Beyond procedures: how do we stake a claim for effective social work practice?

Two questions to start: what is unique about social work? In the presentations you heard today what inspired about social work? We need to define what good looks like... (What Works Centre) This goes back a LONG time

Deep splicing plasticity of the human adenovirus type 5 transcriptome drives virus evolution

Viral genomes have high gene densities and complex transcription strategies rendering transcriptome analysis through short-read RNA-seq approaches problematic. Adenovirus transcription and splicing is especially complex. We used long-read direct RNA sequencing to study adenovirus transcription and splicing during infection. This revealed a previously unappreciated complexity of alternative splicing and potential for secondary initiating codon usage. Moreover, we find that most viral transcripts tend to shorten polyadenylation lengths as infection progresses. Development of an open reading frame centric bioinformatics analysis pipeline provided a deeper quantitative and qualitative understanding of adenovirus’s genetic potential. Across the viral genome adenovirus makes multiple distinctly spliced transcripts that code for the same protein. Over 11,000 different splicing patterns were recorded across the viral genome, most occurring at low levels. This low-level use of alternative splicing patterns potentially enables the virus to maximise its coding potential over evolutionary timescales

Reciprocal regulation between 53BP1 and the anaphase-promoting complex/cyclosome is required for genomic stability during mitotic stress

The anaphase-promoting complex/cyclosome (APC/C) is an E3 ubiquitin ligase that targets substrates for degradation to promote mitotic progression. Here, we show that the DNA damage response protein 53BP1 contains conserved KEN boxes that are required for APC/C-dependent degradation in early mitosis. Mutation of the 53BP1 KEN boxes stabilized the protein and extended mitotic duration, whereas 53BP1 knockdown resulted in a shorter and delayed mitosis. Loss of 53BP1 increased APC/C activity, and we show that 53BP1 is a direct APC/C inhibitor. Although 53BP1 function is not absolutely required for normal cell cycle progression, knockdown was highly toxic in combination with mitotic spindle poisons. Moreover, chemical inhibition of the APC/C was able to rescue the lethality of 53BP1 loss. Our findings reveal a reciprocal regulation between 53BP1 and APC/C that is required for response to mitotic stress and may contribute to the tumor-suppressor functions of 53BP1

The PTTG1-binding factor (PBF/PTTG1IP) regulates p53 activity in thyroid cells

The PTTG1-Binding Factor (PBF/PTTG1IP) has an emerging repertoire of roles, especially in thyroid biology, and functions as a proto-oncogene. High PBF expression is independently associated with poor prognosis and lower disease-specific survival in human thyroid cancer. However, the precise role of PBF in thyroid tumorigenesis is unclear. Here, we present extensive evidence demonstrating that PBF is a novel regulator of p53, a tumor suppressor protein with a key role in maintaining genetic stability, which is infrequently mutated in differentiated thyroid cancer. By coimmunoprecipitation and proximity ligation assays, we show that PBF binds specifically to p53 in thyroid cells, and significantly represses transactivation of responsive promoters. Further, we identify that PBF decreases p53 stability by enhancing ubiquitination, which appears dependent on the E3 ligase activity of Mdm2. Impaired p53 function was evident in a transgenic mouse model with thyroid-specific PBF over-expression (PBF-Tg), which had significantly increased genetic instability as indicated by FISSR-PCR analysis. Consistent with this, ~40% of all DNA repair genes examined were repressed in PBF-Tg primary cultures, including genes with critical roles in maintaining genomic integrity such as Mgmt, Rad51 and Xrcc3. Our data also revealed that PBF induction resulted in upregulation of the E2 enzyme Rad6 in murine thyrocytes, and was associated with Rad6 expression in human thyroid tumors. Overall, this work provides novel insights into the role of the proto-oncogene PBF as a negative regulator of p53 function in thyroid tumorigenesis, where PBF is generally over-expressed and p53 mutations are rare compared to other tumor types

Regulatory regionalism and anti-money-laundering governance in Asia

With the intensification of the Financial Action Task Force's (FATF's) worldwide campaign to promote anti-money-laundering regulation since the late 1990s, all Asian states except North Korea have signed up to its rules and have established a regional institution—the Asia/Pacific Group on Money Laundering—to promote and oversee the implementation of FATF's 40 Recommendations in the region. This article analyses the FATF regime, making two key claims. First, anti-money-laundering governance in Asia reflects a broader shift to regulatory regionalism, particularly in economic matters, in that its implementation and functioning depend upon the rescaling of ostensibly domestic agencies to function within a regional governance regime. Second, although this form of regulatory regionalism is established in order to bypass the perceived constraints of national sovereignty and political will, it nevertheless inevitably becomes entangled within the socio-political conflicts that shape the exercise of state power more broadly. Consequently, understanding the outcomes of regulatory regionalism involves identifying how these conflicts shape how far and in what manner global regulations are adopted and implemented within specific territories. This argument is demonstrated by a case study of Myanmar