The RNA content is crucial for the formation of nuclear compartments, such as nuclear speckles and nucleoli. Phosphatidylinositol 4,5-bisphosphate (PIP2) is found in nuclear speckles, nucleoli, and nuclear lipid islets and is involved in RNA polymerase I/II transcription. Intriguingly, the nuclear localization of PIP2 was also shown to be RNA-dependent. We therefore investigated whether PIP2 and RNA cooperate in the establishment of nuclear architecture. In this study, we unveiled the RNA-dependent PIP2-associated (RDPA) nuclear proteome in human cells by mass spectrometry. We found that intrinsically disordered regions (IDRs) with polybasic PIP2-binding K/R motifs are prevalent features of RDPA proteins. Moreover, these IDRs of RDPA proteins exhibit enrichment for phosphorylation, acetylation, and ubiquitination sites. Our results show for the first time that the RDPA protein Bromodomain-containing protein 4 (BRD4) associates with PIP2 in the RNA-dependent manner via electrostatic interactions, and that altered PIP2 levels affect the number of nuclear foci of BRD4 protein. Thus, we propose that PIP2 spatiotemporally orchestrates nuclear processes through association with RNA and RDPA proteins and affects their ability to form foci presumably via phase separation. This suggests the pivotal role of PIP2 in the establishment of a functional nuclear architecture competent for gene expression.
- MeSH
- Cell Nucleus * metabolism genetics MeSH
- Phosphatidylinositol 4,5-Diphosphate * metabolism MeSH
- Phosphorylation MeSH
- Nuclear Proteins * metabolism genetics MeSH
- Humans MeSH
- Cell Cycle Proteins metabolism genetics MeSH
- Bromodomain Containing Proteins MeSH
- RNA metabolism genetics MeSH
- Transcription Factors * metabolism genetics MeSH
- Protein Binding MeSH
- Intrinsically Disordered Proteins * metabolism genetics chemistry MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
AIMS: The aim of this study was to compare the clinical decision-making for benzodiazepine deprescribing between a healthcare provider (HCP) and an artificial intelligence (AI) chatbot GPT4 (ChatGPT-4). METHODS: We analysed real-world data from a Croatian cohort of community-dwelling benzodiazepine patients (n = 154) within the EuroAgeism H2020 ESR 7 project. HCPs evaluated the data using pre-established deprescribing criteria to assess benzodiazepine discontinuation potential. The research team devised and tested AI prompts to ensure consistency with HCP judgements. An independent researcher employed ChatGPT-4 with predetermined prompts to simulate clinical decisions for each patient case. Data derived from human-HCP and ChatGPT-4 decisions were compared for agreement rates and Cohen's kappa. RESULTS: Both HPC and ChatGPT identified patients for benzodiazepine deprescribing (96.1% and 89.6%, respectively), showing an agreement rate of 95% (κ = .200, P = .012). Agreement on four deprescribing criteria ranged from 74.7% to 91.3% (lack of indication κ = .352, P < .001; prolonged use κ = .088, P = .280; safety concerns κ = .123, P = .006; incorrect dosage κ = .264, P = .001). Important limitations of GPT-4 responses were identified, including 22.1% ambiguous outputs, generic answers and inaccuracies, posing inappropriate decision-making risks. CONCLUSIONS: While AI-HCP agreement is substantial, sole AI reliance poses a risk for unsuitable clinical decision-making. This study's findings reveal both strengths and areas for enhancement of ChatGPT-4 in the deprescribing recommendations within a real-world sample. Our study underscores the need for additional research on chatbot functionality in patient therapy decision-making, further fostering the advancement of AI for optimal performance.
PURPOSE: We report CNS efficacy of first-line osimertinib plus chemotherapy versus osimertinib monotherapy in patients with epidermal growth factor receptor (EGFR)-mutated advanced non-small-cell lung cancer (NSCLC) from the phase III FLAURA2 study according to baseline CNS metastasis status. METHODS: Patients were randomly assigned to osimertinib plus platinum-pemetrexed (combination) or osimertinib monotherapy until disease progression or discontinuation. Brain scans were performed in all patients at baseline and progression and at scheduled assessments until progression for patients with baseline CNS metastases; scans were assessed by neuroradiologist CNS blinded independent central review (BICR). RESULTS: On the basis of baseline CNS BICR, 118 of 279 (combination) and 104 of 278 (monotherapy) randomly assigned patients had ≥one measurable and/or nonmeasurable CNS lesion and were included in the CNS full analysis set (cFAS); 40 of 118 and 38 of 104 had ≥one measurable target CNS lesion and were included in the post hoc CNS evaluable-for-response set (cEFR). In the cFAS, the hazard ratio (HR) for CNS progression or death was 0.58 (95% CI, 0.33 to 1.01). In patients without baseline CNS metastases, the HR for CNS progression or death was 0.67 (95% CI, 0.43 to 1.04). In the cFAS, CNS objective response rates (ORRs; 95% CI) were 73% (combination; 64 to 81) versus 69% (monotherapy; 59 to 78); 59% versus 43% had CNS complete response (CR). In the cEFR, CNS ORRs (95% CI) were 88% (73 to 96) versus 87% (72 to 96); 48% versus 16% had CNS CR. CONCLUSION: Osimertinib plus platinum-pemetrexed demonstrated improved CNS efficacy compared with osimertinib monotherapy, including delaying CNS progression, irrespective of baseline CNS metastasis status. These data support this combination as a new first-line treatment for patients with EGFR-mutated advanced NSCLC, including those with CNS metastases.
- MeSH
- Acrylamides * MeSH
- Aniline Compounds therapeutic use MeSH
- ErbB Receptors genetics MeSH
- Indoles * MeSH
- Protein Kinase Inhibitors therapeutic use MeSH
- Humans MeSH
- Mutation MeSH
- Central Nervous System Neoplasms * diagnostic imaging drug therapy genetics MeSH
- Lung Neoplasms * drug therapy genetics pathology MeSH
- Carcinoma, Non-Small-Cell Lung * drug therapy genetics pathology MeSH
- Pemetrexed therapeutic use MeSH
- Platinum therapeutic use MeSH
- Pyrimidines * MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Clinical Trial, Phase III MeSH
- Randomized Controlled Trial MeSH
People living with diabetes have many medical devices available to assist with disease management. A critical aspect that must be considered is how systems for continuous glucose monitoring and insulin pumps communicate with each other and how the data generated by these devices can be downloaded, integrated, presented and used. Not only is interoperability associated with practical challenges, but also devices must adhere to all aspects of regulatory and legal frameworks. Key issues around interoperability in terms of data ownership, privacy and the limitations of interoperability include where the responsibility/liability for device and data interoperability lies and the need for standard data-sharing protocols to allow the seamless integration of data from different sources. There is a need for standardised protocols for the open and transparent handling of data and secure integration of data into electronic health records. Here, we discuss the current status of interoperability in medical devices and data used in diabetes therapy, as well as regulatory and legal issues surrounding both device and data interoperability, focusing on Europe (including the UK) and the USA. We also discuss a potential future landscape in which a clear and transparent framework for interoperability and data handling also fulfils the needs of people living with diabetes and healthcare professionals.
- MeSH
- Diabetes Mellitus * drug therapy MeSH
- Electronic Health Records MeSH
- Blood Glucose MeSH
- Humans MeSH
- Blood Glucose Self-Monitoring * MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
- Geographicals
- United Kingdom MeSH
IMPORTANCE: Since 2005, a total of 50 face transplants have been reported from 18 centers in 11 countries. The overall survival of the grafts has not yet been established. OBJECTIVE: To assess the survival of the face transplant grafts and evaluate factors potentially influencing it. DESIGN, SETTING, AND PARTICIPANTS: Data on all the transplants included in this multicenter cohort study were collected at participating transplant centers for updated nonpublished data, supplemented with literature review for nonparticipating centers. Data from 2005 until September 2023, were included. Data were analyzed from November 11, 2005, through September 18, 2023. Patients included the first 50 patients in the world to have received a face transplant. EXPOSURE: Face transplant graft. MAIN OUTCOMES AND MEASURES: The primary outcome was the overall survival of the face transplant graft, defined as either transplant loss or patient death. The secondary outcome was the number of acute rejection episodes per year. RESULTS: The 50 transplants were performed on 39 men (81%) and 9 women (19%) with a median age of 35 (range, 19-68) years at the time of the transplant. The median follow-up time was 8.9 (range, 0.2-16.7) years. During the follow-up, 6 transplants were lost with 2 patients retransplanted. There were 10 patients who died, 2 of whom had lost a transplant. The 5- and 10-year survival of the transplants was 85% (SD, 5%) and 74% (SD, 7%), respectively. The sequential number of the transplant in the world was a significant predictor of survival (hazard ratio, 95; 95% CI, 90-100; P < 05). The median number of acute rejection episodes per year was 1.2 (range, 0-5.3) for the transplants that were lost and 0.7 (range, 0-4.6) for the transplants that survived. No correlation with patient and transplant variables was detected for either the transplant survival or the number of rejection episodes. CONCLUSIONS AND RELEVANCE: In this study, the overall survival of the face transplants is encouraging. These data suggest that the acceptable long-term survival of face transplants makes them a reconstructive option for extensive facial defects.
- MeSH
- Global Health MeSH
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Young Adult MeSH
- Graft Survival * MeSH
- Graft Rejection * MeSH
- Aged MeSH
- Facial Transplantation * MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Young Adult MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Comment MeSH
- Multicenter Study MeSH
This study summarizes the response of cyanobacterium Spirulina subsalsa HKAR-19 under simulated light conditions of photosynthetically active radiation (PAR), PAR+UV-A (PA), and PAR+UV-A+UV-B (PAB). Exposure to UV radiation caused a significant (P < 0.05) decrease in chlorophyll a, phycocyanin, and total protein. In contrast, total carotene content increased significantly (P < 0.05) under PA and PAB with increasing irradiation time. The photosynthetic efficiency of photosystem II also decreased significantly in PA and PAB radiation. We have also recorded a decrease in the fluorescence emission intensity of phycocyanin under PA and PAB exposure. The phycocyanin fluorescence shifted towards shorter wavelengths (blue-shift) after 72 h of PA and PAB exposure. Intracellular reactive oxygen species (ROS) levels increased significantly in PA and PAB. Fluorescence microscopic images showed an increase in green fluorescence, indicating ROS generation in UV radiation. We have also quantified ROS generation using green and red fluorescence ratio represented as G/R ratio. A 2-6-fold increase in antioxidative enzymes activity was observed to overcome the damaging effects caused by UV stress as compared to untreated control cultures. The lipid peroxidation was assessed in terms of malondialdehyde content which increases significantly (P < 0.05) as the duration of exposure increases. These results suggest that a combined effect of PAR, UV-A, and UV-B was more deleterious than an individual one.
- MeSH
- Antioxidants * metabolism MeSH
- Chlorophyll A metabolism MeSH
- Chlorophyll * metabolism MeSH
- Photosynthesis * radiation effects MeSH
- Photosystem II Protein Complex metabolism MeSH
- Phycocyanin * metabolism MeSH
- Carotenoids metabolism MeSH
- Lipid Peroxidation radiation effects MeSH
- Reactive Oxygen Species * metabolism MeSH
- Spirulina * radiation effects metabolism MeSH
- Ultraviolet Rays * MeSH
- Publication type
- Journal Article MeSH
PURPOSE: The aim of this study was to describe the incidence and a complex pathoanatomy of posterior malleolus fractures in a Maisonneuve fracture. METHODS: The study included 100 prospectively collected patients with a complete clinical and radiological documentation of an ankle fracture or fracture-dislocation including a fracture of the proximal quarter of the fibula. RESULTS: A posterior malleolus fracture was identified in 74 patients, and in 27% of these cases it carried more than one quarter of the fibular notch. Displacement of the posterior fragment by more than 2 mm was shown by scans in 72% of cases. Small intercalary fragments were identified in 43% of cases. Fractures of the Tillaux-Chaput tubercle were identified in 20 patients. CONCLUSION: Our study has proved a high rate of posterior malleolus fractures associated with a Maisonneuve fracture, and documented their considerable variability in terms of involvement of the fibular notch, tibiotalar contact area, direction of displacement and frequency of intercalary fragments. Of no less importance is a combination of Tillaux-Chaput fractures with a Maisonneuve fracture.
- MeSH
- Fracture Dislocation diagnostic imaging MeSH
- Adult MeSH
- Fibula injuries diagnostic imaging MeSH
- Ankle Fractures * diagnostic imaging surgery MeSH
- Incidence MeSH
- Middle Aged MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- Tomography, X-Ray Computed MeSH
- Prospective Studies MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- Male MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
Brucellosis is a zoonosis caused by Brucella, which poses a great threat to human health and animal husbandry. Pathogen surveillance is an important measure to prevent brucellosis, but the traditional method is time-consuming and not suitable for field applications. In this study, a recombinase polymerase amplification-SYBR Green I (RPAS) assay was developed for the rapid and visualized detection of Brucella in the field by targeting BCSP31 gene, a conserved marker. The method was highly specific without any cross-reactivity with other common bacteria and its detection limit was 2.14 × 104 CFU/mL or g of Brucella at 40 °C for 20 min. It obviates the need for costly instrumentation and exhibits robustness towards background interference in serum, meat, and milk samples. In summary, the RPAS assay is a rapid, visually intuitive, and user-friendly detection that is highly suitable for use in resource-limited settings. Its simplicity and ease of use enable swift on-site detection of Brucella, thereby facilitating timely implementation of preventive measures.
- MeSH
- Brucella * genetics isolation & purification MeSH
- Brucellosis * diagnosis microbiology MeSH
- DNA, Bacterial genetics MeSH
- Humans MeSH
- Limit of Detection MeSH
- Milk microbiology MeSH
- Recombinases * metabolism genetics MeSH
- Sensitivity and Specificity MeSH
- Cattle MeSH
- Nucleic Acid Amplification Techniques * methods MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Cattle MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Epigenetic DNA modifications are pivotal in eukaryotic gene expression, but their regulatory significance in bacteria is less understood. In Synechocystis 6803, the DNA methyltransferase M.Ssp6803II modifies the first cytosine in the GGCC motif, forming N4-methylcytosine (GGm4CC). Deletion of the sll0729 gene encoding M.Ssp6803II (∆sll0729) caused a bluish phenotype due to reduced chlorophyll levels, which was reversed by suppressor mutations. Re-sequencing of 7 suppressor clones revealed a common GGCC to GGTC mutation in the slr1790 promoter's discriminator sequence, encoding protoporphyrinogen IX oxidase, HemJ, crucial for tetrapyrrole biosynthesis. Transcriptomic and qPCR analyses indicated aberrant slr1790 expression in ∆sll0729 mutants. This aberration led to the accumulation of coproporphyrin III and protoporphyrin IX, indicative of impaired HemJ activity. To confirm the importance of DNA methylation in hemJ expression, hemJ promoter variants with varying discriminator sequences were introduced into the wild type, followed by sll0729 deletion. The sll0729 deletion segregated in strains with the GGTC discriminator motif, resulting in wild-type-like pigmentation, whereas freshly prepared ∆sll0729 mutants with the native hemJ promoter exhibited the bluish phenotype. These findings demonstrate that hemJ is tightly regulated in Synechocystis and that N4-methylcytosine is essential for proper hemJ expression. Thus, cytosine N4-methylation is a relevant epigenetic marker in Synechocystis and likely other cyanobacteria.
- MeSH
- Bacterial Proteins metabolism genetics MeSH
- Epigenesis, Genetic * MeSH
- DNA Methylation * MeSH
- Mutation MeSH
- Promoter Regions, Genetic * MeSH
- Gene Expression Regulation, Bacterial MeSH
- Synechocystis * genetics metabolism MeSH
- Tetrapyrroles * metabolism biosynthesis MeSH
- Publication type
- Journal Article MeSH
