Cross-Gender Supervision in Prison and the Constitutional Right of Prisoners to Remain Free from Rape

A variety of state, federal, and international laws theoretically prohibit sexual abuse of prisoners by the guards hired by the state to oversee them. Nevertheless, sexual abuse of female prisoners by male prison guards is a rampant phenomenon that the law has thus far failed to remedy. Cross-gender supervision policies exacerbate the problem by placing women in situations in which they have no escape from their attackers. These policies, which are as dangerous for some prisoners as they are humiliating to all prisoners, have generally withstood scrutiny in courts. This note attempts to reframe the arguments challenging crossgender supervision policies and proposes a more narrowly tailored constitutional claim against them. Clearly establishing the causal link between cross-gender supervision policies and custodial sexual abuse could convince courts to enjoin prisons from hiring male guards to oversee female prisoners in contact positions. Such a result would hopefully both stem the tide of sexual abuse in prisons while simultaneously improving conditions of confinement for female prisoners by restricting prisons from adopting these degrading policies

Development of a clinical ready cell therapy product with improved functionality

Mesenchymal stromal cells (MSCs) currently hold great promise in modifying a plethora of diseases. There have been numerous clinical trials performed using cryopreserved MSCs however still little is known about their exact mechanism of action (MOA) and in vivo cell tracking analysis has proven confusing. The known multi-potency of MSCs has gained the attention of clinicians and researchers far and wide which makes MSCs the most utilized cell type in regenerative medicine, yet still there is only one available MSC product (none in USA or Australia) with market authorisation available for therapeutic use. Currently across most jurisdictions the regulatory bodies require a Phase 3 trial with endpoints met to gain market approval, this has yet to be successfully completed, therefore the development of the MSC product including thorough pilot trials must be of upmost importance and racing to market with an undeveloped product may hinder not only the stature of the organisation but the whole sector. This thesis aimed to present a development story for a pilot study of a cryopreserved MSC final product that was clinical trial ready. In most jurisdictions a Phase 2 trial and onwards should show safety and efficacy. To do that it is imperative that product development covers characteristics of the product, qualified or validated tools for assessing product qualities and development strategies to improve the product qualities in line with targeted clinical outcomes i.e., potency. Donor selection is one of the first and potentially most important steps in the development of an allogenic cell therapy product. We assessed four healthy donors of each sex of a relatively matched age, cultured and fully characterized the cells with the intention to provide data which would help us rank our donors. To do this we applied a matrix approach to determine a donor fit for trial based on «em»in vitro«/em» assessment. This included qualification of assays and assessment of cell characteristics and potency as well as cell secretome characteristics and potency. We were able to identify a characteristic of the wider population in which provided a most suitable donor choice, being female. Female MSC (fMSC) and Male MSC (mMSC) showed similar characteristics in terms of growth, phenotype and MSC secretome (MSC-S) molecules however, when we assessed in vitro immune modulation and the correlation to secretion of potent immunoregulators like Indoleamine 2,3 deoxygenise (IDO1), fMSC consistently outperformed their male counterparts. fMSC consistently suppressed peripheral blood mononuclear cell (PBMC) proliferation significantly more than mMSC. The enhanced immunosuppression of fMSCs was attributed to the production of higher concentrations of the anti-inflammatory IL-1RA, PGE-2, IDO1 and prolonged expression of VCAM-1 post activation relative to mMSCs. In contrast, mMSCs produces more inflammatory G-CSF than fMSCs. Moreover, fMSCs, but not mMSCs induced downregulation of the IL-2 receptor, CD25 and sustained expression of the early T cell activation marker, CD69 in PBMCs thus further highlighting the differences in immunomodulation potentials between the sexes. This analysis allowed us to select fMSC as our first port of call in our quest for a clinical ready MSC product. The multipotency of the MSC has been attributed somewhat not only to the cells themselves but to the secreted molecules, some of which are naturally occurring upon proliferation and others in response to the local micro environmental conditions. The characterisation of the MSC secretome via ligand binding assays, mass spectrometry and microparticle analysis revealed the MSC-S contains a myriad of analytes, including cytokines, chemokines, enzymes, growth factors, extracellular matrix (ECM) proteins and factors involved in ECM remodelling, different types of extracellular vesicles including exosomes, microvesicles, apoptotic bodies and others. Specifically, we identified MSC-S was positive for MCP-1, TGF-β/LAP, IL-6, IL-8, VEGF-A, Eotaxin and RANTES, HGF, TNFR1, TIMP-1, SCGF-b1 and GRO-α, ECM molecules fibronectin and collagen 1 (alpha 1,2 and 4) as well as chaperones HSP27, HSP70 and CLU and microvesicles, likely exosomes with a size of ~120 nm. By employing the MSC-S in combination with DMSO as a cytoprotective agent (CPA) we were able to identify the MSC-S containing molecules ≥10 kDa (S10) was as potent as the unpurified MSC-S as determined by the level of IDO1 expression, whereas all other sub-fractions (0-10 kDa, 0-30 kDa, 0-100 kDa, above 30 kDa and above 100 kDa) had significantly lower expression of IDO1 p<0.05. Further analysis revealed a superiority of the MSC-S10 compared to other CPAs showing increased MSC proliferation and viability post thaw while decreasing MSC apoptotic populations and TNF-α production by Th1 cells. This effect was due to an increase in MSC motility and functionality likely attributed to the MSC-S10 containing anti-oxidative HSP27, HSP70, clusterin as well as cytokines and pro proliferative ECM molecule expression. mRNA-SEQ of the MSC under normal and inflammatory conditions over time revealed the MSC cryopreserved in MSC-S10 showed differentially expressed genes (DEGs) relative to MSC alone. This included a downregulation of stress related DNAJB1, DNAJA4, HSPA6, HSPA1B HSPA1A, SOD2 HSPA7 and HSPH1 and an upregulation of anti-apoptotic BIRC5, BIRC3, BBC3 and BCL2A as well as upregulation of cytoskeletal modelling genes like ARC, AURKA and DPP4. Moreover MSC-S upregulated immunomodulatory genes IL4, G-SCF, IDO1, CCL8, IL33, ITGA2, GBP4 and TNFAIP3. In conclusion we had a developed a fully characterized female MSC with a co-active cytoprotective agent using the purified MSC-S and defined a group of target genes to indicate potency. These measures allowed us to form the opinion we had successfully developed a clinical trial ready MSC therapy

Stem Cell-Derived Exosomes as New Horizon for Cell-Free Therapeutic Development: Current Status and Prospects

Exosomes have come a long way since they were first described in 1981 by Trams et al. as small lipid bilayer-enclosed vesicles of endocytic origin. Their ability to alter cell bioactivity combined with their advancing popularity as disease biomarkers and therapeutic delivery systems has compelled major Government institutions and regulatory authorities to invest further in this ever-growing field of research. Being relatively new, exosome research is besieged by challenges including but not limited to inefficient separation methods and preservation techniques, difficulties in characterization, and lack of standardized protocols. However, as excitement and research on exosomes increase, their relevance and capacity to elicit a distinct biological response is reinforced. Therefore, it is pertinent to further explore their potential as cell-free therapeutics. This review focuses on current difficulties and subsequent strategies to refine existing methodologies for efficient clinical translation of exosomes in a streamlined and cost-effective manner. The chapter is briefly divided into subsections, each relevant for sequential therapeutic development such as their classification, isolation, scaling up, storage, characterizations, regulatory requirements, therapeutic developments, and perspectives. Apart from literature search, we have endeavored to bring in our own experience in this field including some recent clinical developments

On the relationship between structure and dynamics in a supercooled liquid

We present the dynamic propensity distribution as an explicit measure of the degree to which the dynamics in a liquid over the time scale of structural relaxation is determined by the initial configuration. We then examine, for a binary mixture of soft discs in two dimensions, the correlation between the spatial distribution of propensity and that of two localmeasures of configuration structure: the local composition and local free volume. While the small particles dominate the high propensity population,we find no strong correlation between either the local composition or the local free volume and the propensity. It is argued that this is a generic failure of purely local structural measures to capture the inherently non-local character of collective behaviour.Comment: Published, see below or http://www.iop.org/EJ/abstract/0953-8984/17/49/001/ Editing comments have been remove

Child Development

Leaflet to accompany Department of Health Asian Mother and Baby campaig

The modern monitor; or, Flyn's speculations [electronic resource].

With a final errata leaf.Essays by various authors, edited by William Flyn, extracted from the Hibernian Chronicle, Cork.Pages 284-292 misnumbered 266-274.A variant has 'Flyn speculations' in title.Variant from DpElectronic reproduction.English Short Title Catalog,Reproduction of original from British Library