The rockefeller university

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.

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.

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.

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.

Human infection by Zika virus (ZIKV) during pregnancy can lead to vertical transmission and fetal aberrations, including microcephaly. Prophylactic administration of antibodies can diminish or prevent ZIKV infection in animal models, but whether passive immunization can protect nonhuman primates and their fetuses during pregnancy has not been determined. Z004 and Z021 are neutralizing monoclonal antibodies to domain III of the envelope (EDIII) of ZIKV. Together the two antibodies protect nonpregnant macaques against infection even after Fc modifications to prevent antibody-dependent enhancement (ADE) in vitro and extend their half-lives. Here we report on prophylactic coadministration of the Fc-modified antibodies to pregnant rhesus macaques challenged three times with ZIKV during first and second trimester. The two antibodies did not entirely eliminate maternal viremia but limited vertical transmission, protecting the fetus from neurologic damage. Thus, maternal passive immunization with two antibodies to EDIII can shield primate fetuses from the harmful effects of ZIKV.

Many lines of evidence point to links between sleep regulation and energy homeostasis, but mechanisms underlying these connections are unknown. During Caenorhabditis elegans sleep, energetic stores are allocated to nonneural tasks with a resultant drop in the overall fat stores and energy charge. Mutants lacking KIN-29, the C. elegans homolog of a mammalian Salt-Inducible Kinase (SIK) that signals sleep pressure, have low ATP levels despite high-fat stores, indicating a defective response to cellular energy deficits. Liberating energy stores corrects adiposity and sleep defects of kin-29 mutants. kin-29 sleep and energy homeostasis roles map to a set of sensory neurons that act upstream of fat regulation as well as of central sleep-controlling neurons, suggesting hierarchical somatic/neural interactions regulating sleep and energy homeostasis. Genetic interaction between kin-29 and the histone deacetylase hda-4 coupled with subcellular localization studies indicate that KIN-29 acts in the nucleus to regulate sleep. We propose that KIN-29/SIK acts in nuclei of sensory neuroendocrine cells to transduce low cellular energy charge into the mobilization of energy stores, which in turn promotes sleep.

Nicotine addiction, through smoking, is the principal cause of preventable mortality worldwide. Human genome-wide association studies have linked polymorphisms in the CHRNA5-CHRNA3-CHRNB4 gene cluster, coding for the alpha 5, alpha 3, and beta 4 nicotinic acetylcholine receptor (nAChR) subunits, to nicotine addiction. beta 4*nAChRs have been implicated in nicotine withdrawal, aversion, and reinforcement. Here we show that beta 4*nAChRs also are involved in non-nicotine-mediated responses that may predispose to addiction-related behaviors. beta 4 knock-out (KO) male mice show increased novelty-induced locomotor activity, lower baseline anxiety, and motivational deficits in operant conditioning for palatable food rewards and in reward-based Go/No-go tasks. To further explore reward deficits we used intracranial self-administration (ICSA) by directly injecting nicotine into the ventral tegmental area (VIA) in mice. We found that, at low nicotine doses, beta 4KO self-administer less than wild-type (WT) mice. Conversely, at high nicotine doses, this was reversed and beta 4KO self-administered more than WT mice, whereas beta 4-overexpressing mice avoided nicotine injections. Viral expression of beta 4 subunits in medial habenula (MHb), interpeduncular nucleus (IPN), and VTA of beta 4KO mice revealed dose- and region-dependent differences: beta 4*nAChRs in the VTA potentiated nicotine-mediated rewarding effects at all doses, whereas beta 4*nAChRs in the MHb-IPN pathway, limited VTA-ICSA at high nicotine doses. Together, our findings indicate that the lack of functional PP nAChRs result in deficits in reward sensitivity including increased ICSA at high doses of nicotine that is restored by re-expression of beta 4*nAChRs in the MHb-IPN. These data indicate that beta 4 is a critical modulator of reward-related behaviors.

After taking up tumour-associated antigens, dendritic cells in mouse and human tumours upregulate a regulatory gene program that limits dendritic cell immunostimulatory function, and modulating this program can rescue antitumor immunity in mice. Checkpoint blockade therapies have improved cancer treatment, but such immunotherapy regimens fail in a large subset of patients. Conventional type 1 dendritic cells (DC1s) control the response to checkpoint blockade in preclinical models and are associated with better overall survival in patients with cancer, reflecting the specialized ability of these cells to prime the responses of CD8(+) T cells(1-3). Paradoxically, however, DC1s can be found in tumours that resist checkpoint blockade, suggesting that the functions of these cells may be altered in some lesions. Here, using single-cell RNA sequencing in human and mouse non-small-cell lung cancers, we identify a cluster of dendritic cells (DCs) that we name 'mature DCs enriched in immunoregulatory molecules' (mregDCs), owing to their coexpression of immunoregulatory genes (Cd274, Pdcd1lg2 and Cd200) and maturation genes (Cd40, Ccr7 and Il12b). We find that the mregDC program is expressed by canonical DC1s and DC2s upon uptake of tumour antigens. We further find that upregulation of the programmed death ligand 1 protein-a key checkpoint molecule-in mregDCs is induced by the receptor tyrosine kinase AXL, while upregulation of interleukin (IL)-12 depends strictly on interferon-gamma and is controlled negatively by IL-4 signalling. Blocking IL-4 enhances IL-12 production by tumour-antigen-bearing mregDC1s, expands the pool of tumour-infiltrating effector T cells and reduces tumour burden. We have therefore uncovered a regulatory module associated with tumour-antigen uptake that reduces DC1 functionality in human and mouse cancers.

Transcription initiation requires formation of the open promoter complex (RPo). To generate RPo, RNA polymerase (RNAP) unwinds the DNA duplex to form the transcription bubble and loads the DNA into the RNAP active site. RPo formation is a multi-step process with transient intermediates of unknown structure. We use single-particle cryoelectron microscopy to visualize seven intermediates containing Escherichia coli RNAP with the transcription factor TraR en route to forming RPo. The structures span the RPo formation pathway from initial recognition of the duplex promoter in a closed complex to the final RPo. The structures and supporting biochemical data define RNAP and promoter DNA conformational changes that delineate steps on the pathway, including previously undetected transient promoter-RNAP interactions that contribute to populating the intermediates but do not occur in RPo. Our work provides a structural basis for understanding RPo formation and its regulation, a major checkpoint in gene expression throughout evolution.

Parasites can have important detrimental effects on host fitness, thereby influencing their ecology and evolution. Hosts can, in turn, exert strong selective pressures on their parasites, affecting eco-evolutionary dynamics. Although the reciprocal pressures that hosts and parasites exert on each other have long been recognized, the mechanisms are insufficiently understood. Here, we discuss the role of host cognition in host-parasite eco-evolutionary dynamics. Theoretical advances have acknowledged the importance of behavior in shaping these dynamics, but how and why host cognition should affect and/or be affected by parasites is less clear. We propose three scenarios that may create causal and non-causal links between cognition and the richness, prevalence and intensity of parasites. First, host cognition may change the probability of exposure to parasites, either increasing (e.g., altering the relationship with the environment via innovative behaviors) or decreasing (e.g., influencing decision-making to avoid infected conspecifics) exposure. Second, parasites may change host cognitive performance, for example, by reducing host condition. Finally, host cognition and parasites can be associated via common causal factors (e.g., shared molecular pathways), energetic constraints generating trade-offs between cognition and immunocompetence, or trait co-evolution with life history, ecological, or social strategies. The existence of such a variety of non-mutually exclusive mechanisms suggests that host cognition has a great potential to affect and be affected by parasites. However, it also implies that progress in understanding these effects will only be possible if we distinguish between causal and non-causal links.