The lady vanishes: what's missing from the stem cell debate

Most opponents of somatic cell nuclear transfer and embryonic stem cell technologies base their arguments on the twin assertions that the embryo is either a human being or a potential human being, and that it is wrong to destroy a human being or potential human being in order to produce stem cell lines. Proponents’ justifications of stem cell research are more varied, but not enough to escape the charge of obsession with the status of the embryo. What unites the two warring sides in ‘the stem cell wars’ is that women are equally invisible to both: ‘the lady vanishes’. Yet the only legitimate property in the body is that which women possess in their reproductive tissue and the products of their reproductive labour. By drawing on the accepted characterisation in law of property as a bundle of rights, and on a Hegelian model of contract as mutual recognition, we can lessen the impact of the tendency to regard women and their eggs as merely receptacles and women’s reproductive labour as unimportant

The prevalence of cam hip morphology in a general population sample

Objective Cam hip morphology is associated with femoroacetabular impingement (FAI) syndrome and causes hip osteoarthritis (OA). We aimed to assess the prevalence of cam hip morphology in a sample representative of the general population, using a measure with a predefined diagnostic accuracy. Design Patients aged 16–65, who were admitted to a major trauma centre and received a computed tomography (CT) pelvis were retrospectively screened for eligibility. Subjects with proximal femoral, acetabular or pelvic fractures and those who were deceased were excluded. Eligible subjects were divided into 10 groups based on gender and age. 20 subjects from each group were included. Subjects' index of multiple deprivation (IMD) and ethnicity were recorded. CT imaging was assessed and alpha angles (a measure of cam morphology) measured in the anterosuperior aspect of the femoral head neck junction. An alpha angle greater than 60° was considered to represent cam morphology. This measure and technique has a predefined sensitivity of 80% and specificity of 73% to detect cam morphology associated with FAI syndrome. The prevalence of cam morphology was reported as a proportion of subjects affected with 95% confidence intervals. Results 200 subjects were included. The sample was broadly representative of the UK general population in terms of IMD. 155 subjects (86%) identified as white. Cam morphology was present in 47% (95% CI 42,51) of subjects. Conclusions In this sample, broadly representative of the UK general population 47% of subjects had cam hip morphology; a hip shape associated with FAI syndrome and OA

Achieving diffraction-limited performance on the Berkeley MET5

The Berkeley MET5, funded by EUREKA, is a 0.5-NA EUV projection lithography tool located at the Advanced Light Source at Berkeley National Lab. Wavefront measurements of the MET5 optic have been performed using a custom in-situ lateral shearing interferometer suitable for high-NA interferometry. In this paper, we report on the most recent characterization of the MET5 optic demonstrating an RMS wavefront 0.31 nm, and discuss the specialized mask patterns, gratings, and illumination geometries that were employed to accommodate the many challenges associated with high-NA EUV interferometry

High-resolution Fourier-transform XUV photoabsorption spectroscopy of 14N15N

The first comprehensive high-resolution photoabsorption spectrum of 14N15N has been recorded using the Fourier-transform spectrometer attached to the Desirs beamline at the Soleil synchrotron. Observations are made in the extreme ultraviolet (XUV) and span 100,000-109,000 cm-1 (100-91.7 nm). The observed absorption lines have been assigned to 25 bands and reduced to a set of transition energies, f values, and linewidths. This analysis has verified the predictions of a theoretical model of N2 that simulates its photoabsorption and photodissociation cross section by solution of an isotopomer independent formulation of the coupled-channel Schroedinger equation. The mass dependence of predissociation linewidths and oscillator strengths is clearly evident and many local perturbations of transition energies, strengths, and widths within individual rotational series have been observed.Comment: 14 pages, 8 figures, one data archiv

Interfacial Amino Acids Support Spa47 Oligomerization and Shigella Type Three Secretion System Activation

Like many Gram-negative pathogens, Shigella rely on a type three secretion system (T3SS) for injection of effector proteins directly into eukaryotic host cells to initiate and sustain infection. Protein secretion through the needle-like type three secretion apparatus (T3SA) requires ATP hydrolysis by the T3SS ATPase Spa47, making it a likely target for in vivo regulation of T3SS activity and an attractive target for small molecule therapeutics against shigellosis. Here, we developed a model of an activated Spa47 homo-hexamer, identifying two distinct regions at each protomer interface that we hypothesized to provide intermolecular interactions supportingSpa47 oligomerization and enzymatic activation. Mutational analysis and a series of high-resolution crystal structures confirm the importance of these residues, as many of the engineered mutants are unable to form oligomers and efficiently hydrolyze ATP in vitro. Furthermore, in vivo evaluation of Shigella virulence phenotype uncovered a strong correlation between T3SS effector protein secretion, host cell membrane disruption, and cellular invasion by the tested mutant strains, suggesting that perturbation of the identified interfacial residues/interactions influences Spa47 activity through preventing oligomer formation, which in turn regulates Shigella virulence. The most impactful mutations are observed within the conserved Site 2 interface where the native residues support oligomerization and likely contribute to a complex hydrogen bonding network that organizes the active site and supports catalysis. The critical reliance on these conserved residues suggests that aspects of T3SS regulation may also be conserved, providing promise for the development of a cross-species therapeutic that broadly targetsT3SS ATPase oligomerization and activation

Patient experiences of receiving arthroscopic surgery or personalised hip therapy for femoroacetabular impingement in the context of the UK fashion study:a qualitative study

UK FASHIoN was a multicentre randomised controlled trial comparing hip arthroscopic surgery (HA) with personalised hip therapy (PHT, physiotherapist-led conservative care), for patients with hip pain attributed to femoroacetabular impingement (FAI) syndrome. Our aim was to describe the treatment and trial participation experiences of patients, to contextualise the trial results and offer further information to assist treatment decision-making in FAI. We conducted in-depth semi-structured telephone interviews with a purposive sample of trial participants from each of the trial arms. They were interviewed after they received treatment and completed their first year of trial participation. Thematic analysis and constant comparison analytical approaches were used to identify themes of patient treatment experiences during the trial. Forty trial participants were interviewed in this qualitative study. Their baseline characteristics were similar to those in the main trial sample. On average, their hip-related quality of life (iHOT-33 scores) at 12 months follow-up were lower than average for all trial participants, indicating poorer hip-related quality of life as a consequence of theoretical sampling. Patient experiences occurred in five patient groups: those who felt their symptoms improved with hip arthroscopy, or with personal hip therapy, patients who felt their hip symptoms did not change with PHT but did not want HA, patients who decided to change from PHT to HA and a group who experienced serious complications after HA. Interviewees mostly described a trouble-free, enriching and altruistic trial participation experience, although most participants expected more clinical follow-up at the end of the trial. Both HA and PHT were experienced as beneficial by participants in the trial. Treatment success appeared to depend partly on patients' prior own expectations as well as their outcomes, and future research is needed to explore this further. Findings from this study can be combined with the primary results to inform future FAI patients

Hip morphology in elite golfers : asymmetry between lead and trail hips

Aim: During a golf swing, the lead hip (left hip in a right-handed player) rotates rapidly from external to internal rotation, while the opposite occurs in the trail hip. This study assessed the morphology and pathology of golfers’ hips comparing lead and trail hips. Methods: A cohort of elite golfers were invited to undergo MRI of their hips. Hip morphology was evaluated by measuring acetabular depth (pincer shape=negative measure), femoral neck antetorsion (retrotorsion=negative measure) and α angles (cam morphology defined as α angle >55° anteriorly) around the axis of the femoral neck. Consultant musculoskeletal radiologists determined the presence of intra-articular pathology. Results: 55 players (mean age 28 years, 52 left hip lead) underwent MRI. No player had pincer morphology, 2 (3.6%) had femoral retrotorsion and 9 (16%) had cam morphology. 7 trail hips and 2 lead hips had cam morphology (p=0.026). Lead hip femoral neck antetorsion was 16.7° compared with 13.0° in the trail hip (p<0.001). The α angles around the femoral neck were significantly lower in the lead compared with trail hips (p<0.001), with the greatest difference noted in the anterosuperior portion of the head neck junction; 53° vs 58° (p<0.001) and 43° vs 47° (p<0.001). 37% of trail and 16% of lead hips (p=0.038) had labral tears. Conclusions: Golfers’ lead and trail hips have different morphology. This is the first time side-to-side asymmetry of cam prevalence has been reported. The trail hip exhibited a higher prevalence of labral tears

Personalised hip therapy : development of a non-operative protocol to treat femoroacetabular impingement syndrome in the FASHIoN randomised controlled trial

Introduction Femoroacetabular impingement (FAI) syndrome is increasingly recognised as a cause of hip pain. As part of the design of a randomised controlled trial (RCT) of arthroscopic surgery for FAI syndrome, we developed a protocol for non-operative care and evaluated its feasibility. Methods In phase one, we developed a protocol for non-operative care for FAI in the UK National Health Service (NHS), through a process of systematic review and consensus gathering. In phase two, the protocol was tested in an internal pilot RCT for protocol adherence and adverse events. Results The final protocol, called Personalised Hip Therapy (PHT), consists of four core components led by physiotherapists: detailed patient assessment, education and advice, help with pain relief and an exercise-based programme that is individualised, supervised and progressed over time. PHT is delivered over 12–26 weeks in 6–10 physiotherapist-patient contacts, supplemented by a home exercise programme. In the pilot RCT, 42 patients were recruited and 21 randomised to PHT. Review of treatment case report forms, completed by physiotherapists, showed that 13 patients (62%) received treatment that had closely followed the PHT protocol. 13 patients reported some muscle soreness at 6 weeks, but there were no serious adverse events. Conclusion PHT provides a structure for the non-operative care of FAI and offers guidance to clinicians and researchers in an evolving area with limited evidence. PHT was deliverable within the National Health Service, is safe, and now forms the comparator to arthroscopic surgery in the UK FASHIoN trial (ISRCTN64081839)

Impact of Detergent on the Biophysical Properties and Immune Response of the IpaDB Fusion Protein, a Candidate Subunit Vaccine against Shigella spp.

Shigella spp. are causative agents of bacillary dysentery, a human illness with high global morbidity levels, particularly among elderly and infant populations. Shigella infects via the fecal-oral route, and its virulence is dependent upon a type III secretion system (T3SS). Two components of the exposed needle tip complex of the Shigella T3SS, invasion plasmid antigen D (IpaD) and IpaB, have been identified as broadly protective antigens in the mouse lethal pneumonia model. A recombinant fusion protein (DB fusion) was created by joining the coding sequences of IpaD and IpaB. The DB fusion is coexpressed with IpaB\u27s cognate chaperone, IpgC, for proper recombinant expression. The chaperone can then be removed by using the mild detergents octyl oligooxyethelene (OPOE) or N,N-dimethyldodecylamine N-oxide (LDAO). The DB fusion in OPOE or LDAO was used for biophysical characterization and subsequent construction of an empirical phase diagram (EPD). The EPD showed that the DB fusion in OPOE is most stable at neutral pH below 55°C. In contrast, the DB fusion in LDAO exhibited remarkable thermal plasticity, since this detergent prevents the loss of secondary and tertiary structures after thermal unfolding at 90°C, as well as preventing thermally induced aggregation. Moreover, the DB fusion in LDAO induced higher interleukin-17 secretion and provided a higher protective efficacy in a mouse challenge model than did the DB fusion in OPOE. These data indicate that LDAO might introduce plasticity to the protein, promoting thermal resilience and enhanced protective efficacy, which may be important in its use as a subunit vaccine

The N-terminus of IpaB provides a potential anchor to the Shigella type III secretion system tip complex protein IpaD

The type III secretion system (T3SS) is an essential virulence factor for Shigella flexneri, providing a conduit through which host-altering effectors are injected directly into a host cell to promote uptake. The type III secretion apparatus (T3SA) is comprised of a basal body, external needle, and regulatory tip complex. The nascent needle is a polymer of MxiH capped by a pentamer of invasion plasmid antigen D (IpaD). Exposure to bile salts (e.g. deoxycholate) causes a conformational change in IpaD and promotes recruitment of IpaB to the needle tip. It has been proposed that IpaB senses contact with host cell membranes, recruiting IpaC and inducing full secretion of T3SS effectors. While the steps of T3SA maturation and their external triggers have been identified, details of specific protein interactions and mechanisms have remained difficult to study due to the hydrophobic nature of the IpaB and IpaC translocator proteins. Here we explored the ability for a series of soluble N-terminal IpaB peptides to interact with IpaD. We found that DOC is required for the interaction and that a region of IpaB between residues 11–27 is required for maximum binding, which was confirmed in vivo. Furthermore, intramolecular FRET measurements indicated that movement of the IpaD distal domain away from the protein core accompanied the binding of IpaB11-226. Together these new findings provide important new insight into the interactions and potential mechanisms that define the maturation of the Shigella T3SA needle tip complex and provide a foundation for further studies probing T3SS activation