Mathematical characterization of a microfluidic ultrasound driven transfection device.

The objective of this thesis is to develop a mathematical model characterizing the behavior of a microfluidic sonoporation device in order to understand how standing wave conditions influence molecular delivery to cells and determine whether the model predicts device performance. A prior model based on an ultrasonic separation cell that uses standing waves to separate particles is adapted for translation to the microfluidic device. This study generates data on acoustic pressure profiles across the cell as well as identifying optimal driving frequencies. This model is validated and the equations and methods for developing this model are translated to the microfluidic device. An investigation into the variation of cell layer parameters and driving frequencies is conducted to understand their influence on acoustic pressure profiles and resonant frequencies across the cell. These data are compared to experimental trials which measure cellular uptake of fluorescence when driven through the microfluidic device exposed to different ultrasound frequencies. Results suggest that the 6 MHz driving frequency generates the largest pressure profile across the cell but does not correlate with high molecular delivery efficiency during experimental trials. Additional conclusions regarding the acoustic pressure profile dependency on density, thickness, and speed of sound within the layers show a significant effect for specific frequencies. The large variation in results for differing material and geometric parameters shows the need for further refinement of these parameters for the laboratory device. Once additional experimental trials are conducted, more iterations of the model are tested, and cell parameters are more precisely determined, the translated model can be used for extensive characterization of acoustic pressure profiles across the cell for future design iterations of the device

Therapeutic Implications of GIPC1 Silencing in Cancer

GIPC1 is a cytoplasmic scaffold protein that interacts with numerous receptor signaling complexes, and emerging evidence suggests that it plays a role in tumorigenesis. GIPC1 is highly expressed in a number of human malignancies, including breast, ovarian, gastric, and pancreatic cancers. Suppression of GIPC1 in human pancreatic cancer cells inhibits in vivo tumor growth in immunodeficient mice. To better understand GIPC1 function, we suppressed its expression in human breast and colorectal cancer cell lines and human mammary epithelial cells (HMECs) and assayed both gene expression and cellular phenotype. Suppression of GIPC1 promotes apoptosis in MCF-7, MDA-MD231, SKBR-3, SW480, and SW620 cells and impairs anchorage-independent colony formation of HMECs. These observations indicate GIPC1 plays an essential role in oncogenic transformation, and its expression is necessary for the survival of human breast and colorectal cancer cells. Additionally, a GIPC1 knock-down gene signature was used to interrogate publically available breast and ovarian cancer microarray datasets. This GIPC1 signature statistically correlates with a number of breast and ovarian cancer phenotypes and clinical outcomes, including patient survival. Taken together, these data indicate that GIPC1 inhibition may represent a new target for therapeutic development for the treatment of human cancers

Quality of life of Australian chronically-ill adults: patient and practice characteristics matter

BackgroundTo study health-related quality of life (HRQOL) in a large sample of Australian chronically-ill patients and investigate the impact of characteristics of patients and their general practices on their HRQOL and to assess the construct validity of SF-12 in Australia.MethodsCross sectional study with 96 general practices and 7606 chronically-ill patients aged 18 years or more using standard SF-12 version 2. Factor analysis was used to confirm the hypothesized component structure of the SF-12 items. SF-12 physical component score (PCS-12) and mental component score (MCS-12) were derived using the standard US algorithm. Multilevel regression analysis (patients at level 1 and practices at level 2) was applied to relate PCS-12 and MCS-12 to patient and practice characteristics.ResultsThere were significant associations between lower PCS-12 or MCS-12 score and poorer general health (10.8 (regression coefficient) lower for PCS-12 and 7.3 lower for MCS-12), low socio-economic status (5.1 lower PCS-12 and 2.9 lower MCS-12 for unemployed, 0.8 lower PCS-12 and 1.7 lower MCS-12 for non-owner-occupiers, 1.0 lower PCS-12 for less well-educated) and having two or more chronic conditions (up to 2.7 lower PCS-12 and up to 1.5 lower MCS-12 than those having a single disease). Younger age was associated with lower MCS-12 (2.2 and 6.0 lower than middle age and older age respectively) but higher PCS-12 (4.7 and 7.6 higher than middle age and older age respectively). Satisfaction with quality of care (regression coefficient = 1.2) and patients who were married or cohabiting (regression coefficient = 0.6) was positively associated with MCS-12. Patients born in non-English-speaking countries were more likely to have a lower MCS-12 (1.5 lower) than those born in Australia. Employment had a stronger association with the quality of life of males than that of females. Those attending smaller practices had lower PCS-12 (1.0 lower) and MCS-12 (0.6 lower) than those attending larger practices. At the patient level (level 1) 42% and 21% of the variance respectively for PCS-12 and MCS-12 were explained by the patients and practice characteristics. At the practice level (level 2), 73% and 49% of the variance respectively for PCS-12 and MCS-12 were explained by patients and practice characteristics.ConclusionThe strong association between patient characteristics such as socio-economic status, age, and ethnicity and SF-12 physical and mental component summary scores underlines the importance of considering these factors in the management of chronically-ill patients in general practice. The SF-12 appears to be a valid measure for assessing HRQOL of Australian chronically-ill patients.Upali W. Jayasinghe, Judith Proudfoot, Christopher A. Barton, Cheryl Amoroso, Chris Holton, Gawaine Powell Davies, Justin Beilby and Mark F. Harri

A transcriptomic analysis of Echinococcus granulosus larval stages:implications for parasite biology and host adaptation

The cestode Echinococcus granulosus--the agent of cystic echinococcosis, a zoonosis affecting humans and domestic animals worldwide--is an excellent model for the study of host-parasite cross-talk that interfaces with two mammalian hosts. To develop the molecular analysis of these interactions, we carried out an EST survey of E. granulosus larval stages. We report the salient features of this study with a focus on genes reflecting physiological adaptations of different parasite stages.We generated ~10,000 ESTs from two sets of full-length enriched libraries (derived from oligo-capped and trans-spliced cDNAs) prepared with three parasite materials: hydatid cyst wall, larval worms (protoscoleces), and pepsin/H(+)-activated protoscoleces. The ESTs were clustered into 2700 distinct gene products. In the context of the biology of E. granulosus, our analyses reveal: (i) a diverse group of abundant long non-protein coding transcripts showing homology to a middle repetitive element (EgBRep) that could either be active molecular species or represent precursors of small RNAs (like piRNAs); (ii) an up-regulation of fermentative pathways in the tissue of the cyst wall; (iii) highly expressed thiol- and selenol-dependent antioxidant enzyme targets of thioredoxin glutathione reductase, the functional hub of redox metabolism in parasitic flatworms; (iv) candidate apomucins for the external layer of the tissue-dwelling hydatid cyst, a mucin-rich structure that is critical for survival in the intermediate host; (v) a set of tetraspanins, a protein family that appears to have expanded in the cestode lineage; and (vi) a set of platyhelminth-specific gene products that may offer targets for novel pan-platyhelminth drug development.This survey has greatly increased the quality and the quantity of the molecular information on E. granulosus and constitutes a valuable resource for gene prediction on the parasite genome and for further genomic and proteomic analyses focused on cestodes and platyhelminths

Re-evaluating syndicalist opposition to the First World War

It has been argued that support for the First World War by the important French syndicalist organisation, the Confédération Générale du Travail (CGT) has tended to obscure the fact that other national syndicalist organisations remained faithful to their professed workers’ internationalism: on this basis syndicalists beyond France, more than any other ideological persuasion within the organised trade union movement in immediate pre-war and wartime Europe, can be seen to have constituted an authentic movement of opposition to the war in their refusal to subordinate class interests to those of the state, to endorse policies of ‘defencism’ of the ‘national interest’ and to abandon the rhetoric of class conflict. This article, which attempts to contribute to a much neglected comparative historiography of the international syndicalist movement, re-evaluates the syndicalist response across a broad geographical field of canvas (embracing France, Italy, Spain, Ireland, Britain and America) to reveal a rather more nuanced, ambiguous and uneven picture. While it highlights the distinctive nature of the syndicalist response compared with other labour movement trends, it also explores the important strategic and tactical limitations involved, including the dilemma of attempting to translate formal syndicalist ideological commitments against the war into practical measures of intervention, and the consequences of the syndicalists’ subordination of the political question of the war to the industrial struggle

Discovery and functional prioritization of Parkinson's disease candidate genes from large-scale whole exome sequencing.

BACKGROUND: Whole-exome sequencing (WES) has been successful in identifying genes that cause familial Parkinson's disease (PD). However, until now this approach has not been deployed to study large cohorts of unrelated participants. To discover rare PD susceptibility variants, we performed WES in 1148 unrelated cases and 503 control participants. Candidate genes were subsequently validated for functions relevant to PD based on parallel RNA-interference (RNAi) screens in human cell culture and Drosophila and C. elegans models. RESULTS: Assuming autosomal recessive inheritance, we identify 27 genes that have homozygous or compound heterozygous loss-of-function variants in PD cases. Definitive replication and confirmation of these findings were hindered by potential heterogeneity and by the rarity of the implicated alleles. We therefore looked for potential genetic interactions with established PD mechanisms. Following RNAi-mediated knockdown, 15 of the genes modulated mitochondrial dynamics in human neuronal cultures and four candidates enhanced α-synuclein-induced neurodegeneration in Drosophila. Based on complementary analyses in independent human datasets, five functionally validated genes-GPATCH2L, UHRF1BP1L, PTPRH, ARSB, and VPS13C-also showed evidence consistent with genetic replication. CONCLUSIONS: By integrating human genetic and functional evidence, we identify several PD susceptibility gene candidates for further investigation. Our approach highlights a powerful experimental strategy with broad applicability for future studies of disorders with complex genetic etiologies

Facebook Powered Measurement and Evaluation for Iron Folic Acid Health Intervention in India.

As the media landscape changes and billions of people around the world turn to Facebook, Instagram, WhatsApp, and other social media platforms for information and social interactions, the need to develop effective methods of leveraging social media for social behavior change communication (SBCC) becomes increasingly important. Yet, in order for the public health sector to embrace social media for SBCC, we must have methods for measuring the impact of social media-based SBCC. In this letter, we share a new approach for measurement and evaluation of social media-based SBCC campaigns. The approach was developed as part of an iron-folic acid health intervention targeting young women in two states in northern India; Uttar Pradesh and Maydar Pradesh

The Economic Impact of Closed-Incision Negative-Pressure Therapy in High-Risk Abdominal Incisions: A Cost-Utility Analysis

Complex abdominal wall reconstruction is beset by postoperative complications. A recent meta-analysis comparing the use of closed-incision negative-pressure therapy to standard dressings found a statistically significant reduction in surgical-site infection. The use of closed-incision negative-pressure therapy is gaining acceptance in this population; however, the economic impact of this innovative dressing remains unknown. In this study, a cost-utility analysis was performed assessing closed-incision negative-pressure therapy and standard dressings following closure of abdominal incisions in high-risk patients. Cost-utility methodology involved reviewing literature related to closed-incision negative-pressure therapy in abdominal wall surgery, obtaining utility estimates to calculate quality-adjusted life-year scores for successful surgery and surgery complicated by surgical-site infection, summing costs using Medicare Current Procedural Terminology codes, and creating a decision tree illuminating the most cost-effective dressing strategy. One-way sensitivity analysis was performed to assess the robustness of the results. The aforementioned meta-analysis comparing closed-incision negative-pressure therapy to standard dressings included a subset of five studies assessing abdominal wall surgery in 829 patients (260 closed-incision negative-pressure therapy and 569 standard dressings). Decision tree analysis revealed an estimated savings of $1546.52 and a gain of 0.0024 quality-adjusted life-year with closed-incision negative-pressure therapy compared with standard dressings; therefore, closed-incision negative-pressure therapy is a dominant treatment strategy. One-way sensitivity analysis revealed that closed-incision negative-pressure therapy is a cost-effective option when the surgical-site infection rate is greater than 16.39 percent. The use of closed-incision negative-pressure therapy is cost-saving following closure of abdominal incisions in high-risk patients