Evolution of JAK-STAT pathway components : mechanisms and role in immune system development

Background
Lying downstream of a myriad of cytokine receptors, the Janus kinase (JAK) – Signal transducer and activator of transcription (STAT) pathway is pivotal for the development and function of the immune system, with additional important roles in other biological systems. To gain further insight into immune system evolution, we have performed a comprehensive bioinformatic analysis of the JAK-STAT pathway components, including the key negative regulators of this pathway, the SH2-domain containing tyrosine phosphatase (SHP), Protein inhibitors against Stats (PIAS), and Suppressor of cytokine signaling (SOCS) proteins across a diverse range of organisms.

Results
Our analysis has demonstrated significant expansion of JAK-STAT pathway components co-incident with the emergence of adaptive immunity, with whole genome duplication being the principal mechanism for generating this additional diversity. In contrast, expansion of upstream cytokine receptors appears to be a pivotal driver for the differential diversification of specific pathway components.

Conclusion
Diversification of JAK-STAT pathway components during early vertebrate development occurred concurrently with a major expansion of upstream cytokine receptors and two rounds of whole genome duplications. This produced an intricate cell-cell communication system that has made a significant contribution to the evolution of the immune system, particularly the emergence of adaptive immunity.

HIV infection of dendritic cells subverts the IFN induction pathway via IRF-1 and inhibits type 1 IFN production

Many viruses have developed mechanisms to evade the IFN response. Here, HIV-1 was shown to induce a distinct subset of IFN-stimulated genes (ISGs) in monocyte-derived dendritic cells (DCs), without detectable type I or II IFN. These ISGs all contained an IFN regulatory factor 1 (IRF-1) binding site in their promoters, and their expression was shown to be driven by IRF-1, indicating this subset was induced directly by viral infection by IRF-1. IRF-1 and -7 protein expression was enriched in HIV p24 antigen-positive DCs. A HIV deletion mutant with the IRF-1 binding site deleted from the long terminal repeat showed reduced growth kinetics. Early and persistent induction of IRF-1 was coupled with sequential transient up-regulation of its 2 inhibitors, IRF-8, followed by IRF-2, suggesting a mechanism for IFN inhibition. HIV-1 mutants with Vpr deleted induced IFN, showing that Vpr is inhibitory. However, HIV IFN inhibition was mediated by failure of IRF-3 activation rather than by its degradation, as in T cells. In contrast, herpes simplex virus type 2 markedly induced IFNβ and a broader range of ISGs to higher levels, supporting the hypothesis that HIV-1 specifically manipulates the induction of IFN and ISGs to enhance its noncytopathic replication in DCs.

Somatization, but not depression, is characterized by disorders in the tryptophan catabolite (TRYCAT) pathway, indicating increased indoleamine 2,3-dioxygenase and lowered kynurenine aminotransferase activity

BACKGROUND: Reduced plasma tryptophan occurs in depression and somatization. Induction of indoleamine 2,3-dioxygenase (IDO) with consequent synthesis of tryptophan catabolites (TRYCATs) and lowered tryptophan are associated with the onset of depression in the puerperium and during interferon-alpha treatment. Depression is accompanied by lowered kynurenic acid, a neuroprotectant, or increased kynurenine, a neurotoxic TRYCAT.

AIMS AND METHODS: To examine plasma tryptophan; kynurenine; kynurenic acid; the kynurenine / tryptophan (KY/TRP) ratio, indicating IDO activity; and the kynurenine / kynurenic acid (KY/KA) ratio, indicating kynurenine aminotransferase (KAT) activity, in somatization; depression; somatization + depression; and controls. Illness severity is measured by the Somatic Symptom Index (SSI), the Screening for Somatoform Symptoms (SOMS), and the Beck Depression Inventory (BDI).

RESULTS: Tryptophan is significantly lower in patients than in controls and lower in somatization than in depression. KY/TRP is significantly increased in somatization. Kynurenic acid is significantly lower in patients than in controls, and lower in somatization than in depression. KY/KA is significantly higher in somatization and somatization + depression than in depression and controls. There are significant correlations between the severity of somatization, but not depression, and KY/TRP and KY/KA (positive) and tryptophan (negative). Kynurenine and kynurenic acid are significantly correlated in controls, somatization + depression, and depression, but not in somatization.

CONCLUSIONS: Somatization is characterized by increased IDO activity and disorders in KAT activity and an increased neurotoxic potential. The TRYCAT pathway may play a role in the pathophysiology of somatizing and “psychosomatic” symptoms through effects on pain, gut motility, the autonomic nervous system, peripheral NMDA receptors, etc. Even more, biological disorders, such as aberrations in the TRYCAT pathway, which are considered to be a hallmark for depression, are in fact attributable to somatization rather than to depression per se. Future research in depression on the TRYCAT pathway should always control for the possible effects of somatization.

Lower whole blood glutathione peroxidase (GPX) activity in depression, but not in myalgic encephalomyelitis / chronic fatigue syndrome: another pathway that may be associated with coronary artery disease and neuroprogression in depression

BAKGROUND: Major depression and myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) are two disorders accompanied by an upregulation of the inflammatory and oxidative and nitrosative (IO&NS) pathways and a decreased antioxidant status. Moreover, depression is accompanied by disorders in inflammatory and neuroprogressive (IN-PRO) pathways.

METHODS: This study examines whole blood glutathione peroxidase (GPX) in depression and in ME/CFS; GPX is an enzyme that reduces hydroperoxides by oxidizing glutathione and consequently protects the cells from oxidative damage. Blood was sampled in 39 patients with depression, 40 patients with ME/CFS and 24 normal volunteers. Whole blood was analysed for GPX activity using the Ransel assay (Randox). Severity of illness was measured by means of the Hamilton Depression Rating Scale (HDRS) and the Fibromyalgia and Chronic Fatigue Syndrome Rating Scale (FF scale).

RESULTS: We found that whole blood GPX activity was significantly (p=0.001) lower in depressed patients than in normal controls and that there were no significant differences between ME/CFS and controls. In depression and ME/CFS, there were significant and inverse relationships between GPX activity and the FF items, depressed mood and autonomic symptoms. In depression, there were significant and negative correlations between whole blood GPX and the HDRS score and autonomic symptoms.

DISCUSSION: The results show that lowered whole blood GPX activity contributes to the lowered antioxidant status in depression. Since GPX activity is a predictor of neuroprogression and coronary artery disease (CAD), lowered GPX activity in depression contributes to the IN-PRO pathways and the comorbidity between depression and CAD. Our results suggest that patients with depression would benefit from Ebselen or a supplementation with glutathione, N-Acetyl-l-Cysteine and selenium.

Construction pathway : attracting the missing students and workers to university

The Commonwealth Government has the increased participation of under-represented groups to a 20% diversity target for Australian universities. It also has minimum targets of 40% of all Australians (25-34 years) holding a Bachelor’s degree by 2020. These targets are baseline items in a government agenda of improving educational outcomes for Australians and pivotal in addressing skill shortages in industries such as construction. In construction there is a skewing of skill shortages to the higher order or post entry level skills. Demand for higher skilled occupations such as construction managers, outstrips demand for construction trades (DEEWR, 2010). But whilst 41% of the industry have VET qualifications, only 10% possess HE qualifications in construction. Movement between the VET and HE sectors is low: of all construction students qualifying at AQF 4, less than 10% continue on to higher education and less than 1% of VET qualified persons in the construction workforce seek re-entry to university. This paper examines national data in construction education pathways and evaluates, using the DEMO matrix, the enablers in pathways to HE qualifications. The evaluation is based upon survey responses of two cohorts entering higher education from non-traditional pathways- articulating VET students and mature-aged workers. The results indicate that pathway programmes into construction degrees can attract non-traditional cohorts, but elements such as learner engagement, confidence, people-rich resources and collaboration are critical features of successful pathways.

The Role of TAFE as an Equity Pathway to Social Inclusion, Employment, and to University : a submission from The Deakin University Social Work/Gordon TAFE Community Services Work, Geelong Based Project Team

Executive Summary

The Deakin University Social Work/Gordon TAFE Community Services Work Geelong Based Project Team (the Project Team) was assisted by Higher Education Partnership and Participation funding made available through Deakin University Participation and Partnerships Program (DUPPP) to carry out research and project work in 2012/13.

In the following submission to the House of Representatives Inquiry into the role of Technical and Further Education (TAFE) system and its operation, this Project Team seeks to establish a case for:

1. Funding to enable TAFE to continue as:

a) an equity pathway to social inclusion, employment, and to university, particularly in regional areas.
b) an integral complement to the University education sector to deliver on the ambitious objectives of the Federal Government’s widening participation agenda, as a mechanism to deliver the skills, knowledge and workforce needed now, and in the future, in the Australian economy.
2. Increased resources for separate and joint sector development
a) Publicly funded TAFEs need funding to be restored and increased to enable them to maintain the high quality education they provide and to maintain their successful work in supporting communities, regions and disadvantaged individuals to gain skills, training and employment.
b) Universities need increased funding to increase staffing levels and therefore free up teaching staff to spend the necessary time to develop relationships with and provide support to students. This is important for the achieving the goals of the widening participation agenda of increasing access without increasing attrition at the same time.
c) TAFEs and Universities need funding to do the work required to further develop and formalise diploma-degree pathways so that disadvantaged individuals can exit into employment at the diploma level or be supported in an efficient and seamless way to undertake further study.
3. Active use of localised and nuanced partnership approaches by education institutions. This includes:
• Cross teaching by TAFEs and Universities in courses that can be articulated, such as professional practice diplomas and degrees
• Programs negotiated and designed according to the needs of students in each location. TAFEs and Universities need resources in order to do this work
• Focus on regional centres where there is a particular opportunity for government to make an impact on TAFE pathways to employment and/or further education
• Workforce development in regional areas due to new industries is a particular area of need
4. Recognise and capitalise on the complementary and symbiotic nature of each sector’s skills, strengths and capacities.
The submission responds to the second, third and fifth points of the Terms of Reference of the Inquiry and is based on the research work carried out by the Project Team in 2012/13.

We provide evidence of Gordon TAFE in Geelong working as an equity mechanism in the particular case of the welfare/ community services diploma to social work degree pathway. The project team considers that there is a strong case for additional resourcing of TAFE to enable it to continue what it does well. TAFE is the key training and education sectorthe ‘education and social hub’that can successfully attract, retain, and graduate people who may not otherwise access education due to one or more combinations of:

1. having a low SES current or past background;
2. living in regional areas;
3. receiving interrupted primary and secondary education;
4. having disabilities;
5. being sole parents;
6. being from refugee backgrounds;
7. having English as an additional language/culture;
8. retrenchment from employment in dying industries;
9. short, medium and long term unemployment;
10. past and/or current caring roles;
11. marriage/relationship breakdowns;
12. domestic violence;
13. gender, class, age, race/ethnicity and dis/ability discriminations; and
14. socialised expectations and fears.

The recommendations in this submission are based on research findings about important similarities and differences between Gordon TAFE welfare and Deakin University social work students in Geelong, and their respective institutional organisations and contexts. The two institutions employ a repertoire of diverse administrative, teaching, learning and support approaches to meet different mission goals, requirements and needs.