Anna, the Tale Bearer

Cover title.Originally published in 1807, as number 4 in a series entitled The Magic Lantern (Welch 1153). 12 pages, [1] leave of plates: illustrations; 17 cmhttps://digitalcommons.georgefox.edu/quakerbooks/1035/thumbnail.jp

Justina, or, The Filial Daughter

12 pages, [1] leaf of plates: 1 illustration; 17 cm. Published in the 1800s.https://digitalcommons.georgefox.edu/quakerbooks/1034/thumbnail.jp

Male reproductive aging arises via multifaceted mating-dependent sperm and seminal proteome declines, but is postponable in Drosophila

I.S. and S.W. were supported by a Biotechnology and Biological Sciences Research Council (BBSRC) Fellowship to S.W. (BB/K014544/1) and S.W. additionally by a Dresden Senior Fellowship. B.M.K., P.D.C., and R.F. were supported by the Kennedy Trust and John Fell Funds. R.D. was supported by Marie Curie Actions (Grant 655392). B.R.H. was funded by the EP Abraham Cephalosporin-Oxford Graduate Scholarship with additional support from the BBSRC Doctoral Training Programme. M.F.W. was supported by a NIH Grant R01HD038921. Work in the J.S. Laboratory was supported by NIH Grant R15HD080511.Declining ejaculate performance with male age is taxonomically widespread and has broad fitness consequences. Ejaculate success requires fully functional germline (sperm) and soma (seminal fluid) components. However, some aging theories predict that resources should be preferentially diverted to the germline at the expense of the soma, suggesting differential impacts of aging on sperm and seminal fluid and trade-offs between them or, more broadly, be-tween reproduction and lifespan. While harmful effects of male age on sperm are well known, we do not know how much seminal fluid deteriorates in comparison. Moreover, given the predicted trade-offs, it remains unclear whether systemic lifespan-extending inter-ventions could ameliorate the declining performance of the ejacu-late as a whole. Here, we address these problems using Drosophila melanogaster. We demonstrate that seminal fluid deterioration con-tributes to male reproductive decline via mating-dependent mech-anisms that include posttranslational modifications to seminal proteins and altered seminal proteome composition and transfer. Additionally, we find that sperm production declines chronologically with age, invariant to mating activity such that older multiply mated males become infertile principally via reduced sperm transfer and viability. Our data, therefore, support the idea that both germline and soma components of the ejaculate contribute to male reproduc-tive aging but reveal a mismatch in their aging patterns. Our data do not generally support the idea that the germline is prioritized over soma, at least, within the ejaculate. Moreover, we find that lifespan-extending systemic down-regulation of insulin signaling re-sults in improved late-life ejaculate performance, indicating simul-taneous amelioration of both somatic and reproductive aging.Publisher PDFPeer reviewe

Fevipiprant (QAW039), a slowly dissociating CRTh2 antagonist with the potential for improved clinical efficacy

Here we describe the pharmacologic properties of a series of clinically relevant chemoattractant receptor-homologous molecules expressed on T-helper type 2 (CRTh2) receptor antagonists, including fevipiprant (NVP-QAW039 or QAW039), which is currently in development for the treatment of allergic diseases. [3H]-QAW039 displayed high affinity for the human CRTh2 receptor (1.14 ± 0.44 nM) expressed in Chinese hamster ovary cells, the binding being reversible and competitive with the native agonist prostaglandin D2 (PGD2). The binding kinetics of QAW039 determined directly using [3H]-QAW039 revealed mean kinetic on (kon) and off (koff) values for QAW039 of 4.5 × 107 M-1min-1 and 0.048 minute-1, respectively. Importantly, the koff of QAW039 (half-life = 14.4 minutes) was >7-fold slower than the slowest reference compound tested, AZD-1981. In functional studies, QAW039 behaved as an insurmountable antagonist of PGD2-stimulated [35S]-GTPγS activation, and its effects were not fully reversed by increasing concentrations of PGD2 after an initial 15-minute incubation period. This behavior is consistent with its relatively slow dissociation from the human CRTh2 receptor. In contrast for the other ligands tested this time-dependent effect on maximal stimulation was fully reversed by the 15-minute time point, whereas QAW039's effects persisted for >180 minutes. All CRTh2 antagonists tested inhibited PGD2-stimulated human eosinophil shape change, but importantly QAW039 retained its potency in the whole-blood shape-change assay relative to the isolated shape change assay, potentially reflective of its relatively slower off rate from the CRTh2 receptor. QAW039 was also a potent inhibitor of PGD2-induced cytokine release in human Th2 cells. Slow CRTh2 antagonist dissociation could provide increased receptor coverage in the face of pathologic PGD2 concentrations, which may be clinically relevant

Investigating the role of ASPP2 in post-implantation mouse embryos

My research focuses on the role of ASPP2 (Apoptosis-stimulating of p53 protein 2, encoded by the TP53BP2 gene) during early post-implantation development. ASPP2 has multiple important biological functions, including roles in the control of cell polarity, tight junction formation, cell proliferation, differentiation and apoptosis. To study the molecular basis of ASPP2 function in post-implantation development, I generated a mouse line in which exon 4 of ASPP2 is flanked by LoxP sites. Using genetic crossings, this allowed me to generate various mouse lines that were used to study the function of ASPP2 in the whole embryo and in specific tissues. My results indicate that gastrulation is able to proceed in ASPP2-/- embryos – all 3 germ layers appear to form correctly. However, the embryo becomes progressively more disordered as development proceeds, resulting in embryonic lethality by E9.5. Somites are present at E8.5 and E9.5, showing that mesoderm-derived structures can form. The somites, however, are smaller than their wildtype counterparts. Additionally, instead of the normal structure of a single layer of somitic cells surrounding a central cavity, the somites have a disorganised structure with multiple cell layers and often lack a cavity. Heart formation is also affected in these mutant embryos. By E9.5, there is no heart structure, with the absence of a beating heart. I crossed the ASPP2flox/flox mouse line to a line expressing CRE under the Mesp1 promoter, which controls early cardiac progenitor formation. These mice developed normal hearts at E8.5 and E9.5, implying that the perturbation in cardiac development is a secondary defect, likely caused by disturbances to the surrounding tissues meaning that the cardiac progenitors do not receive the signals they require to continue developing. Thus, my research has indicated that ASPP2 is essential for post-implantation embryonic development. The mesoderm initially forms correctly but as the embryo continues to develop, the mesoderm-derived somites become disrupted, indicating a role for ASPP2 in regulating the epithelial architecture of the somites. Similarly, as seen in the heart, the disorganisation of structures leads to secondary defects later in development, ultimately resulting in embryonic lethality. These results demonstrate the importance of ASPP2 and shed light on some of the functions that it may play in development

Factors influencing the career aspirations and preferred modes of working in recent dental graduates in Wales

INTRODUCTION: In England and Wales, National Health Service (NHS) primary dental care services are now commissioned on a local basis. In planning for the future, it is important that commissioning authorities have a clear understanding of the perspectives of recent dental graduates: vocational dental practitioners (VDPs). OBJECTIVES: This study investigated the career aspirations and preferred modes of working of VDPs in Wales. METHODOLOGY: Data were collected via a postal questionnaire, comprising 37 closed and open questions, mailed to all 59 VDPs in Wales. RESULTS: A total of 53 (90%) VDPs participated, of whom 47 saw their future in general dental practice: 5, 35, and 7 indicating a preference to work in the NHS, mixed (NHS and private), and private sector, respectively. None selected the Community Dental Service as their preferred vocation. More than half of all respondents intended to undertake a postgraduate qualification within the next five years and 22 wished to specialise. Of the 53 VDPs, 44 were concerned that lack of NHS contracts would limit where they could practise, and agreed that family and other social commitments were a significant influence on choice of practice location. Access to high-quality premises and continuing professional development were agreed as important by 41 VDPs. A majority (37) agreed that private dentistry was an attractive alternative to NHS dentistry. Of the respondents, 38 (22 females, 16 males) expected to work part-time at some point in the future and 14 said they would consider a career outside dentistry. Only nine VDPs agreed that they would be happy working in a single-handed practice and even fewer (six) indicated they would be happy working for a corporate body. CONCLUSIONS: Numerous factors impact on the career aspirations of VDPs. These factors have been quantified in this study, and healthcare-commissioning bodies need to be aware of them when planning future dental care provision in Wales

An Investigation into the Structure Activity Relationships Associated with the Systematic Modification of the beta2-Adrenoceptor Agonist Indacaterol

The synthesis of a series of indacaterol analogues in which each of the three structural regions of indacaterol are modified in a systematic manner is described. Evaluation of the affinity of these analogues for the 2-adrenoceptor identified the 3,4-dihydroquinolinone and 5-n-butylindanyl analogues to demonstrate the most similar profiles to indacterol. An -methyl aminoindan analogue was discovered to be 25-fold more potent than indacaterol, and functional studies revealed an atypical 2-adrenoceptor activation profile for this compound consistent with that of a slowly dissociating ‘super agonist’