Isoleucine-to-valine substitutions support cellular physiology during isoleucine deprivation.

Aminoacyl-tRNA synthetases (ARSs) couple tRNAs with their corresponding amino acids. While ARSs can bind structurally similar amino acids, extreme specificity is ensured by subsequent editing activity. Yet, we found that upon isoleucine (I) restriction, healthy fibroblasts consistently incorporated valine (V) into proteins at isoleucine codons, resulting from misacylation of tRNAIle with valine by wildtype IARS1.

mTORC1 restricts TFE3 activity by auto-regulating its presence on lysosomes.

To stimulate cell growth, the protein kinase complex mTORC1 requires intracellular amino acids for activation. Amino-acid sufficiency is relayed to mTORC1 by Rag GTPases on lysosomes, where growth factor signaling enhances mTORC1 activity via the GTPase Rheb. In the absence of amino acids, GATOR1 inactivates the Rags, resulting in lysosomal detachment and inactivation of mTORC1.

Dissecting the immune infiltrate of primary luminal B-like breast carcinomas in relation to age.

The impact of aging on the immune landscape of luminal breast cancer (Lum-BC) is poorly characterized. Understanding the age-related dynamics of immune editing in Lum-BC is anticipated to improve the therapeutic benefit of immunotherapy in older patients. To this end, here we applied the 'multiple iterative labeling by antibody neo-deposition' (MILAN) technique, a spatially resolved single-cell multiplex immunohistochemistry method.

Phase-change ultrasound contrast agents for proton range verification: towards anapplication.

In proton therapy, range uncertainties prevent optimal benefit from the superior depth-dose characteristics of proton beams over conventional photon-based radiotherapy. To reduce these uncertainties we recently proposed the use of phase-change ultrasound contrast agents as an affordable and effective range verification tool. In particular, superheated nanodroplets can convert into echogenic microbubbles upon proton irradiation, whereby the resulting ultrasound contrast relates to the proton range with high reproducibility.

Aberrant neurodevelopment in human iPS cell-derived models of Alexander disease.

Alexander disease (AxD) is a rare and severe neurodegenerative disorder caused by mutations in glial fibrillary acidic protein (GFAP). While the exact disease mechanism remains unknown, previous studies suggest that mutant GFAP influences many cellular processes, including cytoskeleton stability, mechanosensing, metabolism, and proteasome function. While most studies have primarily focused on GFAP-expressing astrocytes, GFAP is also expressed by radial glia and neural progenitor cells, prompting questions about the impact of GFAP mutations on central nervous system (CNS) development.

ALS-associated C21ORF2 variant disrupts DNA damage repair, mitochondrial metabolism, neuronal excitability and NEK1 levels in human motor neurons.

Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease leading to motor neuron loss. Currently mutations in > 40 genes have been linked to ALS, but the contribution of many genes and genetic mutations to the ALS pathogenic process remains poorly understood. Therefore, we first performed comparative interactome analyses of five recently discovered ALS-associated proteins (C21ORF2, KIF5A, NEK1, TBK1, and TUBA4A) which highlighted many novel binding partners, and both unique and shared interactors.

Left ventricular strain-volume loops in bicuspid aortic valve disease: new insights in cardiomechanics.

Aims: By combining temporal changes in left ventricular (LV) global longitudinal strain (GLS) with LV volume, LV strain-volume loops can assess cardiac function across the cardiac cycle. This study compared LV strain-volume loops between bicuspid aortic valve (BAV) patients and controls, and investigated the loop's prognostic value for clinical events.

Methods And Results: From a prospective cohort of congenital heart disease patients, BAV patients were selected and compared with healthy volunteers, who were matched for age and sex at group level.

The Development and Characteristics of Planetary Health in Medical Education: A Scoping Review.

Purpose: Climate change, biodiversity loss, and other ecological crises threaten human health globally. The interrelation between human health and ecosystems is addressed in the emerging field of planetary health. Ecological crises have created an urgency to integrate planetary health, including sustainable health care, into medical education.

Deciphering lineage specification during early embryogenesis in mouse gastruloids using multilayered proteomics.

Gastrulation is a critical stage in embryonic development during which the germ layers are established. Advances in sequencing technologies led to the identification of gene regulatory programs that control the emergence of the germ layers and their derivatives. However, proteome-based studies of early mammalian development are scarce.

Ultrasound Shear Wave Elastography in Cardiology.

The advent of high-frame rate imaging in ultrasound allowed the development of shear wave elastography as a noninvasive alternative for myocardial stiffness assessment. It measures mechanical waves propagating along the cardiac wall with speeds that are related to stiffness. The use of cardiac shear wave elastography in clinical studies is increasing, but a proper understanding of the different factors that affect wave propagation is required to correctly interpret results because of the heart's thin-walled geometry and intricate material properties.

Effect of interstitial fluid pressure on shear wave elastography: an experimental and computational study.

. An elevated interstitial fluid pressure (IFP) can lead to strain-induced stiffening of poroelastic biological tissues. As shear wave elastography (SWE) measures functional tissue stiffness based on the propagation speed of acoustically induced shear waves, the shear wave velocity (SWV) can be used as an indirect measurement of the IFP.

Galectin-3 and prohibitin 1 are autoantigens in IgG4-related cholangitis without clear-cut protective effects against toxic bile acids.

Background And Aims: IgG4-related cholangitis (IRC) is the hepatobiliary manifestation of IgG4-related disease, a systemic B cell-driven fibro-inflammatory disorder. Four autoantigens have recently been described in IgG4-RD: annexin A11, galectin-3, laminin 511-E8, and prohibitin 1. We have previously reported a protective role of annexin A11 and laminin 511-E8 in human cholangiocytes against toxic bile acids.

Automatic Max-Likelihood Envelope Detection Algorithm for Quantitative High-Frame-Rate Ultrasound for Neonatal Brain Monitoring.

Objective: Post-operative brain injury in neonates may result from disturbed cerebral perfusion, but accurate peri-operative monitoring is lacking. High-frame-rate (HFR) cerebral ultrasound could visualize and quantify flow in all detectable vessels using spectral Doppler; however, automated quantification in small vessels is challenging because of low signal amplitude. We have developed an automatic envelope detection algorithm for HFR pulsed wave spectral Doppler signals, enabling neonatal brain quantitative parameter maps during and after surgery.

An Ultrasound Matrix Transducer for High-Frame-Rate 3-D Intra-cardiac Echocardiography.

Objective: Described here is the development of an ultrasound matrix transducer prototype for high-frame-rate 3-D intra-cardiac echocardiography.

Methods: The matrix array consists of 16 × 18 lead zirconate titanate elements with a pitch of 160 µm × 160 µm built on top of an application-specific integrated circuit that generates transmission signals and digitizes the received signals. To reduce the number of cables in the catheter to a feasible number, we implement subarray beamforming and digitization in receive and use a combination of time-division multiplexing and pulse amplitude modulation data transmission, achieving an 18-fold reduction.

A farnesyl-dependent structural role for CENP-E in expansion of the fibrous corona.

Correct chromosome segregation during cell division depends on proper connections between spindle microtubules and kinetochores. During prometaphase, kinetochores are temporarily covered with a dense protein meshwork known as the fibrous corona. Formed by oligomerization of ROD/ZW10/ZWILCH-SPINDLY (RZZ-S) complexes, the fibrous corona promotes spindle assembly, chromosome orientation, and spindle checkpoint signaling.

A comparison of ultrafast and conventional spectral Doppler ultrasound to measure cerebral blood flow velocity during inguinal hernia repair in infants.

Background: Ultrafast cerebral Doppler ultrasound enables simultaneous quantification and visualization of cerebral blood flow velocity. The aim of this study is to compare the use of conventional and ultrafast spectral Doppler during anesthesia and their potential to show the effect of anesthesiologic procedures on cerebral blood flow velocities, in relation to blood pressure and cerebral oxygenation in infants undergoing inguinal hernia repair.

Methods: A single-center prospective observational cohort study in infants up to six months of age.

Continuous shear wave measurements for dynamic cardiac stiffness evaluation in pigs.

Ultrasound-based shear wave elastography is a promising technique to non-invasively assess the dynamic stiffness variations of the heart. The technique is based on tracking the propagation of acoustically induced shear waves in the myocardium of which the propagation speed is linked to tissue stiffness. This measurement is repeated multiple times across the cardiac cycle to assess the natural variations in wave propagation speed.

Higher Order Singular Value Decomposition Filter for Contrast Echocardiography.

Assessing the coronary circulation with contrast-enhanced echocardiography has high clinical relevance. However, it is not being routinely performed in clinical practice because the current clinical tools generally cannot provide adequate image quality. The contrast agent's visibility in the myocardium is generally poor, impaired by motion and nonlinear propagation artifacts.

Experiences with an integrated screening programme targeted at women who had a hypertensive disorder or diabetes in pregnancy in the Netherlands: a qualitative study.

Objectives: Pregnancy is a predictor of women's health later in life. The risk of eventually developing cardiovascular disease (CVD) and/or type 2 diabetes (T2D) increases three to seven times, after pre-eclampsia, hypertension gravidarum or gestational diabetes. The Heart for Women in The Hague project was designed to offer targeted screening to this high-risk population.

Obesity-associated changes in molecular biology of primary breast cancer.

Obesity is associated with an increased risk of developing breast cancer (BC) and worse prognosis in BC patients, yet its impact on BC biology remains understudied in humans. This study investigates how the biology of untreated primary BC differs according to patients' body mass index (BMI) using data from >2,000 patients. We identify several genomic alterations that are differentially prevalent in overweight or obese patients compared to lean patients.

Added Predictive Value of Female-Specific Factors and Psychosocial Factors for the Risk of Stroke in Women Under 50.

Background And Objectives: Female-specific factors and psychosocial factors may be important in the prediction of stroke but are not included in prediction models that are currently used. We investigated whether addition of these factors would improve the performance of prediction models for the risk of stroke in women younger than 50 years.

Methods: We used data from the Stichting Informatievoorziening voor Zorg en Onderzoek, population-based, primary care database of women aged 20-49 years without a history of cardiovascular disease.