Examination of runs of homozygosity distribution patterns and relevant candidate genes of potential economic interest in Russian goat breeds using whole-genome sequencing

Background/Objectives: Whole-genome sequencing (WGS) data provide valuable information about the genetic architecture of local livestock but have not yet been applied to Russian native goats, in particular, the Orenburg and Karachay breeds. A preliminary search for selection signatures based on single nucleotide polymorphism (SNP) genotype data in these breeds was not informative. Therefore, in this study, we aimed to address runs of homozygosity (ROHs) patterns and find the respective signatures of selection overlapping candidate genes in Orenburg and Karachay goats using the WGS approach. Methods: Paired-end libraries (150 bp reads) were constructed for each animal. Next-generation sequencing was performed using a NovaSeq 6000 sequencer (Illumina, Inc., San Diego, CA, USA), with ~20X genome coverage. ROHs were identified in sliding windows, and ROH segments shared by at least 50% of the samples were considered as ROH islands. Results: ROH islands were identified on chromosomes CHI3, CHI5, CHI7, CHI12, CHI13, and CHI15 in Karachay goats; and CHI3, CHI11, CHI12, CHI15, and CHI16 in Orenburg goats. Shared ROH islands were found on CHI12 (containing the PARP4 and MPHOSPH8 candidate genes) and on CHI15 (harboring STIM1 and RRM1). The Karachay breed had greater ROH length and higher ROH number compared to the Orenburg breed (134.13 Mb and 695 vs. 78.43 Mb and 438, respectively). The genomic inbreeding coefficient (FROH) varied from 0.032 in the Orenburg breed to 0.054 in the Karachay breed. Candidate genes associated with reproduction, milk production, immunity-related traits, embryogenesis, growth, and development were identified in ROH islands in the studied breeds. Conclusions: Here, we present the first attempt of elucidating the ROH landscape and signatures of selection in Russian local goat breeds using WGS analysis. Our findings will pave the way for further insights into the genetic mechanisms underlying adaption and economically important traits in native goats

Colchicine Binding Site Tubulin Inhibitors Impair Vincristine-Resistant Neuroblastoma Cell Function

High-risk neuroblastoma remains a clinically challenging pediatric cancer, with an approximate five-year survival rate of ~60%. Frontline therapy for this group of patients includes surgery and intensive chemotherapy that involves combinations of the tubulin inhibitor vincristine with several other chemotherapeutics. Unfortunately, unresponsiveness to therapy and relapse are common, with tumors often displaying resistance to vincristine. Recently, we characterized a novel set of tubulin inhibitors that are distinct from vincristine and bind within the colchicine binding site present on tubulin monomers. Colchicine binding site inhibitors (CBSIs) have gained traction as improved chemotherapeutics due to their potential to overcome tubulin inhibitor-induced resistance. In this study, we investigate the functional impact of CBSI treatment on multiple neuroblastoma cell lines, including those that are vincristine-resistant. We demonstrate that our newly developed compounds are effective at disrupting cell division in non-resistant and resistant cells and have cellular activity against vincristine-resistant cell lines. Interestingly, we find that vincristine-resistant cell lines differ in their ability to undergo apoptotic cell death in response to CBSI treatment. Taken together, these findings provide a solid foundation to further investigate the utility of CBSIs for neuroblastoma treatment, while highlighting the distinct resistance mechanisms that can emerge in these childhood cancers

Modern triple resonance protein NMR backbone assignment, using AlphaFold and unlabelling to drive chemical shifts assignment in proteins

NMR is a powerful technique to study the structure, dynamics and interactions of proteins. However, to obtain atomic resolution data, NMR signals must first be correlated with specific chemical groups – a problem called assignment. The software AlphaFold has shown to be a great advancement in modern-day science. Until now, structural analysis of proteins had been bottlenecked by months/ years’ worth of slower techniques that were traditionally used to determine a protein structure In this project we have designed and applied a semi-automated assignment program called SNAPS (Simple NMR Assignment using Predicted Shifts). This allows the user to go from a set of NMR spectra of a protein with a known 3D AlphaFold or X-ray crystallography structure to a fully assigned chemical shifts of the backbone resonances. In addition, unlabelling experimental data can be incorporated into the use of the program to generate more reliable assignment data by helping the program along in the mapping of the amino acids for assignment by providing places in the assignment where the amino acid it is known. The program was largely written by Dr Alex Heyam from the university of Leeds but testing scripts and well as a NEF importer was written to ensure the program was user-friendly and ensured rigid, fool-proof datasets being imported for backbone assignment. The program also underwent large-scale testing on roughly 150 proteins with known 3D crystal structures as well as 15N unlabelleing data being implemented to improve assignment. AlphaFold structures could also be implemented for use in the program also. Assignment was as good as 86-88% dependent upon parameters, with the unlabelling being slightly more effective with assignment (for PDB crystal structures)

Thanaleisure and the super-rich: the case of the Titan submersible disaster

This commentary reflects on the Titan submersible disaster as a case study of the thanatic leisure habits of the super-rich. Previous analyses of elite consumption have explored their tendency to seek out exclusivity and luxury, and to monopolise space (Thurlow and Jaworski 2012; Featherstone 2014; Atkinson 2021). Drawing on literature from the fields of thanatourism and dark leisure, the commentary theorises how deep sea submersible tourism offers adjacency to death and suffering as a means to pursue mythical masculine desires, confront artificial frontiers and hardships, and assert status. It concludes with a discussion of how the wastefulness, pollution and redemption struggles that characterise what is here defined as thanaleisure add to our understanding of thanacapitalism (Korstanje 2016). That is, as an economic system that not only commodifies death and suffering, but justifies its own existence through promoting the hypermobility of the few at the expense of the majority

Precision targeting of rhabdomyosarcoma by combining primary CAR NK cells and radiotherapy

Background: Rhabdomyosarcoma (RMS) is the most common type of soft-tissue sarcoma in children, and it remains a challenging cancer with poor outcomes in high-risk and metastatic patients. This study reports the use of epidermal growth factor receptor (EGFR)-targeted chimeric antigen receptor (CAR) natural killer (NK) cells in combination with radiotherapy as a novel immunotherapeutic approach for RMS treatment. Methods: Primary human NK cells from healthy donors were engineered using lentiviral transduction to express a cetuximab-based EGFR-specific CAR. The ability of the engineered NK cells to lyse RMS cells was then assessed in vitro in RMS monolayers and spheroids, as well as against chemotherapy-resistant and primary patient-derived RMS cells. Migratory properties of NK cells were observed in a subcutaneous RMS xenograft model using in vivo imaging, and the efficacy of EGFR-CAR NK cells in combination with localized fractionated radiotherapy was analyzed. Results: Primary human EGFR-CAR NK cells demonstrated enhanced cytotoxicity against multiple RMS cell lines in both two-dimensional culture and three-dimensional spheroid models. Furthermore, EGFR-CAR NK cells were highly efficient against chemotherapy-resistant RMS cells and patient-derived samples. Importantly, EGFR-CAR NK cells also exhibited improved tumor homing compared with non-transduced NK cells in an in vivo RMS xenograft model. Notably, the combination of EGFR-CAR NK cell therapy with fractionated radiotherapy further enhanced NK cell infiltration into the tumor and reduced tumor growth. Conclusion: This study provides a proof-of-concept for EGFR-CAR NK cells as a promising immunotherapy for RMS, particularly when combined with radiotherapy to overcome barriers of solid tumors. This combinatorial approach may hold potential to improve outcomes for patients with RMS and other EGFR-expressing malignancies

Cascading constraint and subsidiary discretion: Perspectives on police discretion from police-led drug diversion and stop and search in England

This article explores how discretion is managed and exercised across senior, middle, and street levels of policing. It uses qualitative data from two studies in England. The first, a study across three police force areas, involved interviews and focus groups with 221 people who were designers, deliverers, and recipients of police-led drug diversion. The second study used 354 hours of ethnographic observation and 21 interviews to examine stop-and-search practices in one other police force. Rather than a simply expanding scope of discretion at lower levels of the hierarchy, the findings reveal a multi-level process of cascading constraints and subsidiary discretion. At each level, we observe the exercise of occupational professionalism and autonomous judgement, but higher-level constraints shape how discretion is applied in pursuit of organizational professionalism

IoT-enabled Spatiotemporal Resilience Analysis for an Unmanned System of Systems

As research on the Internet of Things (IoT) and unmanned equipment continues to advance, the unmanned system of systems (USS) has been developed unprecedentedly. Much of the existing research on USS focuses on the effects of changes of system resilience with respect to time, but little on spatial changes. However, USS missions might involve physical strikes against unmanned systems. Alternatively, they could involve signal jamming of data transmissions at the data layer. Therefore, it is crucial to account for variations in the performance of the data layer. Time plays a key role in determining the mission performance of the USS, while spatial location affects the transmission performance of the data layer. To examine how time and space issues impact the resilience of the USS, this paper introduces a spatiotemporal resilience assessment framework. This framework evaluates the resilience of USS from both time and space perspectives. Additionally, the paper proposes a spatiotemporal resilience optimization scheme for the entire USS mission process. The scheme enhances spatiotemporal resilience and focuses on optimization during the prevention and recovery phases. Finally, the proposed methods are validated using a case study involving a USS with positive hexagonal formation

Rights and support: a conversation

with Fatima Ahdash, Emily Jackson, Dafni Lima, Daniel Monk, Julie McCandless, Beth Tarleton, Rachel Taylor, and Sarah Trotter Note from the editors: in the conversation that follows, which took place on Friday 18 October 2024, members of the project discuss the three reflection pieces that feature in the rights and support section of the special issue: Daniel Monk's paper, 'Elective home education: rights and their limits', Rachel Taylor's paper 'The limits of parental authority', and Beth Tarleton and Nadine Tilbury's paper 'Substituted parenting: assumptions, stigma and parents with learning disabilities'

The role of apology beliefs for apology tendencies across cultures with varying honor norms

Apologies serve as crucial tools for relationship repair, promoting reconciliation, and demonstrating accountability. However, beliefs about the morality, effectiveness, and responsibility-signaling nature of apologies may vary across cultures, particularly in contexts shaped by honor norms where apologies fit central cultural concerns for morality and strength in ambiguous ways. This study investigates the relation between apology beliefs and cultural honor norms across 14 Mediterranean, East Asian, and Anglo-Western samples (N = 5296). We assessed personal and normative beliefs about apologies and their alignment with apology tendencies (willingness to apologize and past offered apologies) as well as intersubjectively rated honor norms. Results revealed that stronger beliefs in the morality and effectiveness of apologies, as well as perceptions of apologies as admissions of responsibility, consistently predicted greater willingness to apologize across regions and past apologies offered. Against our expectations, honor norms moderated only a few of these relations, with significant interactions suggesting weaker links between apology beliefs and apology tendencies at stronger honor norms. Complementary analyses comparing regional categorizations (Anglo-West, East Asia, and MENA) further supported a picture of relative cultural similarities but also highlighted a wider array of relevant apology beliefs in the MENA region as well as a greater focus on personal morality beliefs in Anglo Western societies and personal effectiveness beliefs in East Asian societies. Our findings underscore the universal significance of apology beliefs in fostering reconciliation while also revealing some cultural variability in how personal beliefs and cultural norms may interact in shaping apology-related behaviors across diverse societies

How to Enhance Sleep for Athletes? A Narrative Review of Sleep Hygiene and Sleep Extension Practices

Sleep is becoming widely accepted as a crucial for athletes, with potential impacts on both performance and recovery, yet despite this, sleep amongst athletes is commonly suboptimal. This review aims firstly to summarise underlying reasons why athletes commonly present with poor sleep with a view to informing subsequent interventions, and secondly, to summarise sleep hygiene and sleep extension practices to potentially offset this, with consideration for the content and delivery approach of such interventions