Histone Lactylation Drives CD8 T Cell Metabolism and Function.

The activation and functional differentiation of CD8 T cells are linked to metabolic pathways that result in the production of lactate. Lactylation is a lactate-derived histone post-translational modification (hPTM); however, the relevance of histone lactylation in the context of CD8 T cell activation and function is not known. Here, we show the enrichment of H3K18-lactylation (H3K18la) and H3K9-lactylation (H3K9la) in human and murine CD8 T cells which act as transcription initiators of key genes regulating CD8 T cell phenotype and function. Further, we note distinct impacts of H3K18la and H3K9la on CD8 T cell subsets linked to their specific metabolic profiles. Importantly, we demonstrate that modulation of H3K18la and H3K9la by targeting metabolic and epigenetic pathways regulates CD8 T cell effector function including anti-tumor immunity in preclinical models. Overall, our study uncovers the unique contributions of H3K18la and H3K9la in modulating CD8 T cell phenotype and function intricately associated with metabolic state.

Lethal dog attacks on adult rhesus macaques (Macaca mulatta) in an anthropogenic landscape.

For nonhuman primates living in anthropogenic areas, predation by larger predators is relatively rare. However, smaller predators, such as free-ranging as well as domesticated dogs, can shape the socioecology of urban nonhuman primates, either directly by attacking and killing them or indirectly by modifying their activity patterns. Here, we describe three (two probably fatal) cases of dog attacks on adult rhesus macaques inhabiting an anthropogenic landscape in Northern India and the circumstances surrounding these incidents. We discuss the importance of considering human presence and intervention in dog-nonhuman primate relationships while studying nonhuman primate populations across anthropogenic gradients, and its potential influences on group social dynamics and transmission of zoonotic agents.

Interplay of cardiac remodelling and myocardial stiffness in hypertensive heart disease: a shear wave imaging study using high-frame rate echocardiography.

AIMS: To determine myocardial stiffness by means of measuring the velocity of naturally occurring myocardial shear waves (SWs) at mitral valve closure (MVC) and investigate their changes with myocardial remodelling in patients with hypertensive heart disease. METHODS AND RESULTS: Thirty-three treated arterial hypertension (HT) patients with hypertrophic left ventricular (LV) remodelling (59 ± 14 years, 55% male) and 26 aged matched healthy controls (55±15 years, 77% male) were included. HT patients were further divided into a concentric remodelling (HT1) group (13 patients) and a concentric hypertrophy (HT2) group (20 patients). LV parasternal long-axis views were acquired with an experimental ultrasound scanner at 1266 ± 317 frames per seconds. The SW velocity induced by MVC was measured from myocardial acceleration maps. SW velocities differed significantly between HT patients and controls (5.83 ± 1.20 m/s vs. 4.04 ± 0.96 m/s; P < 0.001). In addition, the HT2 group had the highest SW velocities (P < 0.001), whereas values between controls and the HT1 group were comparable (P = 0.075). Significant positive correlations were found between SW velocity and LV remodelling (interventricular septum thickness: r = 0.786, P < 0.001; LV mass index: r = 0.761, P < 0.001). SW velocity normalized for wall stress indicated that myocardial stiffness in the HT2 group was twice as high as in controls (P < 0.001), whereas values of the HT1 group overlapped with the controls (P = 1.00). CONCLUSIONS: SW velocity as measure of myocardial stiffness is higher in HT patients compared with healthy controls, particularly in advanced hypertensive heart disease. Patients with concentric remodelling have still normal myocardial properties whereas patients with concentric hypertrophy show significant stiffening.

How Does Regional Hypertrophy Affect Strain Measurements With Different Speckle-Tracking Methods?

BACKGROUND: In this study, we evaluate the impact of abnormal myocardial shapes, such as regional hypertrophy, on longitudinal strain measurements with different tracking approaches. METHODS: We selected 40 patients with normal ejection fraction and prominent septal bulge. We assessed longitudinal strain with full wall (FW) tracking, (GE EchoPAC) as well as endo-, mid-, and epicardial (EME) tracking (Tomtec ImageArena), on the same image acquired with a GE machine (using raw data and full frame rate DICOM data, respectively). We used a region of interest (ROI) which follows precisely the endo- and epicardial contours (true contour ROI) and one where the bulging region was excluded (straight ROI). RESULTS: In segments with bulge, absolute segmental longitudinal strain values were in all myocardial layers significantly higher with a straight ROI compared to a true contour ROI, both with FW tracking and EME tracking. The highest difference was found in the endocardial layer (3.4 ± 2.5% and 7.7 ± 7.1%, respectively, both P < 0.001). In the bulged segments, the effect of ROI shape was more pronounced in EME tracking software compared to FW tracking software. Bulged segments also influenced global longitudinal strain measurements, mostly in the endocardial layer (P < 0.001). Global longitudinal strain values obtained with the straight ROI correlated better with longitudinal fractional shortening of the LV. CONCLUSIONS: Regional bulging has a significant effect on both global and segmental strain measurements. Endocardial strain values obtained with EME tracking and a true contour ROI were most sensitive to bulging. Midwall strain values derived from FW tracking using a straight ROI were most robust.

Velocities of Naturally Occurring Myocardial Shear Waves Increase With Age and in Cardiac Amyloidosis.

OBJECTIVES: This study sought to evaluate whether velocity of naturally occurring myocardial shear waves (SW) could relate to myocardial stiffness (MS) in vivo. BACKGROUND: Cardiac SW imaging has been proposed as a noninvasive tool to assess MS. SWs occur after mechanical excitation of the myocardium (e.g., mitral valve closure [MVC] and aortic valve closure [AVC]), and their propagation velocity is theoretically related to MS, thus providing an opportunity to assess stiffness at end-diastole (ED) and end-systole. However, given that SW propagation in vivo is complex, it remains unclear whether natural SW velocity effectively relates to MS. METHODS: This study prospectively enrolled 50 healthy volunteers (HV) (43.7 ± 17.1 years of age) and 18 patients with cardiac amyloidosis (CA) (68.0 ± 9.8 years of age). HV were divided into 3 age groups: group I, 20 to 39 years of age (n = 24); group II, 40 to 59 years of age (n = 11); and group III, 60 to 80 years of age (n = 15). Parasternal long-axis views were acquired using an experimental scanner. Tissue (Doppler) acceleration maps were extracted from an anatomical M-mode along the midline of the left ventricular septum. RESULTS: SW propagation velocity was significantly higher in CA patients than in HV after both MVC (3.54 ± 0.93 m/s vs. 6.33 ± 1.63 m/s, respectively; p < 0.001) and AVC (3.75 ± 0.76 m/s vs. 5.63 ± 1.13 m/s, respectively; p < 0.001). Similarly, SW propagation velocity differed significantly among age groups in HV, with a significantly higher value for group III than for group I, both occurring after MVC (p < 0.001) and AVC (p < 0.01). Moreover, SW propagation velocity after MVC was found to be significantly higher in patients with an increasing grade of diastolic dysfunction (p < 0.001). Finally, positive correlation was found between SW velocities after MVC and mitral inflow-to-mitral relaxation velocity ratio (E/E') (r = 0.74; p = 0.002). CONCLUSIONS: End-diastole SW velocities were significantly higher in patients with CA, patients with a higher grade of diastolic dysfunction, and elderly volunteers. These findings thus suggest that the speed of naturally induced SWs may be related to MS.

2D myocardial deformation imaging based on RF-based non-rigid image registration.

Myocardial deformation imaging is a well-established echocardiographic technique for the assessment of myocardial function. Although some solutions make use of speckle tracking of the reconstructed B-mode images, others apply block matching on the underlying radio-frequency (RF) data in order to increase sensitivity to small inter-frame motion and deformation. However, for both approaches, lateral motion estimation remains a challenge due to the relatively poor lateral resolution of the ultrasound image in combination with the lack of phase information in this direction. Hereto, non-rigid image registration (NRIR) of B-mode images has previously been proposed as an attractive solution. However, hereby, the advantages of RF-based tracking were lost. The aim of this study was therefore to develop an NRIR motion estimator adopted to RF data sets. The accuracy of this estimator was quantified using synthetic data and was contrasted against a state of the art block matching solution. The results show that RF-based NRIR outperforms BM in terms of tracking accuracy particularly, as hypothesized, in the lateral direction. Finally, this RF-based NRIR algorithm was applied clinically, illustrating its ability to estimate both in-plane velocity components in-vivo.

2-D Myocardial Deformation Imaging Based on RF-Based Nonrigid Image Registration.

Myocardial deformation imaging is a well-established echocardiographic technique for the assessment of myocardial function. Although some solutions make use of speckle tracking of the reconstructed B-mode images, others apply block matching (BM) on the underlying radio frequency (RF) data in order to increase sensitivity to small interframe motion and deformation. However, for both approaches, lateral motion estimation remains a challenge due to the relatively poor lateral resolution of the ultrasound image in combination with the lack of phase information in this direction. Hereto, nonrigid image registration (NRIR) of B-mode images has previously been proposed as an attractive solution. However, hereby, the advantages of RF-based tracking were lost. The aim of this paper was, therefore, to develop an NRIR motion estimator adapted to RF data sets. The accuracy of this estimator was quantified using synthetic data and was contrasted against a state-of-the-art BM solution. The results show that RF-based NRIR outperforms BM in terms of tracking accuracy, particularly, as hypothesized, in the lateral direction. Finally, this RF-based NRIR algorithm was applied clinically, illustrating its ability to estimate both in-plane velocity components in vivo.

Realistic Vendor-Specific Synthetic Ultrasound Data for Quality Assurance of 2-D Speckle Tracking Echocardiography: Simulation Pipeline and Open Access Database.

Two-dimensional (2-D) echocardiography is the modality of choice in the clinic for the diagnosis of cardiac disease. Hereto, speckle tracking (ST) packages complement visual assessment by the cardiologist by providing quantitative diagnostic markers of global and regional cardiac function (e.g., displacement, strain, and strain-rate). Yet, the reported high vendor-dependence between the outputs of different ST packages raises clinical concern and hampers the widespread dissemination of the ST technology. In part, this is due to the lack of a solid commonly accepted quality assurance pipeline for ST packages. Recently, we have developed a framework to benchmark ST algorithms for 3-D echocardiography by using realistic simulated volumetric echocardiographic recordings. Yet, 3-D echocardiography remains an emerging technology, whereas the compelling clinical concern is, so far, directed to the standardization of 2-D ST only. Therefore, by building upon our previous work, we present in this paper a pipeline to generate realistic synthetic sequences for 2-D ST algorithms. Hereto, the synthetic cardiac motion is obtained from a complex electromechanical heart model, whereas realistic vendor-specific texture is obtained by sampling a real clinical ultrasound recording. By modifying the parameters in our pipeline, we generated an open-access library of 105 synthetic sequences encompassing: 1) healthy and ischemic motion patterns; 2) the most common apical probe orientations; and 3) vendor-specific image quality from seven different systems. Ground truth deformation is also provided to allow performance analysis. The application of the provided data set is also demonstrated in the benchmarking of a recent academic ST algorithm.