The rockefeller university

Vulnerability to relapse during periods of attempted abstinence from cocaine use is hypothesized to result from the rewiring of brain reward circuitries, particularly ventral tegmental area (VTA) dopamine neurons. How cocaine exposures act on midbrain dopamine neurons to precipitate addiction-relevant changes in gene expression is unclear. We found that histone H3 glutamine 5 dopaminylation (H3Q5dop) plays a critical role in cocaine-induced transcriptional plasticity in the midbrain. Rats undergoing withdrawal from cocaine showed an accumulation of H3Q5dop in the VTA. By reducing H3Q5dop in the VTA during withdrawal, we reversed cocaine-mediated gene expression changes, attenuated dopamine release in the nucleus accumbens, and reduced cocaine-seeking behavior. These findings establish a neurotransmission-independent role for nuclear dopamine in relapse-related transcriptional plasticity in the VTA.

Fanconi anemia (FA) is the most common genetic cause of bone marrow failure and is caused by inherited pathogenic variants in any of 22 genes. Of these, only FANCB is X-linked. We describe a cohort of 19 children with FANCB variants, from 16 families of the International Fanconi Anemia Registry. Those with FANCB deletion or truncation demonstrate earlier-than-average onset of bone marrow failure and more severe congenital abnormalities compared with a large series of FA individuals in published reports. This reflects the indispensable role of FANCB protein in the enzymatic activation of FANCD2 monoubiquitination, an essential step in the repair of DNA interstrand crosslinks. For FANCB missense variants, more variable severity is associated with the extent of residual FANCD2 monoubiquitination activity. We used transcript analysis, genetic complementation, and biochemical reconstitution of FANCD2 monoubiquitination to determine the pathogenicity of each variant. Aberrant splicing and transcript destabilization were associated with 2 missense variants. Individuals carrying missense variants with drastically reduced FANCD2 monoubiquitination in biochemical and/or cell-based assays tended to show earlier onset of hematologic disease and shorter survival. Conversely, variants with near-normal FANCD2 monoubiquitination were associated with more favorable outcome. Our study reveals a genotype-phenotype correlation within the FA-B complementation group of FA, where severity is associated with level of residual FANCD2 monoubiquitination.

To spatially co-exist and differentially specify fates within developing tissues, morphogenetic cues must be correctly positioned and interpreted. Here, we investigate mouse hair follicle development to understand how morphogens operate within closely spaced, fate-diverging progenitors. Coupling transcriptomics with genetics, we show that emerging hair progenitors produce both WNTs and WNT inhibitors. Surprisingly, however, instead of generating a negative feedback loop, the signals oppositely polarize, establishing sharp boundaries and consequently a short-range morphogen gradient that we show is essential for three-dimensional pattern formation. By establishing a morphogen gradient at the cellular level, signals become constrained. The progenitor preserves its WNT signaling identity and maintains WNT signaling with underlying mesenchymal neighbors, while its overlying epithelial cells become WNT-restricted. The outcome guarantees emergence of adjacent distinct cell types to pattern the tissue.

Gastruloids are embryo-like structures that display key features of post-implantation embryonic development, yet whether they fully recapitulate in vivo embryogenesis remains unsolved. Recently in Nature, van den Brink et al. (2020) performed high-resolution gene expression analysis to identify significant similarities between mouse gastruloids and embryos in positional lineage segregation and somite formation.

The response of chiral fermions to time and space dependent axial imbalance and constant magnetic field is analyzed. The axial-vector-vector-vector (AVV) three-point function is studied using a real-time approach at finite temperature in the weak external field approximation. The chiral magnetic conductivity is given analytically for noninteracting fermions. It is pointed out that local charge conservation plays an important role when the axial imbalance is inhomogeneous. Proper regularization is needed which makes the constant axial imbalance limit delicate: for static but spatially oscillating chiral charge the chiral magnetic effect (CME) current vanishes. In the homogeneous (but possible time-dependent) limit of the axial imbalance the CME current is determined solely by the chiral anomaly. As a phenomenological consequence, the observability of the charge asymmetry caused by the CME turns out to be a matter of interplay between various scales of the system. Possible plasma instabilities resulting from the gradient corrections to the CME current are also pointed out.

Background: Cancer cells rewire their metabolism to meet the energetic and biosynthetic demands of their high proliferation rates and environment. Metabolic reprogramming of cancer cells may result in strong dependencies on nutrients that could be exploited for therapy. While these dependencies may be in part due to the nutrient environment of tumors, mutations or expression changes in metabolic genes also reprogram metabolic pathways and create addictions to extracellular nutrients. Scope of review: This review summarizes the major nutrient dependencies of cancer cells focusing on their discovery and potential mechanisms by which metabolites become limiting for tumor growth. We further detail available therapeutic interventions based on these metabolic features and highlight opportunities for restricting nutrient availability as an anti-cancer strategy. Major conclusions: Strategies to limit nutrients required for tumor growth using dietary interventions or nutrient degrading enzymes have previously been suggested for cancer therapy. The best clinical example of exploiting cancer nutrient dependencies is the treatment of leukemia with L-asparaginase, a first-line chemotherapeutic that depletes serum asparagine. Despite the success of nutrient starvation in blood cancers, it remains unclear whether this approach could be extended to other solid tumors. Systematic studies to identify nutrient dependencies unique to individual tumor types have the potential to discover targets for therapy. Published by Elsevier GmbH.

Ribosome-associated quality control (RQC) purges aberrant mRNAs and nascent polypeptides in a multi-step molecular process initiated by the E3 ligase ZNF598 through sensing of ribosomes collided at aberrant mRNAs and monoubiquitination of distinct small ribosomal subunit proteins. We show that G3BP1-family-USP10 complexes are required for deubiquitination of RPS2, RPS3, and RPS10 to rescue modified 40S subunits from programmed degradation. Knockout of USP10 or G3BP1 family proteins increased lysosomal ribosomal degradation and perturbed ribosomal subunit stoichiometry, both of which were rescued by a single K214R substitution of RPS3. While the majority of RPS2 and RPS3 monoubiquitination resulted from ZNF598-dependent sensing of ribosome collisions initiating RQC, another minor pathway contributed to their monoubiquitination. G3BP1 family proteins have long been considered RNA-binding proteins, however, our results identified 40S subunits and associated mRNAs as their predominant targets, a feature shared by stress granules to which G3BP1 family proteins localize under stress.

Background: The aim is to compare the machine learning-based coronary-computed tomography fractional flow reserve (CT-FFRML) and coronary-computed tomographic morphological plaque characteristics with the resting full-cycle ratio (RFRTM) as a novel invasive resting pressure-wire index for detecting hemodynamically significant coronary artery stenosis. Methods: In our single center study, patients with coronary artery disease (CAD) who had a clinically indicated coronary computed tomography angiography (cCTA) and subsequent invasive coronary angiography (ICA) with pressure wire-measurement were included. On-site prototype CT-FFRML software and on-site CT-plaque software were used to calculate the hemodynamic relevance of coronary stenosis. Results: We enrolled 33 patients (70% male, mean age 68 +/- 12 years). On a per-lesion basis, the area under the receiver operating characteristic curve (AUC) of CT-FFRML (0.90) was higher than the AUCs of the morphological plaque characteristics length/minimal luminal diameter(4) (LL/MLD4; 0.80), minimal luminal diameter (MLD; 0.77), remodeling index (RI; 0.76), degree of luminal diameter stenosis (0.75), and minimal luminal area (MLA; 0.75). Conclusion: CT-FFRML and morphological plaque characteristics show a significant correlation to detected hemodynamically significant coronary stenosis. Whole CT-FFRML had the best discriminatory power, using RFRTM as the reference standard.

Cancer cells need to acquire specific molecular traits in order to spread to distant organs. In this issue of Developmental Cell, Marsh et al. show that autophagy restricts the outgrowth of breast cancer metastases in contrast to its impact on primary tumor progression.