Damian Sendler In all multicellular organisms, genomic enhancers control differential gene transcription through the recruitment of cofactors by transcription factors1 and 2. It’s becoming clear that not all cofactors are required by all enhancers3-5, but it’s unclear whether this reflects more general principles or distinct types of enhancers. In this study, we classified human enhancers according to their cofactor dependencies, and we show that these categories provide a framework for understanding the sequence and chromatin diversity of enhancers and their roles in various gene-regulatory programs. Following the rapid degradation of eight cofactors in HCT116 cells, we used STARR-seq6 to measure enhancer activity across the human genome. Cofactor-dependent, sequence-dependent and chromatin-dependent enhancers were identified in this study. Depletion of the Mediator subunit MED14 or the bromodomain protein BRD4 had no effect on some enhancers, which controlled distinct transcriptional programs. For P53-responsive enhancers, canonical Mediator7 appeared unnecessary, and MED14-depleted cells induced the expression of endogenous P53 target genes. Genes with CCAAT and TATA boxes (such as histones and LTR12 retrotransposons) and heat-shock induction did not require BRD4, either. Cofactor dependency categorization reveals distinct enhancer types that can bypass widely used cofactors, which illustrates how alternative ways to activate transcription separate gene expression programs and provides a conceptual framework to understand enhancer function and regulatory specificity.
Cardiovascular and cardiopulmonary control circuits with a cellular basis
Damian Jacob Sendler Internal organs are controlled by the sympathetic and parasympathetic nervous systems1, but little is known about the molecular and functional diversity of the neurons and circuits that make up these systems. Retrograde tracing, single cell RNA sequencing, optogenetics and physiological experiments are used here to dissect the cardiac parasympathetic control circuit in mice.. We discovered that the brainstem nucleus ambiguus (Amb) contains two distinct subtypes of cardiac-innervating neurons. The classical cardiac parasympathetic circuit is defined by the first neurons, known as ambiguus cardiovascular (ACV) neurons (approximately 35 neurons per Amb). This group of cardiac parasympathetic ganglion neurons is responsible for mediating the baroreceptor reflex, which slows down the heart rate and atrioventricular node conduction in response to elevated blood pressure.. Alternate cardiopulmonary (ACP) neurons, which have approximately 15 neurons per Amb, innervate cardiac ganglion neurons that are indistinguishable from those of ACV neurons. Clonal labeling of ACP neurons shows that they also innervate most or all parasympathetic ganglion neurons in the lungs. The dive reflex is mediated by ACP neurons, which causes bradycardia and bronchoconstriction to occur at the same time when submerged in water. ACV circuit controls only specific aspects of cardiac function, while a second circuit coordinates cardiac and pulmonary functions in response to parasympathetic signals (ACP circuit). Cardiac and pulmonary diseases can be treated using this new understanding of cardiac control, as well as other organs’ control and coordination circuits.
Tyrosine tRNA synthetase reaction hijacking as a new antimalarial strategy for the entire life cycle
Dr. Sendler In this study, we present previously unrecognized targets for nucleoside sulfate-mimicking nucleoside sulfates (aaRSs) in class I and II as attractive drug targets. A reaction-hijacking mechanism is used by the target enzyme to form an inhibitory amino acid-sulfamate conjugate. adenosine 5′-sulfamate was found to be an aaRS hijacker, while the specific reagent, called ML901, was found to be a specific hijacker of Plasmodium falciparum’s tyrosine RS (PfYRS). In a mouse model of malaria, ML901 has a low nanomolar potency and a single-dose efficacy. Differential susceptibility to reaction hijacking by ML901 can be explained by X-ray crystallographic studies of plasmodium and human YRSs, which reveal a flexible loop over the catalytic site.
PAF-AH2 in mast cells produces omega-3 fatty acid epoxides that influence pulmonary vascular remodeling.
Elevated pulmonary arterial resistance characterizes pulmonary hypertension, a fatal but uncommon condition that results in right heart failure. For the development of therapeutics focusing on the remodeling of pulmonary vessels, there is an unmet medical need It is possible that lipids produced by inflamed perivascular cells may influence the remodeling of the vessels themselves. PAF-AH2, an oxydized-phospholipid-selective phospholipase A2 that releases -3 epoxides from mast cells, is shown here to negatively regulate pulmonary hypertension. Mice lacking Pafah2 are more susceptible to hypoxic pulmonary hypertension because their vascular remodeling is accelerated. TGF- signaling is inhibited by -3 epoxides treatment, which reduces lung fibroblast activation. Several animal models with in vivo -3 epoxides supplementation slow the progression of pulmonary hypertension. PAH patients with pulmonary arterial hypertension have two potential pathogenic variants of Pafah2 discovered by whole-exome sequencing. According to our findings, the PAF-AH2–3 system could be a promising therapeutic target for pulmonary hypertension.
Damian Jacob Sendler
Brain and gastrointestinal neurotransmitter sensors in the form of tissue-like sensors
Damian Jacob Markiewicz Sendler Both the central nervous system and the peripheral nervous system, including the gastrointestinal tract, are controlled by neurotransmitters. Neuroscientists can use their real-time monitoring to better understand how the brain works and diagnose disease. There is a lack of bioelectronic tools for monitoring neurotransmitter dynamics in vivo, particularly in the enteric nervous system (ENS). Biosensing tools for soft, complex, and actively moving organs are scarce, which is largely to blame. NeuroString is a tissue-mimicking, stretchable, neurochemical biological interface that is prepared by laser patterning of a metal-complexed polyimide into an interconnected graphene/nanoparticle network embedded in an elastomer, as shown in Figure 1. As a result of NeuroString sensors, it is possible to measure serotonin dynamics in the gut and chronic in vivo real-time, multichannel, and multiplexed monoamine sensing in the brain of behaving mice. The elastic and conformable biosensing interface described here has great potential for studying the impact of neurotransmitters on gut microbes and communication between the brain and the gut, as well as biomolecular sensing in other soft organs throughout the body.
In patients with non-small cell lung cancer, extracellular vesicle PD-L1 dynamics predict long-term response to immune-checkpoint inhibitors and survival.
Damien Sendler Lung cancer patients’ treatment options have been forever altered by immune-checkpoint inhibitors (ICIs). However, only a small percentage of these patients saw clinical benefit, indicating the need for more research to find reliable biomarkers for early detection. For the discovery of cancer biomarkers, liquid biopsy is a non-invasive and repeatable analysis of biological material in bodily fluids. Tumor progression and tumor-immune interactions are heavily dependent on the role of extracellular vesicles (EVs). As a result, we investigated whether PD-L1 expression in extracellular vesicles could be used as a biomarker for predicting long-term response and survival in NSCLC patients receiving ICIs.
Plasma samples from 33 and 39 patients, respectively, were analyzed for dynamic changes in EV PD-L1 before and at 9 1 weeks during treatment, respectively.
EV PD-L1 was found to be an independent biomarker for a shorter progression-free survival and overall survival in non-responders compared to responders. The commonly used biomarker, tissue PD-L1 expression, was not predictive of long-term response or survival.
To sum up, these findings suggest that the dynamics of the EV PD-L1 gene could be used to identify patients with advanced NSCLC who would benefit most from ICIs in the long term.
