Redirecting the pioneering function of FOXA1 with covalent small molecules.

Pioneer transcription factors (TFs) bind to and open closed chromatin, facilitating engagement by other regulatory factors involved in gene activation or repression. Chemical probes are lacking for pioneer TFs, which has hindered their mechanistic investigation in cells. Here, we report the chemical proteomic discovery of electrophilic compounds that stereoselectively and site-specifically bind the pioneer TF forkhead box protein A1 (FOXA1) at a cysteine (C258) within the forkhead DNA-binding domain.

Functional Investigations of p53 Acetylation Enabled by Heterobifunctional Molecules.

Post-translational modifications (PTMs) dynamically regulate the critical stress response and tumor suppressive functions of p53. Among these, acetylation events mediated by multiple acetyltransferases lead to differential target gene activation and subsequent cell fate. However, our understanding of these events is incomplete due to, in part, the inability to selectively and dynamically control p53 acetylation.

The 4.2 ka event is not remarkable in the context of Holocene climate variability.

The "4.2 ka event" is a commonly described abrupt climate excursion that occurred about 4200 years ago. However, the extent to which this event is coherent across regional and larger scales is unclear.

Redirecting the pioneering function of FOXA1 with covalent small molecules.

Pioneer transcription factors (TFs) exhibit a specialized ability to bind to and open closed chromatin, facilitating engagement by other regulatory factors involved in gene activation or repression. Chemical probes are lacking for pioneer TFs, which has hindered their mechanistic investigation in cells. Here, we report the chemical proteomic discovery of electrophilic small molecules that stereoselectively and site-specifically bind the pioneer TF, FOXA1, at a cysteine (C258) within the forkhead DNA-binding domain.

Inherited blood cancer predisposition through altered transcription elongation.

Despite advances in defining diverse somatic mutations that cause myeloid malignancies, a significant heritable component for these cancers remains largely unexplained. Here, we perform rare variant association studies in a large population cohort to identify inherited predisposition genes for these blood cancers. CTR9, which encodes a key component of the PAF1 transcription elongation complex, is among the significant genes identified.

Small-molecule tools for YEATS domain proteins.

Chromatin reader domains are protein folds that bind to post-translational modifications of histones and other chromatin-associated proteins. Compared to other families of reader domains, the discovery that YEATS domains bind to acylated lysines is relatively recent. Four human proteins harbor a YEATS domain, and each is present in protein complexes that regulate chromatin and transcription (ENL, AF9, YEATS2, and YEATS4).

Collateral lethality between HDAC1 and HDAC2 exploits cancer-specific NuRD complex vulnerabilities.

Transcriptional co-regulators have been widely pursued as targets for disrupting oncogenic gene regulatory programs. However, many proteins in this target class are universally essential for cell survival, which limits their therapeutic window. Here we unveil a genetic interaction between histone deacetylase 1 (HDAC1) and HDAC2, wherein each paralog is synthetically lethal with hemizygous deletion of the other.

Acetyl-CoA biosynthesis drives resistance to histone acetyltransferase inhibition.

Histone acetyltransferases (HATs) are implicated as both oncogene and nononcogene dependencies in diverse human cancers. Acetyl-CoA-competitive HAT inhibitors have emerged as potential cancer therapeutics and the first clinical trial for this class of drugs is ongoing (NCT04606446). Despite these developments, the potential mechanisms of therapeutic response and evolved drug resistance remain poorly understood.

Functional mapping of sensorimotor activation in the human thalamus at 9.4 Tesla.

Although the thalamus is perceived as a passive relay station for almost all sensory signals, the function of individual thalamic nuclei remains unresolved. In the present study, we aimed to identify the sensorimotor nuclei of the thalamus in humans using task-based fMRI at a field strength of 9.4T by assessing the individual subject-specific sensorimotor BOLD response during a combined active motor (finger-tapping) and passive sensory (tactile-finger) stimulation.

Volume of subcortical brain regions in social anxiety disorder: mega-analytic results from 37 samples in the ENIGMA-Anxiety Working Group.

There is limited convergence in neuroimaging investigations into volumes of subcortical brain regions in social anxiety disorder (SAD). The inconsistent findings may arise from variations in methodological approaches across studies, including sample selection based on age and clinical characteristics. The ENIGMA-Anxiety Working Group initiated a global mega-analysis to determine whether differences in subcortical volumes can be detected in adults and adolescents with SAD relative to healthy controls.

Innovative technologies for reverse total shoulder arthroplasty in Australia: Market access challenges and implications for patients, decision-makers, and manufacturers.

Purpose: The success of reverse total shoulder arthroplasty (RTSA) has expanded its use for a broader range of shoulder indications worldwide. Evidence regarding the relative efficacy and long-term safety of medical technologies used in RTSA is subjected to rigorous assessment. Nonetheless, substantial challenges impede market access for innovative shoulder implant technologies for RTSA in Australia, resulting in delayed patient access.

Gait decline while dual-tasking is an early sign of white matter deterioration in middle-aged and older adults.

Loss of white matter integrity (WMI) is associated with gait deficits in middle-aged and older adults. However, these deficits are often only apparent under cognitively demanding situations, such as walking and simultaneously performing a secondary cognitive task. Moreover, evidence suggests that declining executive functions (EF) are linked to gait decline, and their co-occurrence may point to a common underlying pathology, i.

Endocarditis: Who Is Particularly at Risk and Why? Ten Years Analysis of Risk Factors for In-hospital Mortality in Infective Endocarditis.

Background: Endocarditis is continuously increasing. Evidence exist that the prognosis is adversely affected by the extent of the disease. We looked at risk factors influencing in-hospital mortality (HM).

Personalized neurorehabilitative precision medicine: from data to therapies (MWKNeuroReha) - a multi-centre prospective observational clinical trial to predict long-term outcome of patients with acute motor stroke.

Background: Stroke is one of the most frequent diseases, and half of the stroke survivors are left with permanent impairment. Prediction of individual outcome is still difficult. Many but not all patients with stroke improve by approximately 1.

Correlates of individual voice and face preferential responses during resting state.

Human nonverbal social signals are transmitted to a large extent by vocal and facial cues. The prominent importance of these cues is reflected in specialized cerebral regions which preferentially respond to these stimuli, e.g.

Liver cirrhosis: Still an elusive risk factor in the current EuroSCORE system.

Objectives: Liver cirrhosis increases the risk of death in patients having cardiac surgery, and the risk is markedly dependent on the actual stage. The EuroSCORE II, however, does not specifically address the risk of death of patients with liver cirrhosis. We investigated the predictive power of EuroSCORE II in patients with liver cirrhosis.

Increased functional connectivity in a population at risk of developing Parkinson's disease.

Background: While the concept of prodromal Parkinson's disease (PD) is well established, reliable markers for the diagnosis of this disease stage are still lacking. We investigated the functional connectivity of the putamina in a resting-state functional MRI analysis in persons with at least two prodromal factors for PD, which is considered a high risk for PD (HRPD) group, in comparison to PD patients and controls.

Methods: We included 16 PD patients, 20 healthy controls and 20 HRPD subjects.

Evaluation of Cost, Payments, Healthcare Utilization, and Perioperative and Post-Operative Outcomes of Patients Treated with Posterior Lumbar Spinal Surgery Using Open versus Minimally Invasive Surgical Approaches.

Purpose: Minimally invasive surgery (MIS) of the spine has been associated with favorable outcomes compared to open surgery. This study evaluated matched cohorts treated with MIS versus open posterior lumbar fusion for costs, payments, healthcare utilization and outcomes.

Patients And Methods: This study used the Premier Healthcare and IBM MarketScan Commercial and Medicare Databases.

The impact of chronotype on circadian rest-activity rhythm and sleep characteristics across the week.

Circadian rhythms are maintained by a complex "system of systems" that continuously coordinates biological processes with each other and the environment. Although humans predominantly entrain to solar time, individual persons vary in their precise behavioral timing due to endogenous and exogenous factors. Endogenous differences in the timing of individual circadian rhythms relative to a common environmental cue are known as chronotypes, ranging from earlier than average (Morningness) to later than average (Eveningness).

Chemical Inhibition of ENL/AF9 YEATS Domains in Acute Leukemia.

Transcriptional coregulators, which mediate chromatin-dependent transcriptional signaling, represent tractable targets to modulate tumorigenic gene expression programs with small molecules. Genetic loss-of-function studies have recently implicated the transcriptional coactivator, ENL, as a selective requirement for the survival of acute leukemia and highlighted an essential role for its chromatin reader YEATS domain. Motivated by these discoveries, we executed a screen of nearly 300,000 small molecules and identified an amido-imidazopyridine inhibitor of the ENL YEATS domain (IC = 7 μM).

Comparing the efficacy of γ- and electron-irradiation of PBMCs to promote secretion of paracrine, regenerative factors.

Cell-free secretomes represent a promising new therapeutic avenue in regenerative medicine, and γ-irradiation of human peripheral blood mononuclear cells (PBMCs) has been shown to promote the release of paracrine factors with high regenerative potential. Recently, the use of alternative irradiation sources, such as artificially generated β- or electron-irradiation, is encouraged by authorities. Since the effect of the less hazardous electron-radiation on the production and functions of paracrine factors has not been tested so far, we compared the effects of γ- and electron-irradiation on PBMCs and determined the efficacy of both radiation sources for producing regenerative secretomes.

Asymmetric high-order anatomical brain connectivity sculpts effective connectivity.

Bridging the gap between symmetric, direct white matter brain connectivity and neural dynamics that are often asymmetric and polysynaptic may offer insights into brain architecture, but this remains an unresolved challenge in neuroscience. Here, we used the graph Laplacian matrix to simulate symmetric and asymmetric high-order diffusion processes akin to particles spreading through white matter pathways. The simulated indirect structural connectivity outperformed direct as well as absent anatomical information in sculpting effective connectivity, a measure of causal and directed brain dynamics.