Stapled Peptides as Inhibitors of mRNA Deadenylation.

Therapeutic intervention targeting mRNA typically aims at reducing the levels of disease-causing sequences. Achieving the opposite effect of blocking the destruction of beneficial mRNA remains underexplored. The degradation of mRNA starts with the removal of poly(A) tails reducing their stability and translational activity which is mainly regulated by the CCR4-NOT complex. The subunit NOT9 binds various RNA binding proteins which recruit mRNA in a sequence-specific manner to the CCR4-NOT complex to promote their deadenylation. These RNA binding proteins interact with NOT9 through a helical NOT9 binding motif which we used as a starting point for development of the hydrocarbon stapled peptide NIP-2. The peptide (KD = 60.4 nM) was able to inhibit RNA-binding (IC50 = 333 nM) as well as the deadenylation activity of the CCR4-NOT complex in vitro while being cell-permeable (EC50 = 2.44 µM). A co-crystal structure of NIP-2 bound to NOT9 allowed further optimization of the peptide through point mutation leading to NIP-2-H27A-N3(KD = 122 nM) with high cell permeability (cell-permeability EC50 = 0.34 µM). The optimized peptide was able to inhibit deadenylation of target mRNAs when used in HeLa cells at a concentration of 100 µM demonstrating the feasibility of increasing mRNA stability.

Cost-effectiveness analysis of proximal femoral nail versus bipolar hemiarthroplasty for femoral neck fracture.

BACKGROUND: Hip fractures are a serious public health problem with high rates of morbidity, mortality, disability and care costs. The aim of the research was to perform cost effectiveness analysis of hip fracture treatments using proximal femoral nail and bipolar hemiarthroplasty surgeries. METHODS: The analysis was completed based on the perspectives of the paying institution and patient. A decision tree model was used to determine whether proximal femoral nail or bipolar arthroplasty was most cost effective for the management of a femoral neck fracture in this patient population. RESULTS: The findings from the decision tree model suggested that ICERs for BHP were TRY 43,164.53 TL/QALY based on reimbursement and TRY 3,977.35 TL/QALY based on patient expenditures. Compared to the calculated threshold value of TRY 60.575 TL, we concluded BHP to be a cost-effective option. Moreover, all parameter changes yielded stable results on the one-way sensitivity analysis. When it comes to the probabilistic sensitivity analysis, BHP with specified threshold value was found to be cost-effective in all the comparisons. Currently available data the use of bipolar hemiarthroplasty as the more cost- effective treatment strategy in this specific population. CONCLUSION: Overall, our findings showed HA as a cost-effective surgical technique at the calculated threshold in a population over 60 years of age. The impacts of HA on patients' quality of life and costs are remarkable.

Illuminating Dark Chemical Matter Using the Cell Painting Assay.

Screening for small-molecule modulators of disease-relevant targets and phenotypes is the first step on the way to new drugs. Large compound libraries have been synthesized by academia and, particularly, pharmaceutical companies to meet the need for novel chemical entities that are as diverse as possible. Screening of these compound libraries revealed a portion of small molecules that is inactive in more than 100 different assays and was therefore termed "dark chemical matter" (DCM). Deorphanization of DCM promises to yield very selective compounds as they are expected to have less off-target effects. We employed morphological profiling using the Cell Painting assay to detect bioactive DCM. Within the DCM collection, we identified bioactive compounds and confirmed several modulators of microtubules, DNA synthesis, and pyrimidine biosynthesis. Profiling approaches are, therefore, powerful tools to probe compound collections for bioactivity in an unbiased manner and are particularly suitable for deorphanization of DCM.

Why Violence Cannot be Prevented in Healthcare Settings in Türkiye?: A Retrospective Policy Analysis.

Preventive policies have been devised with the aim of curbing health-related violence, and their efficacy is believed to furnish evidence for their continued implementation, thereby enhancing their effectiveness. This study undertakes a retrospective analysis of these policies in the context of Türkiye. A comprehensive examination involved the review of 26 documents, employing a progressive scanning approach for data collection. This methodology encompassed the utilization of gray literature databases (OECD iLibrary and WHO Iris), extensive Google searches, thorough website scans, and consultations with subject-matter experts. Data analysis was meticulously conducted within the framework of the Health Policy Triangle. The findings reveal active participation from diverse stakeholders, including governmental bodies, political entities, professional organizations, and trade unions, in various preventive initiatives aimed at mitigating health-related violence. Notably, the adoption of legislation for health violence prevention, perceived as a paramount achievement, can be attributed to persistent efforts by both the media and other influential actors and stakeholders. These endeavors have sustained the topic's prominence on the policy agenda, positioning it as a promising source for the development of novel violence prevention and management strategies. This study underscores the necessity for a comprehensive investigation into the working conditions, personal rights, and wage policies of healthcare workers, in light of documented factors that frequently precipitate violence. Concomitantly, it advocates for the development of effective mechanisms to address these issues.

Lean Methodology for Pathology Laboratories: A Case Study from a Public Hospital

OBJECTIVE: The increase in the financial imposition of laboratories together with developing technology and evidence-based medicine applications increased the importance of quality and efficiency studies in laboratories. The aim of the study is to examine the processes of pathology laboratory, determine the causes of waste and select lean management techniques to eliminate the causes of waste. MATERIAL AND METHOD: A five-phase plan was used for the application of lean management in the pathology laboratory. After a comprehensive literature review, these phases were determined as follows; the support of the senior management, observation, training of employees, drawing of value stream maps and creation of value stream plan. Gastric biopsy process was selected as product/service family when value stream maps were generated. In addition, fishbone diagram and Pareto analysis were used to determine the causes of waste. RESULTS: In the current state, 73.6% of the time spent on a gastric biopsy sample in the pathology laboratory was wasted. The most common causes of waste were identified as problems with cleaning, equipment supply problems, lack of clinical information, equipment malfunction and errors. A value stream plan was developed with lean techniques to eliminate the causes of these wastes. In the pathology laboratory, a 4.6% improvement will be achieved with the achievement of the future stated target. CONCLUSION: A model for lean management techniques in a developing country that will enable the pathology laboratories to work more efficiently and with improved quality has been developed in this study.

(-)-Englerin†A is a potent and selective activator of TRPC4 and TRPC5 calcium channels.

Current therapies for common types of cancer such as renal cell cancer are often ineffective and unspecific, and novel pharmacological targets and approaches are in high demand. Here we show the unexpected possibility for the rapid and selective killing of renal cancer cells through activation of calcium-permeable nonselective transient receptor potential canonical (TRPC) calcium channels by the sesquiterpene (-)-englerin A. This compound was found to be a highly efficient, fast-acting, potent, selective, and direct stimulator of TRPC4 and TRPC5 channels. TRPC4/5 activation through a high-affinity extracellular (-)-englerin A binding site may open up novel opportunities for drug discovery aimed at renal cancer.

Reform of the health care system in Turkey: a review of universal health insurance.

Starting with the 1990s, Turkey has been restructuring its health care system. In December 2003, the Government of Turkey announced a comprehensive reform programme, entitled "Transformation in Health". This reform package consisted of reorganizing health services delivery and finance systems, including the establishment of a family practitioner system and universal health insurance. Some interest groups describe this reform package as "privatisation" or as an attempt to "cut benefits", and strongly oppose the reform package. The aim of this study is to review the draft universal health insurance law and to propose recommendations in light of other countries' experiences. All systems need clear policy objectives, and mechanisms for achieving reforms. All systems are, to a greater or lesser extent, the product of the history and culture of a country. Thus it is possible to learn from the experience of other countries, but unwise to copy them exactly. This is important for countries undergoing the reform process including Turkey.

Tests of stationarity and cointegration of health care expenditure and gross domestic product: an application to Turkey.

This study examines the long-run relationship among the per capita private, public, and total health care expenditure and per capita gross domestic product and population growth of Turkey. We find some evidence of multivariate cointegrating relationships among the health care expenditure and gross domestic product, and population growth. We further find a bivariate cointegrating relationship between private health care expenditure and per capita gross domestic product. Accordingly, a 10% increase in gross domestic product would translate into a 21.9% increase in total health care expenditure while controlling population growth. The income elasticity of health expenditure is found to be greater than 1, implying that health care is a luxury good in Turkey. Finally we note that there exists one-way causality running from per capita gross domestic product to various definitions of health care expenses.