached vesicles strongly suggest a reactivity like astrocyte response without significant morphological changes. Discussion: Obtained results uncover astrocyte genome immediate vulnerability and DDR activation, plus a functional response that might in part, be signaled through extracellular vesicles, evidencing the complex influence that astrocytes may have on the CNS even upon short-term aggressions. [ABSTRACT FROM AUTHOR]

Summary: The DNA damage response (DDR) is the cellular process of preserving an intact genome and is often deregulated in lymphoma cells. The ataxia telangiectasia and Rad3‐related (ATR) kinase is a crucial factor of DDR in the response to DNA single‐strand breaks. ATR inhibitors are agents that have shown considerable clinical potential in this context. We characterized the activity of the ATR inhibitor elimusertib (BAY 1895344) in a large panel of lymphoma cell lines. Furthermore, we evaluated its activity combined with the clinically approved PI3K inhibitor copanlisib in vitro and in vivo. Elimusertib exhibits potent anti‐tumour activity across various lymphoma subtypes, which is associated with the expression of genes related to replication stress, cell cycle regulation and, as also sustained by CRISPR Cas9 experiments, CDKN2A loss. In several tumour models, elimusertib demonstrated widespread anti‐tumour activity stronger than ceralasertib, another ATR inhibitor. This activity is present in both DDR‐proficient and DDR‐deficient lymphoma models. Furthermore, a combination of ATR and PI3K inhibition by treatment with elimusertib and copanlisib has in vitro and in vivo anti‐tumour activity, providing a potential new treatment option for lymphoma patients. [ABSTRACT FROM AUTHOR]

Copyright of Zeitschrift für Sozialpädagogik is the property of Julius Beltz GmbH & Co. KG Beltz Juventa and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

This paper explores community perceptions about traditional authorities' roles during the disarmament, demobilisation and reintegration (DDR) of former combatants. We have selected the case of Somalia, where both government institutions and traditional authorities have partnered with international actors and institutions, as well as non-governmental organisations (NGOs), to prevent and counter violent extremism (P/CVE). International actors have related to traditional authorities based on the assumption that these actors wield a kind of social power that facilitates the reintegration of former members of the violent extremist organisation al-Shabaab. Based on mixed methodology research we explain social reintegration in Somalia from the community perspective, and find that P/CVE programmes are expressive of co-optation of traditional authorities. We make the case that 'risk coping' helps explain why a majority of civilians prefer the government-led formal reintegration pathway of ex-combatants to the traditional authorities pathway. We conclude by discussing the implications that this has for NGOs/INGOs active in this P/CVE sector. [ABSTRACT FROM AUTHOR]

Simple Summary: Exploring the impact of heat shock protein (HSP) inhibition in cancer may give new insights into the cellular processes that these molecules sustain to promote cancer survival and may accelerate the discovery of more HSP inhibitors to be introduced in clinical trials. In this study, we explored the expression and role of high-molecular-weight HSP110 in the survival of Primary Effusion Lymphoma (PEL) cells. We found that the proper expression of this HSP is required to prevent lysosomal permeabilization, DNA damage, c-Myc downregulation and STAT3 de-phosphorylation. Indeed, HSP silencing strongly reduces PEL cell survival through the dysregulation of these processes that have been found to be interconnected. Heat shock proteins (HSPs) are highly expressed in cancer cells and represent a promising target in anti-cancer therapy. In this study, we investigated for the first time the expression of high-molecular-weight HSP110, belonging to the HSP70 family of proteins, in Primary Effusion Lymphoma (PEL) and explored its role in their survival. This is a rare lymphoma associated with KSHV, for which an effective therapy remains to be discovered. The results obtained from this study suggest that targeting HSP110 could be a very promising strategy against PEL, as its silencing induced lysosomal membrane permeabilization, the cleavage of BID, caspase 8 activation, downregulated c-Myc, and strongly impaired the HR and NHEJ DNA repair pathways, leading to apoptotic cell death. Since chemical inhibitors of this HSP are not commercially available yet, this study encourages a more intense search in this direction in order to discover a new potential treatment that is effective against this and likely other B cell lymphomas that are known to overexpress HSP110. [ABSTRACT FROM AUTHOR]

TGFβ signaling and the DNA damage response (DDR) are two cellular toolboxes with a strong impact on cancer biology. While TGFβ as a pleiotropic cytokine affects essentially all hallmarks of cancer, the multifunctional DDR mostly orchestrates cell cycle progression, DNA repair, chromatin remodeling and cell death. One oncogenic effect of TGFβ is the partial activation of epithelial-to-mesenchymal transition (EMT), conferring invasiveness, cellular plasticity and resistance to various noxae. Several reports show that both individual networks as well as their interface affect chemo-/radiotherapies. However, the underlying mechanisms remain poorly resolved. EMT often correlates with TGFβ-induced slowing of proliferation, yet numerous studies demonstrate that particularly the co-activated EMT transcription factors counteract anti-proliferative signaling in a partially non-redundant manner. Collectively, evidence piled up over decades underscore a multifaceted, reciprocal inter-connection of TGFβ signaling / EMT with the DDR / cell cycle progression, which we will discuss here. Altogether, we conclude that full cell cycle arrest is barely compatible with the propagation of oncogenic EMT traits and further propose that 'EMT-linked DDR plasticity' is a crucial, yet intricate facet of malignancy, decisively affecting metastasis formation and therapy resistance. [ABSTRACT FROM AUTHOR]

Glioma is a common primary central nervous system tumor with complex pathogenesis. DNA damage and repair (DDR) is widely involved in regulating cell proliferation and tumorigenesis by correcting and repairing DNA damage mechanisms. Recent studies have reported the following properties in cancer cells in glioma, increased DNA damage and reduced DNA repair capacity. However, the relationship between glioma and DDR-related genes was unclear. DDR-related risk score model was built. The validity of this model was validated in detail through the Kaplan-Meier survival analysis, tumor mutational burden (TMB) analysis, immune cell infiltration, sensitivity to treatment regimens. Moreover, the model's adaptability was validated in different glioma data cohorts and different glioma subgroups. To further investigate the molecular mechanism of one of DDR-related gene (NUDT1) in glioma, U251 cell was used for the knockdown experiment, followed by MTT, wound healing and transwell analysis. Ten prognostic-related DDR-related signature genes were obtained, including EID3, MGMT, YWHAG, PMS1, SHPRH, HUS1, NUDT1, GADD45G, APEX1 and FAM175A. The RT-qPCR results suggested that the latter five genes were highly expressed in glioma patients. Interestingly, high TMB score had longer survival. In high-risk score groups, reduced immune cell infiltration in the tumor microenvironment lead to poorer patient outcomes. Sensitivity to treatment regimens analysis indicated that low-risk score groups were more sensitive to chemotherapeutics. Moreover, the risk score model had a good prediction effect on different glioma datasets and different glioma subgroups. In vitro mechanism study showed that knockdown of NUDT1 reduced tumorigenesis. Furthermore, knockdown of NUDT1 remarkably reduced the expression level of HIF-1α. DDR-related risk score model built-in this work has good predictive performance for glioma. Ten prognostic-related DDR-related signature genes were obtained, including EID3, MGMT, YWHAG, PMS1, SHPRH, HUS1, NUDT1, GADD45G, APEX1 and FAM175A. In high-risk score groups, reduced immune cell infiltration in the tumor microenvironment leads to poorer patient outcomes. The risk score model had a good prediction effect on different glioma datasets and different glioma subgroups. Knockdown of NUDT1 reduced tumorigenesis of glioma and remarkably reduced the expression level of HIF-1α. [ABSTRACT FROM AUTHOR]

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The article deals with the problem of ethical assessment of the liquidation of the GDR as a state structure and its integration into the political and economic space of the FRG. According to a number of historical and sociological sources, “reunification” was not the reason for the search and finding of a common language between West and East Germans, but, on the contrary, the reasons for discord and deep mutual distrust and rejection. On this basis, the work analyzes the views of both sides, and also conducts a philosophical reflection on the value bases (ethical axioms) of the key evaluative positions of both East and West Germans regarding the actions of the West German government, the conditions for concluding a monetary union of the two Germanys, as well as in relation to privatizations East German companies.

Ex vivo gene editing in hematopoietic stem and progenitor cells (HSPCs) represents a promising curative treatment strategy for monogenic blood disorders. Gene editing using the homology-directed repair (HDR) pathway enables precise genetic modifications ranging from single base pair correction to replacement or insertion of large DNA segments. Hence, HDR-based gene editing could facilitate broad application of gene editing across monogenic disorders, but the technology still faces challenges for clinical translation. Among these, recent studies demonstrate induction of a DNA damage response (DDR) and p53 activation caused by DNA double-strand breaks and exposure to recombinant adeno-associated virus vector repair templates, resulting in reduced proliferation, engraftment, and clonogenic capacity of edited HSPCs. While different mitigation strategies can reduce this DDR, more research is needed on this phenomenon to ensure safe and efficient implementation of HDR-based gene editing in the clinic.

Neurons in the brain are continuously exposed to various sources of DNA damage. Although the mechanisms of DNA damage repair in mitotic cells have been extensively characterized, the repair pathways in post-mitotic neurons are still largely elusive. Moreover, inaccurate repair can result in deleterious mutations, including deletions, insertions, and chromosomal translocations, ultimately compromising genomic stability. Since neurons are terminally differentiated cells, they cannot employ homologous recombination (HR) for double-strand break (DSB) repair, suggesting the existence of neuron-specific repair mechanisms. Our research has centered on the microtubule-associated protein tau (MAPT), a crucial pathological protein implicated in neurodegenerative diseases, and its interplay with neurons’ DNA damage response (DDR). This review aims to provide an updated synthesis of the current understanding of the complex interplay between DDR and cytoskeletal proteins in neurons, with a particular focus on the role of tau in neurodegenerative disorders.