Characterization and Comparison of Mesoporous Silica Particles for Optimized Drug Delivery

In this study we have investigated the suitability of a number of different mesoporous silica nanoparticle structures for carrying a drug cargo. We have fully characterized the nanoparticles in terms of their physical parameters; size, surface area, internal pore size and structure. These data are all required if we are to make an informed judgement on the suitability of the structure for drug delivery in vivo. With these parameters in mind, we investigated the loading/unloading profile of a model therapeutic into the pore structure of the nanoparticles. We demonstrate that the release can be controlled by capping the pores on the nanoparticles to achieve temporal control of the unloading. We have also examined the rate and mechanism of the degradation of the nanoparticles over an extended period of time. The eventual dissolution of the nanoparticles after cargo release is a desirable property for a drug delivery system

Vice-Chancellor's Gender Equality Fund Final Report 2021: Equity, Policy and Practice: Disruptions to Candidature and Barriers to Career Progression for Women HDR Candidates

Whilst prior research has established barriers to career progression for women academics, the experiences of women HDR candidates and the barriers to candidature progression, including movement to on-going, academic labour, or careers outside of academia, has not received the same level of attention. This project therefore aims to generate a better understanding of equity considerations for research disruption, with particular reference to the COVID-19 pandemic, for women HDR candidates. There are two key research questions for this project: 1. What are the barriers to HDR progression for WSU women candidates? 2. How might WSU support the progression of women HDR candidates through targeted strategies? This report provides recommendations for best practice for supporting the progression of women HDR candidates at Western

Vice-Chancellor's Gender Equality Fund Final Report 2019: Redressing the Promotion Gap: Practices and Processes to Minimise Gender Disparities in Academic Advancement

Like many universities in Australia and internationally, women at Western Sydney University (WSU) remain under-represented in senior academic positions. In addition, there is a persistent gender pay gap for female academic staff across the institution. Despite the robust literature, researchers and higher education institutions have struggled to understand how vertical gender segregation might be alleviated in academia, and to establish effective gender equity programs which target gender differences in promotion. In addition, little research has evaluated the impact of existing programs beyond the individual level and in comparison to other institutional initiatives. The degree to which gender initiatives are effective in making change is one of the most important and challenging questions in striving for gender equity in contemporary universities, yet this has been inadequately addressed by researchers. There are two key research questions for this project: how does WSU’s promotion policy and process compare with other Australian institutions, and; how might WSU alter current policy and practice to reduce the gender promotion gap? Data was collected through interviews with women academics who had progressed to Professor or Associate Professor whilst at Western Sydney, and both internal and external members of the Western Sydney University Academic Promotions Committee. The research also included an assessment of the WSU promotions policy and relevant promotions and gender equality process documents, and a comparison was carried out between WSU and two other institutions. We find that women are at a disadvantage in achieving measures of excellence in academic competitions for promotion. What is more, gender bias also works around these measures, so that even when women do successfully compete in terms of the metrics, they are blocked by institutional gatekeepers or marginalized and stigmatized for attempting to play a game for which they are seen to be corporeally mismatched. These processes were recognized by the women who bid for promotion but also by several of the promotions committee members. Although there is some useful policy and processes in place in our institutions in relation to promotion, gender bias continues to work through cultural practices. There is also evidence of a reticence to see the metrics of excellence, that serve academic capitalism very well, as anything but neutral or to see gender inequities as systemic. In order to redress the promotion gap, we therefore need to challenge these perceptions and look to cultural and educative solutions. This project provides recommendations for increasing women’s promotion rates, which will also assist in reducing the gender pay gap

Sequence and functional characterization of hypoxia inducible factors, HIF1α, HIF2αa, and HIF3α, from the estuarine fish, Fundulus heteroclitus

Author Posting. © The Author(s), 2016. This is the author's version of the work. It is posted here under a nonexclusive, irrevocable, paid-up, worldwide license granted to WHOI. It is made available for personal use, not for redistribution. The definitive version was published in American Journal of Physiology-Regulatory Integrative and Comparative Physiology, 312 (2017): R412-R425, doi:10.1152/ajpregu.00402.2016.The hypoxia inducible factor (HIF) family of transcription factors plays central roles in the development, physiology, pathology, and environmental adaptation of animals. Because many aquatic habitats are characterized by episodes of low dissolved oxygen, fish represent ideal models to study the roles of HIF in the response to aquatic hypoxia. The estuarine fish Fundulus heteroclitus occurs in habitats prone to hypoxia, it responds to low oxygen via behavioral, physiological, and molecular changes, and one member of the HIF family, HIF2α, has been previously described. Herein, cDNA sequencing, phylogenetic analyses, and genomic approaches were used to determine other members of the HIFα family from F. heteroclitus and their relationships to HIFα subunits from other vertebrates. In vitro and cellular approaches demonstrated that full-length forms of HIF1α, 2α, and 3α independently formed complexes with the β subunit (ARNT) to bind to hypoxia response elements and activate reporter gene expression. Quantitative PCR showed that HIFα mRNA abundance varied among organs of normoxic fish in an isoform-specific fashion. Analysis of the F. heteroclitus genome revealed a locus encoding a second HIF2α, HIF2αb, a predicted protein lacking oxygen sensing and transactivation domains. Finally, sequence analyses demonstrated polymorphism in the coding sequence of each F. heteroclitus HIFα subunit, suggesting that genetic variation in these transcription factors may play a role in the variation in hypoxia responses among individuals or populations.This research was supported in part by the National Science Foundation (IBN-0236494 and DEB-1120263) and by National Institute of Environmental Health Sciences (NIEHS) grant P42ES007381 (Superfund Basic Research Program at Boston University). Data interpretation was aided by reference to a preliminary draft of the F. heteroclitus genome sequence, which was supported by funding from the National Science Foundation (collaborative research grants DEB-1120512, DEB-1265282, DEB-1120013, DEB-1120263, DEB-1120333, DEB-1120398)

Plasmonic Nanobubbles Rapidly Detect and Destroy Drug-Resistant Tumors

The resistance of residual cancer cells after oncological resection to adjuvant chemoradiotherapies results in both high recurrence rates and high non-specific tissue toxicity, thus preventing the successful treatment of such cancers as head and neck squamous cell carcinoma (HNSCC). The patients' survival rate and quality of life therefore depend upon the efficacy, selectivity and low non-specific toxicity of the adjuvant treatment. We report a novel, theranostic in vivo technology that unites both the acoustic diagnostics and guided intracellular delivery of anti-tumor drug (liposome-encapsulated doxorubicin, Doxil) in one rapid process, namely a pulsed laser-activated plasmonic nanobubble (PNB). HNSCC-bearing mice were treated with gold nanoparticle conjugates, Doxil, and single near-infrared laser pulses of low energy. Tumor-specific clusters of gold nanoparticles (solid gold spheres) converted the optical pulses into localized PNBs. The acoustic signals of the PNB detected the tumor with high specificity and sensitivity. The mechanical impact of the PNB, co-localized with Doxil liposomes, selectively ejected the drug into the cytoplasm of cancer cells. Cancer cell-specific generation of PNBs and their intracellular co-localization with Doxil improved the in vivo therapeutic efficacy from 5-7% for administration of only Doxil or PNBs alone to 90% thus demonstrating the synergistic therapeutic effect of the PNB-based intracellular drug release. This mechanism also reduced the non-specific toxicity of Doxil below a detectable level and the treatment time to less than one minute. Thus PNBs combine highly sensitive diagnosis, overcome drug resistance and minimize non-specific toxicity in a single rapid theranostic procedure for intra-operative treatment

MicroRNAs 1, 133, and 206: Critical factors of skeletal and cardiac muscle development, function, and disease

microRNAs (miRNAs) are a class of highly conserved small non-coding RNAs that negatively regulate gene expression post-transcriptionally. miRNAs are known to mediate myriad cell processes, including proliferation, differentiation, and apoptosis. With more than 600 miRNAs identified in humans, it is generally believed that many miRNAs function through simultaneously inhibiting multiple regulatory mRNA targets, suggesting that miRNAs participate in regulating the expression of many, if not all, genes. While many miRNAs are expressed ubiquitously, some are expressed in a tissue specific manner. The muscle specific miR-1, miR-133 and miR-206 are perhaps the most studied and best characterized miRNAs to date. Many studies demonstrate that these miRNAs are necessary for proper skeletal and cardiac muscle development and function, and have a profound influence on multiple myopathies, such as hypertrophy, dystrophy, and conduction defects

Towards practice-based studies of HRM: an actor-network and communities of practice informed approach

HRM may have become co-terminus with the new managerialism in the rhetorical orthodoxies of the HRM textbooks and other platforms for its professional claims. However, we have detailed case-study data showing that HR practices can be much more complicated, nuanced and indeed resistive toward management within organizational settings. Our study is based on ethnographic research, informed by actor-network theory and community of practice theory conducted by one of the authors over an 18-month period. Using actor-network theory in a descriptive and critical way, we analyse practices of managerial resistance, enrolment and counter-enrolment through which an unofficial network of managers used a formal HRM practice to successfully counteract the official strategy of the firm, which was to close parts of a production site. As a consequence, this network of middle managers effectively changed top management strategy and did so through official HRM practices, coupled with other actor-network building processes, arguably for the ultimate benefit of the organization, though against the initial views of the top management. The research reported here, may be characterized as a situated study of HRM-in-practice and we draw conclusions which problematize the concept of HRM in contemporary management literature

The Ubiquitin Ligase ASB4 Promotes Trophoblast Differentiation through the Degradation of ID2

Vascularization of the placenta is a critical developmental process that ensures fetal viability. Although the vascular health of the placenta affects both maternal and fetal well being, relatively little is known about the early stages of placental vascular development. The ubiquitin ligase Ankyrin repeat, SOCS box-containing 4 (ASB4) promotes embryonic stem cell differentiation to vascular lineages and is highly expressed early in placental development. The transcriptional regulator Inhibitor of DNA binding 2 (ID2) negatively regulates vascular differentiation during development and is a target of many ubiquitin ligases. Due to their overlapping spatiotemporal expression pattern in the placenta and contrasting effects on vascular differentiation, we investigated whether ASB4 regulates ID2 through its ligase activity in the placenta and whether this activity mediates vascular differentiation. In mouse placentas, ASB4 expression is restricted to a subset of cells that express both stem cell and endothelial markers. Placentas that lack Asb4 display immature vascular patterning and retain expression of placental progenitor markers, including ID2 expression. Using JAR placental cells, we determined that ASB4 ubiquitinates and represses ID2 expression in a proteasome-dependent fashion. Expression of ASB4 in JAR cells and primary isolated trophoblast stem cells promotes the expression of differentiation markers. In functional endothelial co-culture assays, JAR cells ectopically expressing ASB4 increased endothelial cell turnover and stabilized endothelial tube formation, both of which are hallmarks of vascular differentiation within the placenta. Co-transfection of a degradation-resistant Id2 mutant with Asb4 inhibits both differentiation and functional responses. Lastly, deletion of Asb4 in mice induces a pathology that phenocopies human pre-eclampsia, including hypertension and proteinuria in late-stage pregnant females. These results indicate that ASB4 mediates vascular differentiation in the placenta via its degradation of ID2

Analysis of Poly(ADP-Ribose) Polymerases in Arabidopsis Telomere Biology

Maintaining the length of the telomere tract at chromosome ends is a complex process vital to normal cell division. Telomere length is controlled through the action of telomerase as well as a cadre of telomere-associated proteins that facilitate replication of the chromosome end and protect it from eliciting a DNA damage response. In vertebrates, multiple poly(ADP-ribose) polymerases (PARPs) have been implicated in the regulation of telomere length, telomerase activity and chromosome end protection. Here we investigate the role of PARPs in plant telomere biology. We analyzed Arabidopsis thaliana mutants null for PARP1 and PARP2 as well as plants treated with the PARP competitive inhibitor 3-AB. Plants deficient in PARP were hypersensitive to genotoxic stress, and expression of PARP1 and PARP2 mRNA was elevated in response to MMS or zeocin treatment or by the loss of telomerase. Additionally, PARP1 mRNA was induced in parp2 mutants, and conversely, PARP2 mRNA was induced in parp1 mutants. PARP3 mRNA, by contrast, was elevated in both parp1 and parp2 mutants, but not in seedlings treated with 3-AB or zeocin. PARP mutants and 3-AB treated plants displayed robust telomerase activity, no significant changes in telomere length, and no end-to-end chromosome fusions. Although there remains a possibility that PARPs play a role in Arabidopsis telomere biology, these findings argue that the contribution is a minor one

The employee as 'Dish of the Day’:human resource management and the ethics of consumption

This article examines the ethical implications of the growing integration of consumption into the heart of the employment relationship. Human resource management (HRM) practices increasingly draw upon the values and practices of consumption, constructing employees as the ‘consumers’ of ‘cafeteria-style’ benefits and development opportunities. However, at the same time employees are expected to market themselves as items to be consumed on a corporate menu. In relation to this simultaneous position of consumer/consumed, the employee is expected to actively engage in the commodification of themselves, performing an appropriate organizational identity as a necessary part of being a successful employee. This article argues that the relationship between HRM and the simultaneously consuming/consumed employee affects the conditions of possibility for ethical relations within organizational life. It is argued that the underlying ‘ethos’ for the integration of consumption values into HRM practices encourages a self-reflecting, self-absorbed subject, drawing upon a narrow view of individualised autonomy and choice. Referring to Levinas’ perspective that the primary ethical relation is that of responsibility and openness to the Other, it is concluded that these HRM practices affect the possibility for ethical being