Changes in the Relationship between the Outcomes of Cohabiting Partnerships and Fertility among Young British Women: Evidence from the 1958 and 1970 Birth Cohort Studies

We investigate the effects of a range of time-varying fertility indicators, including pregnancy, and the presence and characteristics of children, on the outcomes of nonmarital unions for two cohorts of British women. We compare the effect of conceptions and births on the odds that a cohabiting partnership is dissolved or that it is converted to marriage for women born in 1958 and 1970. The analysis uses a multilevel competing risks model to allow for multiple partnerships and conceptions, and to distinguish between two outcomes of cohabiting unions (separation and marriage). We also use a multiprocess model, in which the outcomes of cohabitation are modelled simultaneously with fertility, to allow for the potential joint determination of partnership and childbearing decisions. The analysis is based on partnership and birth histories between the ages of 16 and 29, and social background, in the National Child Development Study and the 1970 British Birth Cohort Study

Induced pluripotent stem cell platforms for disease modelling of skeletal muscle laminopathies

Laminopathies are a clinically and genetically heterogeneous group of 16 disorders caused by mutations in LMNA. This gene codes for lamin A and lamin C, which together with lamin B1 and B2 form the nuclear lamina, a mesh-like structure located underneath the inner nuclear membrane. Laminopathy disorders show striking tissue specificity, with subtypes affecting striated muscle, peripheral nerve, and others causing multisystem disease with accelerated aging. The exact mechanisms underlying the pathology of laminopathies, and the cause of the tissue specific phenotypes are unknown, although several mechanisms have been proposed. Understanding the pathology of these disorders is limited by the rarity of cases, and lack of easily accessible cell types. Induced pluripotent stem cells (iPSCs) can be derived from easily accessible cell types, have unlimited proliferation potential, and can be differentiated into cell types that would otherwise be difficult and invasive to obtain. This PhD project aimed to use iPSCs from patients with skeletal muscle laminopathies to model disease phenotypes in vitro. In this thesis, fibroblasts from a patient with a skeletal muscle laminopathy were reprogrammed into iPSCs. This line, along with three already reprogrammed iPSC lines from skeletal muscle laminopathy patients were differentiated into mesodermal/mesenchymal progenitors, myogenic precursor cells and myotubes. Disease-associated phenotypes were observed in these cells, namely abnormal nuclear shape and mislocalisation of nuclear lamina proteins. Furthermore, work towards developing a therapy based on lamin A/C exon skipping was conducted. These results demonstrate that iPSCs from skeletal muscle laminopathy patients can be used to model disease-associated phenotypes in vitro. This lays the foundation for future therapy testing and disease modelling in skeletal muscle laminopathies using patient specific iPSCs

Finding solutions for complex systems: saving traction energy in rail

Complex optimisation problems, which are concerned with optimising a given aspect of a complex system, such as time or energy, are difficult to solve. Often a range of solutions exist, and the difficulty lies in determining which solutions to implement in which part of the system. Within this work, a novel method is developed that allows the solver to overcome the key challenges for these types of problems, which are: defining the system parts (subsystems); minimising model complexity; quantifying solution effectiveness; and identifying relationships between solutions and subsystems. The method is demonstrated through application to the problem of railway traction energy saving. Subsystems are defined using quantified network and service characteristics. For each subsystem, the trends between six key solutions and the key performance indicators are analysed using multivariate data analysis and visualisation techniques. The relationships between subsystems are then explored at system level. The analysis determines the suitable solutions for each type of railway, providing information for operators about which solutions to target. Based on the results, the implementation of permanent magnet motor technology is considered, illustrating that the method is a suitable tool for informing further studies

The reproductive success of bovine sperm after sex‑sorting: a meta‑analysis

In the three decades since its inception, the sex-sorting technology has progressed significantly. However, field studies report conflicting findings regarding reproductive outcomes. Therefore, we conducted this meta-analysis of all trials published between 1999 and 2021. Non-return rates after 24 or 60 d (NRR 24/60), pregnancy, calving, abortion, and stillbirth rates were compared after AI with sex-sorted vs non-sorted sperm. Additionally, the impact of recent developments in the sex-sorting technology was assessed. Of 860 studies found, 45 studies (72 trials) provided extractable data and were included. Overall, the results of this meta-analysis provided evidence that the NRR 24/60 was diminished by 13%, pregnancy rates were reduced by 23% (25% cows, 21% heifers) and calving rates were reduced by 24% when using sex-sorted sperm. Enhancing the dosage to 4 million sex-sorted sperm/straw (including recent improvements, high vs low dose) as well as using fresh sex-sorted sperm (sorted vs non-sorted) increased pregnancy rate ratios by 7 percentage points. The refinement of the sex-sorting technology after 2015 resulted in a lowered reduction of pregnancy and calving rate of 19% and 23%, respectively. Whereas abortion rates were similar, the stillbirth of male calves was increased by 6.3%

Bovine sperm-oviduct interactions are characterized by specific sperm behaviour, ultrastructure and tubal reactions which are impacted by sex sorting

To date sperm-oviduct interactions have largely been investigated under in vitro conditions. Therefore we set out to characterize the behaviour of bovine spermatozoa within the sperm reservoir under near in vivo conditions and in real-time using a novel live cell imaging technology and a newly established fluorescent sperm binding assay. Sperm structure and tubal reactions after sperm binding were analysed using scanning and transmission electron microscopy and histochemistry. As a model to specify the impact of stress on sperm-oviduct interactions, frozen-thawed conventional and sex-sorted spermatozoa from the same bulls (n = 7) were co-incubated with oviducts obtained from cows immediately after slaughter. Our studies revealed that within the oviductal sperm reservoir agile (bound at a tangential angle of about 30°, actively beating undulating tail), lagging (bound at a lower angle, reduced tail movement), immotile (absence of tail movement) and hyperactivated (whip-like movement of tail) spermatozoa occur, the prevalence of which changes in a time-dependent pattern. After formation of the sperm reservoir, tubal ciliary beat frequency is significantly increased (p = 0.022) and the epithelial cells show increased activity of endoplasmic reticula. After sex sorting, spermatozoa occasionally display abnormal movement patterns characterized by a 360° rotating head and tail. Sperm binding in the oviduct is significantly reduced (p = 0.008) following sexing. Sex-sorted spermatozoa reveal deformations in the head, sharp bends in the tail and a significantly increased prevalence of damaged mitochondria (p < 0.001). Our results imply that the oviductal cells specifically react to the binding of spermatozoa, maintaining sperm survival within the tubal reservoir. The sex-sorting process, which is associated with mechanical, chemical and time stress, impacts sperm binding to the oviduct and mitochondrial integrity affecting sperm motility and function

The Impact of Social Contagion on Non-Suicidal Self-Injury: A Review of the Literature

In this review, we explore social contagion as an understudied risk factor for non-suicidal self-injury (NSSI) among adolescents and young adults, populations with a high prevalence of NSSI. We review empirical studies reporting data on prevalence and risk factors that, through social contagion, may influence the transmission of NSSI. Findings in this literature are consistent with social modeling/learning of NSSI increasing risk of initial engagement in NSSI among individuals with certain individual and/or psychiatric characteristics. Preliminary research suggests iatrogenic effects of social contagion of NSSI through primary prevention are not likely. Thus, social contagion factors may warrant considerable empirical attention. Intervention efforts may be enhanced, and social contagion reduced, by implementation of psychoeducation and awareness about NSSI in schools, colleges, and treatment programs

Chemogenomic Profiling of Antileishmanial Efficacy and Resistance in the Related Kinetoplastid Parasite <i>Trypanosoma brucei</i>

The arsenal of drugs used to treat leishmaniasis, caused by Leishmania spp., is limited and beset by emergent resistance and toxicity. Our understanding of drug mode-of-action and potential routes to resistance is also limited. Forward genetic approaches have revolutionised our understanding of drug mode-of-action in the related kinetoplastid parasite, Trypanosoma brucei. Therefore, we screened our genome-scale T. brucei RNAi library for knockdowns that render cells resistant to the current anti-leishmanial drugs, sodium stibogluconate (antimonial), paromomycin, miltefosine and amphotericin-B. Identification of T. brucei orthologues of the known Leishmania antimonial and miltefosine plasma membrane transporters effectively validated our approach, while a cohort of 42 novel drug efficacy determinants provides new insights and serves as a resource

Library Annual Report 2020/21

Library and Archives Annual Report 2020/2

Modeling Skeletal Muscle Laminopathies Using Human Induced Pluripotent Stem Cells Carrying Pathogenic LMNA Mutations

Laminopathies are a clinically heterogeneous group of disorders caused by mutations in LMNA. The main proteins encoded by LMNA are Lamin A and C, which together with Lamin B1 and B2, form the nuclear lamina: a mesh-like structure located underneath the inner nuclear membrane. Laminopathies show striking tissue specificity, with subtypes affecting striated muscle, peripheral nerve, and adipose tissue, while others cause multisystem disease with accelerated aging. Although several pathogenic mechanisms have been proposed, the exact pathophysiology of laminopathies remains unclear, compounded by the rarity of these disorders and lack of easily accessible cell types to study. To overcome this limitation, we used induced pluripotent stem cells (iPSCs) from patients with skeletal muscle laminopathies such as LMNA-related congenital muscular dystrophy and limb-girdle muscular dystrophy 1B, to model disease phenotypes in vitro. iPSCs can be derived from readily accessible cell types, have unlimited proliferation potential and can be differentiated into cell types that would otherwise be difficult and invasive to obtain. iPSC lines from three skeletal muscle laminopathy patients were differentiated into inducible myogenic cells and myotubes. Disease-associated phenotypes were observed in these cells, including abnormal nuclear shape and mislocalization of nuclear lamina proteins. Nuclear abnormalities were less pronounced in monolayer cultures of terminally differentiated skeletal myotubes than in proliferating myogenic cells. Notably, skeletal myogenic differentiation of LMNA-mutant iPSCs in artificial muscle constructs improved detection of myonuclear abnormalities compared to conventional monolayer cultures across multiple pathogenic genotypes, providing a high-fidelity modeling platform for skeletal muscle laminopathies. Our results lay the foundation for future iPSC-based therapy development and screening platforms for skeletal muscle laminopathies