Medicine, Dentistry & Health Sciences Collected Works - Research Publications
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ItemThe McCoy Society’s 1936 expedition to Lady Julia Percy Island, Specimens in the Tiegs Zoology Museum(Cultural Collections Unit, University of Melbourne Library, 2017)
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ItemSkulduggery in the museum, Remnants of Piltdown Man in the Harry Brookes Allen Museum of Anatomy and Pathology(Cultural Collections Unit, University of Melbourne Library, 2019)
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Item'Not man, but man-like’ Early 20th-century anthropological plaster casts in the Harry Brookes Allen Museum of Anatomy and Pathology(Cultural Collections Unit, University of Melbourne Library, 2019)A description of early 20th-century plaster casts of skulls and bones of primates and prehistoric humans (hominins) within The Harry Brookes Allen Museum of Anatomy and Pathology collections.
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Itemc-Jun N-terminal Kinase Phosphorylation of Stathmin Confers Protection against Cellular Stress(AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 2010-09-10)The cell stress response encompasses the range of intracellular events required for adaptation to stimuli detrimental to cell survival. Although the c-Jun N-terminal kinase (JNK) is a stress-activated kinase that can promote either cell survival or death in response to detrimental stimuli, the JNK-regulated mechanisms involved in survival are not fully characterized. Here we show that in response to hyperosmotic stress, JNK phosphorylates a key cytoplasmic microtubule regulatory protein, stathmin (STMN), on conserved Ser-25 and Ser-38 residues. In in vitro biochemical studies, we identified STMN Ser-38 as the critical residue required for efficient phosphorylation by JNK and identified a novel kinase interaction domain in STMN required for recognition by JNK. We revealed that JNK was required for microtubule stabilization in response to hyperosmotic stress. Importantly, we also demonstrated a novel cytoprotective function for STMN, as the knockdown of STMN levels by siRNA was sufficient to augment viability in response to hyperosmotic stress. Our findings show that JNK targeting of STMN represents a novel stress-activated cytoprotective mechanism involving microtubule network changes.
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ItemGenome analysis and CRISPR typing of Salmonella enterica serovar Virchow(BMC, 2014-05-21)BACKGROUND: Salmonella enterica subsp. enterica serovar Virchow has been recognized as a significant health burden in Asia, Australia and Europe. In addition to its global distribution, S. Virchow is clinically significant due to the frequency at which it causes invasive infections and its association with outbreaks arising from food-borne transmission. Here, we examine the genome of an invasive isolate of S. Virchow SVQ1 (phage type 8) from an outbreak in southeast Queensland, Australia. In addition to identifying new potential genotyping targets that could be used for discriminating between S. Virchow strains in outbreak scenarios, we also aimed to carry out a comprehensive comparative analysis of the S. Virchow genomes. RESULTS: Genome comparisons between S. Virchow SVQ1 and S. Virchow SL491, a previously published strain, identified a high degree of genomic similarity between the two strains with fewer than 200 single nucleotide differences. Clustered Regularly Interspaced Palindromic Repeats (CRISPR) regions were identified as a highly variable region that could be used to discriminate between S. Virchow isolates. We amplified and sequenced the CRISPR regions of fifteen S. Virchow isolates collected from seven different outbreaks across Australia. We observed three allelic types of the CRISPR region from these isolates based on the presence/absence of the spacers and were able to discriminate S. Virchow phage type 8 isolates originating from different outbreaks. A comparison with 27 published Salmonella genomes found that the S. Virchow SVQ1 genome encodes 11 previously described Salmonella Pathogenicity Islands (SPI), as well as additional genomic islands including a remnant integrative conjugative element that is distinct from SPI-7. In addition, the S. Virchow genome possesses a novel prophage that encodes the Type III secretion system effector protein SopE, a key Salmonella virulence factor. The prophage shares very little similarity to the SopE prophages found in other Salmonella serovars suggesting an independent acquisition of sopE. CONCLUSIONS: The availability of this genome will serve as a genome template and facilitate further studies on understanding the virulence and global distribution of the S. Virchow serovar, as well as the development of genotyping methods for outbreak investigations.
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ItemIL-15 Preconditioning Augments CAR T Cell Responses to Checkpoint Blockade for Improved Treatment of Solid Tumors(CELL PRESS, 2020-11-04)Chimeric antigen receptor (CAR) T cell therapy has been highly successful in hematological malignancies leading to their US Food and Drug Administration (FDA) approval. However, the efficacy of CAR T cells in solid tumors is limited by tumor-induced immunosuppression, leading to the development of combination approaches, such as adjuvant programmed cell death 1 (PD-1) blockade. Current FDA-approved methods for generating CAR T cells utilize either anti-CD3 and interleukin (IL)-2 or anti-CD3/CD28 beads, which can generate a T cell product with an effector/exhausted phenotype. Whereas different cytokine preconditioning milieu, such as IL-7/IL-15, have been shown to promote T cell engraftment, the impact of this approach on CAR T cell responses to adjuvant immune-checkpoint blockade has not been assessed. In the current study, we reveal that the preconditioning of CAR T cells with IL-7/IL-15 increased CAR T cell responses to anti-PD-1 adjuvant therapy. This was associated with the emergence of an intratumoral CD8+CD62L+TCF7+IRF4- population that was highly responsive to anti-PD-1 therapy and mediated the vast majority of transcriptional and epigenetic changes in vivo following PD-1 blockade. Our data indicate that preservation of CAR T cells in a TCF7+ phenotype is crucial for their responsiveness to adjuvant immunotherapy approaches and should be a key consideration when designing clinical protocols.
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ItemCharacterization of the ATP4 ion pump in Toxoplasma gondii(AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 2019-04-05)The Plasmodium falciparum ATPase PfATP4 is the target of a diverse range of antimalarial compounds, including the clinical drug candidate cipargamin. PfATP4 was originally annotated as a Ca2+ transporter, but recent evidence suggests that it is a Na+ efflux pump, extruding Na+ in exchange for H+ Here we demonstrate that ATP4 proteins belong to a clade of P-type ATPases that are restricted to apicomplexans and their closest relatives. We employed a variety of genetic and physiological approaches to investigate the ATP4 protein of the apicomplexan Toxoplasma gondii, TgATP4. We show that TgATP4 is a plasma membrane protein. Knockdown of TgATP4 had no effect on resting pH or Ca2+ but rendered parasites unable to regulate their cytosolic Na+ concentration ([Na+]cyt). PfATP4 inhibitors caused an increase in [Na+]cyt and a cytosolic alkalinization in WT but not TgATP4 knockdown parasites. Parasites in which TgATP4 was knocked down or disrupted exhibited a growth defect, attributable to reduced viability of extracellular parasites. Parasites in which TgATP4 had been disrupted showed reduced virulence in mice. These results provide evidence for ATP4 proteins playing a key conserved role in Na+ regulation in apicomplexan parasites.
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ItemA multilevel study of neighborhood disadvantage, individual socioeconomic position, and body mass index: Exploring cross-level interaction effects(ELSEVIER, 2019-06)This study examined associations between neighborhood disadvantage and body mass index (BMI), and tested whether this differed by level of individual socioeconomic position (SEP). Data were from 9953 residents living in 200 neighborhoods in Brisbane, Australia in 2007. Multilevel linear regression analyses were undertaken by gender to determine associations between neighborhood disadvantage, individual SEP (education, occupation and household income) and BMI (from self-reported height and weight); with cross-level interactions testing whether the relationship between neighborhood disadvantage and BMI differed by level of individual SEP. Both men (Quintile 4, where Quintile 5 is the most disadvantaged β = 0.66 95%CI 0.20, 1.12) and women (Quintile 5 β = 1.32 95%CI 0.76, 1.87) from more disadvantaged neighborhoods had a higher BMI. BMI was significantly higher for those with lower educational attainment (men β = 0.71 95%CI 0.36, 1.07 and women β = 1.66 95%CI 0.78, 1.54), and significantly lower for those in blue collar occupations (men β = -0.67 95%CI -1.09, -0.25 and women β = -0.71 95%CI -1.40, -0.01). Among men, those with a lower income had a significantly lower BMI, while the opposite was found among women. None of the interaction models had a significantly better fit than the random intercept models. The relationship between neighborhood disadvantage and BMI did not differ by level of education, occupation, or household income. This suggests that individual SEP is unlikely to be an effector modifier of the relationship between neighborhood disadvantage and BMI. Further research is required to assist policy-makers to make more informed decisions about where to intervene to counteract BMI-inequalities.
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ItemJAK2 is dispensable for maintenance of JAK2 mutant B-cell acute lymphoblastic leukemias(COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT, 2018-06-01)Activating JAK2 point mutations are implicated in the pathogenesis of myeloid and lymphoid malignancies, including high-risk B-cell acute lymphoblastic leukemia (B-ALL). In preclinical studies, treatment of JAK2 mutant leukemias with type I JAK2 inhibitors (e.g., Food and Drug Administration [FDA]-approved ruxolitinib) provided limited single-agent responses, possibly due to paradoxical JAK2Y1007/1008 hyperphosphorylation induced by these agents. To determine the importance of mutant JAK2 in B-ALL initiation and maintenance, we developed unique genetically engineered mouse models of B-ALL driven by overexpressed Crlf2 and mutant Jak2, recapitulating the genetic aberrations found in human B-ALL. While expression of mutant Jak2 was necessary for leukemia induction, neither its continued expression nor enzymatic activity was required to maintain leukemia survival and rapid proliferation. CRLF2/JAK2 mutant B-ALLs with sustained depletion or pharmacological inhibition of JAK2 exhibited enhanced expression of c-Myc and prominent up-regulation of c-Myc target genes. Combined indirect targeting of c-Myc using the BET bromodomain inhibitor JQ1 and direct targeting of JAK2 with ruxolitinib potently killed JAK2 mutant B-ALLs.
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ItemKnowledge, risk perception and preparedness towards coronavirus disease-2019 (COVID-19) outbreak among Ghanaians: a quick online cross-sectional survey(AFRICAN FIELD EPIDEMIOLOGY NETWORK-AFENET, 2020-04)INTRODUCTION: Coronavirus disease 2019 (COVID-19) is recognized as global pandemic, affecting more than 300,000 worldwide. Ghana joined the international community by confirming first two COVID-19 cases on March 12, 2020. The study aimed to assess the public knowledge, risk perception and preparedness to respond the COVID-19 in the early stage of the outbreak in Ghana. METHODS: A cross-sectional study was conducted to collect information from Ghanaian during the early stage of the outbreak from 12th to 20th March 2020. Electronic based questionnaire was developed to collected information on the public knowledge, risk perceptions and preparedness to respond the COVID-19. All people who were aged 18 years and over were invited to participate in the study. RESULTS: A total of 350 participants were recruited into the analysis; 56% were males, with the majority of the study population aged between 18-30 years (61.4%), single (68.9%) and attained tertiary education (95.1%). Regarding COVID-19, 62.7% had "good" knowledge about the outbreak, 68.3% had a high risk of contracting the COVID-19 infection and 81.4% had a moderate preparedness skill to prevent and control the disease. Internet (77.1%) was the major sources of information. Knowledge of COVID-19 was significantly associated with education (p<0.001), age (p=0.018), employment (p=0.011) and health-related occupation (P=0.001) but only religion was associated with risk perception. CONCLUSION: Though overall public knowledge was good, disparity exist among the least educated population, there was high risk perceptions and moderate preparedness skill to respond to COVID-19 among our study population. We recommend that educational campaigns through timely online update on COVID-19, van mobilization and mass media broadcasting should target all groups including those in the rural communities.