Mass Spectrometry Reveals Protein Kinase CK2 High-Order Oligomerization via the Circular and Linear Assembly.

CK2 is an intrinsically active protein kinase that is crucial for cellular viability. However, conventional kinase regulatory mechanisms do not apply to CK2, and its mode of regulation remains elusive. Interestingly, CK2 is known to undergo reversible ionic-strength-dependent oligomerization. Furthermore, a regulatory mechanism based on autoinhibitory oligomerization has been postulated on the basis of the observation of circular trimeric oligomers and linear CK2 assemblies in various crystal structures. Here, we employ native mass spectrometry to monitor the assembly of oligomeric CK2 species in an ionic-strength-dependent manner. A subsequent combination of ion mobility spectrometry-mass spectrometry and hydrogen-deuterium exchange mass spectrometry techniques was used to analyze the conformation of CK2 oligomers. Our findings support ionic-strength-dependent CK2 oligomerization, demonstrate the transient nature of the α/β interaction, and show that CK2 oligomerization proceeds via both the circular and linear assembly.This research was supported by the Wellcome Trust Strategic Award (090340/Z/09/Z), the Agency for Science Technology and Research (A*STAR) Singapore (Ph.D. sponsorship, W.G.S.), and the Croucher Foundation and the Cambridge Overseas Trust (Croucher Cambridge International Scholarship, D.S.-H.C).This is the author accepted manuscript. The final version is available from the American Chemical Society via http://dx.doi.org/10.1021/acschembio.6b0006

Leadership and Vision: Moving From a Patriarchal Model to a Plurality of Elders

The goal of this project is to establish a new leadership structure for Cornerstone Evangelical Baptist Church in Vancouver, Canada. Currently, Cornerstone is led by the founding pastor, and as he approaches retirement, a new structure needs to be put in place. The thesis argues that a plurality of leaders, versus a single patriarchal leader, is a healthier form of governance. This process needs to be carefully studied and implemented with special consideration of Confucius ideology, which influences many Chinese churches. A plurality of leaders serving alongside a pastor will help discern and articulate a clear purpose and vision for the church. Through an examination of Scripture, church leadership has always been done in a group or a team. There are clear distinctions between elders, deacons, and full-time staff. The goal for Cornerstone is to create a structure that utilizes and empowers each group for effective service. This is a five-year process of training and reorganizing. Most of the training occurs at the annual leaders’ retreat. Specific workshops have been developed for discovering Cornerstone’s purpose, addressing conflict resolution, building the leadership team, setting goals, and creating a vision statement and strategy plan. This process concludes with a congregational vote to amend the bylaws to reflect the changes to the leadership structure of the church. The board of directors and the senior pastor will lead this new structure and serve as the spiritual leaders of the church

Disrupting the Constitutive, Homodimeric Protein-Protein Interface in CK2β Using a Biophysical Fragment-Based Approach.

Identifying small molecules that induce the disruption of constitutive protein-protein interfaces is a challenging objective. Here, a targeted biophysical screening cascade was employed to specifically identify small molecules that could disrupt the constitutive, homodimeric protein-protein interface within CK2β. This approach could potentially be applied to achieve subunit disassembly of other homo-oligomeric proteins as a means of modulating protein function.This research was supported by the Agency for Science, Technology and Research (A*STAR) Singapore (Ph.D. sponsorship, W.G.S.) and the Wellcome Trust Strategic Award (090340/Z/09/Z)

Characterization of the histone methyltransferase PRDM9 using biochemical, biophysical and chemical biology techniques

PRDM proteins have emerged as important regulators of disease and developmental processes. To gain insight into the mechanistic actions of the PRDM family, we have performed comprehensive characterization of a prototype member protein, the histone methyltransferase PRDM9, using biochemical, biophysical and chemical biology techniques. In the present paper we report the first known molecular characterization of a PRDM9-methylated recombinant histone octamer and the identification of new histone substrates for the enzyme. A single C321P mutant of the PR/SET domain was demonstrated to significantly weaken PRDM9 activity. Additionally, we have optimized a robust biochemical assay amenable to high-throughput screening to facilitate the generation of small-molecule chemical probes for this protein family. The present study has provided valuable insight into the enzymology of an intrinsically active PRDM protein

Prospect theory, analyst forecast, and stock returns

See article http://ink.library.smu.edu.sg/lkcsb_research/1158/ or http://dx.doi.org/10.1016/j.mulfin.2004.03.00

The Community IntraVenous Antibiotic Study (CIVAS): a mixed methods evaluation of patient preferences for and cost effectiveness of different service models for delivering outpatient parenteral antimicrobial therapy

Background: Outpatient parenteral antimicrobial therapy (OPAT) is widely used in most developed countries, providing considerable opportunities for improved cost savings. However, it is implemented only partially in the UK, using a variety of service models. Objectives: The aims of this research were to (1) establish the extent of OPAT service models in England and identify their development; (2) evaluate patients’ preferences for different OPAT service delivery models; (3) assess the cost-effectiveness of different OPAT service delivery models; and (4) convene a consensus panel to consider our evidence and make recommendations. Methods: This mixed-methods study included seven centres providing OPAT using four main service models: (1) hospital outpatient (HO) attendance; (2) specialist nurse (SN) visiting at home; (3) general nurse (GN) visiting at home; and (4) self-administration (SA) or carer administration. Health-care providers were surveyed and interviewed to explore the implementation of OPAT services in England. OPAT patients were interviewed to determine key service attributes to develop a discrete choice experiment (DCE). This was used to perform a quantitative analysis of their preferences and attitudes. Anonymised OPAT case data were used to model cost-effectiveness with both Markov and simulation modelling methods. An expert panel reviewed the evidence and made recommendations for future service provision and further research. Results: The systematic review revealed limited robust literature but suggested that HO is least effective and SN is most effective. Qualitative study participants felt that different models of care were suited to different types of patient and they also identified key service attributes. The DCE indicated that type of service was the most important factor, with SN being strongly preferred to HO and SA. Preferences were influenced by attitudes to health care. The results from both Markov and simulation models suggest that a SN model is the optimal service for short treatment courses (up to 7 days). Net monetary benefit (NMB) values for HO, GN and SN services were £2493, £2547 and £2655, respectively. For longer treatment, SA appears to be optimal, although SNs provide slightly higher benefits at increased cost. NMB values for HO, GN, SN and SA services were £8240, £9550, £10,388 and £10,644, respectively. The simulation model provided useful information for planning OPAT services. The expert panel requested more guidance for service providers and commissioners. Overall, they agreed that mixed service models were preferable. Limitations: Recruitment to the qualitative study was suboptimal in the very elderly and ethnic minorities, so the preferences of patients from these groups might not be represented. The study recruited from Yorkshire, so the findings may not be applicable nationally. Conclusions: The quantitative preference analysis and economic modelling favoured a SN model, although there are differences between sociodemographic groups. SA provides cost savings for long-term treatment but is not appropriate for all. Future work: Further research is necessary to replicate our results in other regions and populations and to evaluate mixed service models. The simulation modelling and DCE methods used here may be applicable in other health-care settings. Funding: The National Institute for Health Research Health Service and Delivery Research programme

Developing a transparent reporting tool for AI-based diagnostic prediction models of disease and syndrome in Chinese medicine: a Delphi protocol

IntroductionThe application of artificial intelligence in diagnostic prediction models for diseases and syndromes in Chinese Medicine (CM) has been rapidly expanding, accompanied by a significant increase in related research publications. However, existing reporting guidelines for diagnostic prediction models are primarily tailored to Western medicine, which differs fundamentally from CM in its theoretical framework, terminology, and classification systems. To address this gap, it is essential to establish a transparent and standardized reporting tool specifically designed for CM diagnostic and syndrome prediction models. This will enhance the transparency, reproducibility, and clinical relevance of research findings in this emerging field.MethodsThis study adopts a structured, multi-phase Delphi protocol. A core working group will first conduct a comprehensive review of published studies on CM diagnostic prediction models to develop an initial item pool for the Transparent Reporting Tool for AI-based Diagnostic Prediction Models of Disease and Syndrome in Chinese Medicine (TRAPODS-CM). Delphi questionnaires will then be distributed via email to a multidisciplinary panel of experts in CM, computer science, and evidence-based methodology who meet the inclusion criteria. The number of Delphi rounds will be determined by evaluating the active coefficient, expert authority, and expert consensus. Final consensus on the TRAPODS-CM checklist will be achieved through online meetings. The study will be governed by a Steering Committee, with the core working group responsible for implementation. After publication, the finalized checklist will be disseminated via multimedia platforms, seminars, and academic conferences to maximize its academic and clinical impact.Ethics and DisseminationThis project has received ethical approval from the National Natural Science Foundation of China (Grant No. 82374336) and the Institutional Review Board of Nanyang Technological University (IRB-2024-1007). The study findings will be disseminated through peer-reviewed publications