Competition for cysteine acylation by C16:0 and C18:0 derived lipids is a global phenomenon in the proteome.

S-acylation is a reversible posttranslational protein modification consisting of attachment of a fatty acid to a cysteine via a thioester bond. Research over the last few years has shown that a variety of different fatty acids, such as palmitic acid (C16:0), stearate (C18:0), or oleate (C18:1), are used in cells to S-acylate proteins. We recently showed that GNAI proteins can be acylated on a single residue, Cys3, with either C16:0 or C18:1, and that the relative proportion of acylation with these fatty acids depends on the level of the respective fatty acid in the cell's environment. This has functional consequences for GNAI proteins, with the identity of the acylating fatty acid affecting the subcellular localization of GNAIs. Unclear is whether this competitive acylation is specific to GNAI proteins or a more general phenomenon in the proteome. We perform here a proteome screen to identify proteins acylated with different fatty acids. We identify 218 proteins acylated with C16:0 and 308 proteins acylated with C18-lipids, thereby uncovering novel targets of acylation. We find that most proteins that can be acylated by C16:0 can also be acylated with C18-fatty acids. For proteins with more than one acylation site, we find that this competitive acylation occurs on each individual cysteine residue. This raises the possibility that the function of many different proteins can be regulated by the lipid environment via differential S-acylation.

Comparative validation of machine learning algorithms for surgical workflow and skill analysis with the HeiChole benchmark.

PURPOSE: Surgical workflow and skill analysis are key technologies for the next generation of cognitive surgical assistance systems. These systems could increase the safety of the operation through context-sensitive warnings and semi-autonomous robotic assistance or improve training of surgeons via data-driven feedback. In surgical workflow analysis up to 91% average precision has been reported for phase recognition on an open data single-center video dataset. In this work we investigated the generalizability of phase recognition algorithms in a multicenter setting including more difficult recognition tasks such as surgical action and surgical skill. METHODS: To achieve this goal, a dataset with 33 laparoscopic cholecystectomy videos from three surgical centers with a total operation time of 22 h was created. Labels included framewise annotation of seven surgical phases with 250 phase transitions, 5514 occurences of four surgical actions, 6980 occurences of 21 surgical instruments from seven instrument categories and 495 skill classifications in five skill dimensions. The dataset was used in the 2019 international Endoscopic Vision challenge, sub-challenge for surgical workflow and skill analysis. Here, 12 research teams trained and submitted their machine learning algorithms for recognition of phase, action, instrument and/or skill assessment. RESULTS: F1-scores were achieved for phase recognition between 23.9% and 67.7% (n = 9 teams), for instrument presence detection between 38.5% and 63.8% (n = 8 teams), but for action recognition only between 21.8% and 23.3% (n = 5 teams). The average absolute error for skill assessment was 0.78 (n = 1 team). CONCLUSION: Surgical workflow and skill analysis are promising technologies to support the surgical team, but there is still room for improvement, as shown by our comparison of machine learning algorithms. This novel HeiChole benchmark can be used for comparable evaluation and validation of future work. In future studies, it is of utmost importance to create more open, high-quality datasets in order to allow the development of artificial intelligence and cognitive robotics in surgery.

Influence of heart rate and heart rate variability on the feasibility of ultra-fast, high-pitch coronary photon-counting computed tomography angiography.

Coronary computed tomography angiography has become a mainstay in diagnosing coronary artery disease and is increasingly used in screening symptomatic patients. Recently, photon-counting computed tomography (PCCT) has been introduced into clinical practice, offering higher spatial and temporal resolution. As the applied radiation dose is highly dependent on the choice of scan mode and is lowest using the ultra-fast high-pitch (FLASH) mode, guidelines for their application are needed. From a retrospective study investigating the properties of a novel photon-counting computed tomography, all patients who underwent FLASH-mode PCCT angiography were selected between January and April 2022. This resulted in a study population of 46 men and 27 women. We recorded pre- and intrascan ECG readings and calculated heart rate (maximum heart rate 73 bpm) as well heart rate variability (maximum HRV 37 bpm) as measured by the standard deviation of the heart rate. Diagnostic quality and motion artifacts scores were recorded for each coronary artery segment by consensus between two readers. We found a highly significant association between heart rate variability and image quality (p < 0.001). The heart rate itself was not independently associated with image quality. Both heart rate and heart rate variability were significantly associated with the presence of motion artifacts in a combined model. Scan heart rate variability-but not heart rate itself-is a highly significant predictor of reduced image quality on high-pitch coronary photon-counting computed tomography angiography. This may be due to better scanner architecture and an increased temporal resolution compared to conventional energy-integrating detector computed tomography, which has to be addressed in a comparison study in the future.

Carbon ion irradiation plus CTLA4 blockade elicits therapeutic immune responses in a murine tumor model.

Radiotherapy can act as an in situ vaccine, activating preventive tumor-specific immune responses in patients. Although carbon ion radiotherapy has superior biophysical properties over conventional photon irradiation, the immunological effects induced by this radiation type are poorly understood. Multiple strategies combining radiotherapy with immune checkpoint inhibition (radioimmunotherapy) to enhance antitumor immunity have been described; however, immune cell composition in tumors following radioimmunotherapy with carbon ions remains poorly explored. We developed a bilateral tumor model based on time-shifted subcutaneous injection of murine Her2+ EO771 tumor cells into immune-competent mice followed by selective irradiation of the primary tumor. αCTLA4-, but not αPD-L1-based radioimmunotherapy, induced complete tumor rejection and mediated the eradication of even non-irradiated, distant tumors. Cured mice were protected against the EO771 rechallenge, indicating long-lasting, tumor-specific immunological memory. Single-cell RNA sequencing and flow cytometric analyses of irradiated tumors revealed activation of NK cells and distinct tumor-associated macrophage clusters with upregulated expression of TNF and IL1 responsive genes. Distant tumors in the irradiated mice showed higher frequencies of naïve T cells activated upon the combination with CTLA4 blockade. Thus, radioimmunotherapy with carbon ions plus CTLA4 inhibition reshapes the tumor-infiltrating immune cell composition and can induce complete rejection even of non-irradiated tumors. Our data suggest combining radiotherapy approaches with CTLA4 blockade to achieve durable antitumor immunity. Evaluation of future radioimmunotherapy approaches should not be restricted to immunological impact at the irradiation site but should also consider systemic immunological effects on non-irradiated tumors.

Looking at the past through a telescope: adults postdated their earliest childhood memories.

Our previous studies have consistently shown a telescoping error in children's dating of earliest childhood memories. Preschool children through adolescents systematically date their earliest memories at older ages, in comparison with the age estimates provided by their parents or by themselves previously. In the current study, we examined the dating of earliest childhood memories in two samples of college adults and collected independent age estimates from their parents. Consistent with our findings with children, adults significantly postdated their earlier memories by approximately 12 months (Study 1) and 6 months (Study 2). The actual age of earliest memories was 2.5 years after adjusted for telescoping errors, 1 year earlier than what is commonly believed at 3.5 years. These findings challenge commonly held theoretical assumptions about childhood amnesia and highlight critical methodological issues in the study of childhood memory.