The rockefeller university

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.

At the body surface, skin's stratified squamous epithelium is challenged by environmental extremes. The surface of the skin is composed of enucleated, flattened surface squames. They derive from underlying, transcriptionally active keratinocytes that display filaggrin-containing keratohyalin granules (KGs) whose function is unclear. Here, we found that filaggrin assembles KGs through liquid-liquid phase separation. The dynamics of phase separation governed terminal differentiation and were disrupted by human skin barrier disease-associated mutations. We used fluorescent sensors to investigate endogenous phase behavior in mice. Phase transitions during epidermal stratification crowded cellular spaces with liquid-like KGs whose coalescence was restricted by keratin filament bundles. We imaged cells as they neared the skin surface and found that environmentally regulated KG phase dynamics drive squame formation. Thus, epidermal structure and function are driven by phase-separation dynamics.

Objective Naltrexone and nalmefene are approved for the treatment of alcohol use disorders, in different countries. Naltrexone is also approved for the treatment for opioid use disorders, most recently in a depot formulation. These compounds target primarily mu(mu)- and kappa(kappa)-opioid receptor systems, which are involved in the downstream neurobiological effects of alcohol and in the modulation of neuroendocrine stress systems. The study objective was to compare the neuroendocrine effects of naltrexone and nalmefene on adrenocorticotropic hormone (ACTH), cortisol, and prolactin, in normal volunteers. Method Adult normal volunteers (n = 11 male and n = 9 female) were studied in a stress-minimized inpatient setting on three consecutive days, after intravenous saline, naltrexone HCl (10 mg), or nalmefene HCl (10 mg), in fixed order. ACTH, cortisol, and prolactin were analyzed pre-injection and up to 180 min post-injection. Results Naltrexone and nalmefene caused elevations in ACTH and cortisol compared with saline. Nalmefene had a greater effect on ACTH and cortisol, compared with naltrexone. Both compounds also caused elevations in prolactin in males (females were not examined, due to the influence of menstrual cycle on prolactin). Conclusions This study suggests that both nalmefene and naltrexone have effects potentially due to kappa-partial agonism in humans, as well as antagonist effects at mu-receptors.

Feeding is a complex motivated behavior controlled by a distributed neural network that processes sensory information to generate adaptive behavioral responses. Accordingly, studies using appetitive Pavlovian conditioning confirm that environmental cues that are associated with food availability can induce feeding even in satiated subjects. However, in mice, appetitive conditioning generally requires intensive training and thus can impede molecular studies that often require large numbers of animals. To address this, we developed and validated a simple and rapid context-induced feeding (Ctx-IF) task in which cues associated with food availability can later lead to increased food consumption in sated mice. We show that the associated increase in food consumption is driven by both positive and negative reinforcement and that spaced training is more effective than massed training. Ctx-IF can be completed in ~1 week and provides an opportunity to study the molecular mechanisms and circuitry underlying non-homeostatic eating. We have used this paradigm to map brain regions that are activated during Ctx-IF with cFos immunohistochemistry and found that the insular cortex, and other regions, are activated following exposure to cues denoting the availability of food. Finally, we show that inhibition of the insular cortex using GABA agonists impairs performance of the task. Our findings provide a novel assay in mice for defining the functional neuroanatomy of appetitive conditioning and identify specific brain regions that are activated during the development of learned behaviors that impact food consumption.

Background: IL-17 antagonists induce impressive clinical benefits in psoriasis, but it is unknown to what extent cellular and molecular psoriasis characteristics are suppressed by a clinically relevant dose/schedule of any IL-17-receptor antagonist. Objective: We sought to examine the effects of the IL-17 receptor-A antagonist brodalumab, on clinical and molecular psoriasis features over a 12-week period. Methods: A subset of patients (n = 116) enrolled in 3 phase-3 randomized clinical trials (AMAGINE-1 [Efficacy, Safety, and Withdrawal and Retreatment With Brodalumab in Moderate to Severe Plaque Psoriasis Subjects], -2 [P3 Study Brodalumab in Treatment of Moderate to Severe Plaque Psoriasis], and -3 [Efficacy and Safety of Brodalumab Compared With Placebo and Ustekinumab in Moderate to Severe Plaque Psoriasis in Subjects]) participated in a mechanistic substudy where punch biopsies were collected (lesional and nonlesional skin) between baseline and 12 weeks. This cohort included moderate-to-severe psoriasis patients treated with 140 mg (n = 46), 210 mg (n = 41) brodalumab, or placebo (n = 29). Key epidermal psoriatic features, including T-cell and dendritic cell subsets, were examined using immunohistochemistry. Treatment-induced changes in lesional skin gene expression profiles were evaluated using Affymetrix arrays. Results: IL-17 receptor-A antagonism caused extensive improvements in clinical, histologic, and transcriptomic features of psoriasis. Cellular infiltrates (CD3+, CD8+, CD11c+, CD163+), markers of keratinocyte proliferation (Ki67+, KRT16), and inflammatory cytokines (IL-17A/C/F, IL-23A, IL-12B) decreased progressively, reaching close to nonlesional levels, paralleled by decreases in epidermal thickness. Psoriasis transcriptome gene expression improved similar to 85% to 95% in responders whose psoriasis area severity index improved by 75% from baseline by week 12 (n = 63), compared with similar to 30% to 65% in nonresponders (n = 12), while the residual disease genomic profile was 10% of the psoriasis transcriptome, which is less than for earlier generation drugs. IL-17-dependent gene expression, including keratinocyte genes, improved earlier and more extensively following brodalumab treatment compared with ustekinumab treatment (anti-IL-23/IL-12). Conclusions: The clinically approved dose and schedule for brodalumab leads to nearly complete resolution of clinical, histologic, and transcriptomic features of psoriasis. Evidently, IL-17-induced release of keratinocyte-derived inflammatory mediators is a key driver of psoriasis pathogenesis.