The rockefeller university

Multiplexed imaging is a powerful approach in spatial biology, although it is complex, expensive and labor-intensive. Here, we present the IBEX Knowledge-Base, a central resource for reagents, protocols and more, to enhance knowledge sharing, optimization and innovation of spatial proteomics techniques.

Mycobacterium tuberculosis (Mtb), a leading cause of death from infection, completes its life cycle entirely in humans except for transmission through the air. To begin to understand how Mtb survives aerosolization, we mimicked liquid and atmospheric conditions experienced by Mtb before and after exhalation using a model aerosol fluid (MAF) based on the water- soluble, lipidic, and cellular constituents of necrotic tuberculosis lesions. MAF induced drug tolerance in Mtb, remodeled its transcriptome, and protected Mtb from dying in microdroplets desiccating in air. Yet survival was not passive: Mtb appeared to rely on hundreds of genes to survive conditions associated with transmission. Essential genes subserving proteostasis offered most protection. A large number of conventionally nonessential genes appeared to contribute as well, including genes encoding proteins that resemble antidesiccants. The candidate transmission survival genome of Mtb may offer opportunities to reduce transmission of tuberculosis.

The intestinal immune system must concomitantly tolerate food and commensals and protect against pathogens. Antigen-presenting cells (APCs) orchestrate these immune responses by presenting luminal antigens to CD4+ T cells and inducing their differentiation into regulatory (peripheral regulatory T cell) or inflammatory [T helper (Th) cell] subsets. We used a proximity labeling method (LIPSTIC) to identify APCs that presented dietary antigens under tolerizing and inflammatory conditions and to understand cellular mechanisms by which tolerance to food is induced and can be disrupted by infection. Helminth infections disrupted tolerance induction proportionally to the reduction in the ratio between tolerogenic APCs-including migratory dendritic cells (cDC1s) and Ror gamma t+ APCs-and inflammatory APCs, which were primarily cDC2s. These inflammatory cDC2s expanded by helminth infection did not present dietary antigens, thus avoiding diet-specific Th2 responses.

Males of many species have evolved behavioral traits to both attract females and repel rivals. Here, we explore mate selection in Drosophila from both the male and female perspective to shed light on how these key components of sexual selection-female choice and male-male competition-work in concert to guide reproductive strategies. We find that male flies fend off competing suitors by interleaving their courtship of a female with aggressive wing flicks, which both repel competitors and generate a "song"that obscures the female's auditory perception of other potential mates. Two higher-order circuit nodes-P1a and pC1x neurons-are coordinately recruited to allow males to flexibly interleave these agonistic actions with courtship displays, assuring they persistently pursue females until their rival falters. Together, our results suggest that female mating decisions are shaped by male-male interactions, underscoring how a male's ability to subvert his rivals is central to his reproductive success.

Changing a circuit dynamically, without actually changing the hardware itself, is called reconfiguration, and is of great importance due to its manifold technological applications. Circuit reconfiguration appears to be a feature of the cerebral cortex, so understanding the dynamical principles underlying self-reconfiguration may prove of import to elucidate brain function. We present a very simple example of dynamical reconfiguration: a family of networks whose signal pathways can be switched on the fly, only through use of their inputs, with no changes to their synaptic weights. These are single-layer convolutional recurrent network with local unitary synaptic weights and a smooth sigmoidal activation function. We generate traveling waves using the high spatiotemporal frequencies of the input, and we use the low spatiotemporal frequencies of the input to landscape the ongoing activity, channeling said traveling waves through an input-specified spatial pattern. This mechanism uses inherent properties of marginally stable, dynamically critical systems, which are a direct consequence of their unitary convolution kernels: every network in the family can do this. We show these networks solve the classical connectedness detection problem, by allowing signal propagation only along the regions to be evaluated for connectedness, and forbidding it elsewhere.

Hidradenitis suppurativa (HS) is a chronic inflammatory disease that is difficult to control, and its mechanism remains unclear. Hepatocyte GF (HGF) has been reported to be significantly upregulated in the serum and skin of patients with HS, especially in the lesions with tunnels. In this study, we examined the transcriptome of HGF-treated keratinocytes and compared it with genetic profiling of HS lesions. HGF was highly expressed in HS skin, especially in the deep dermis, compared with that in healthy controls, and its source was mainly fibroblasts. HGF upregulated more genes in keratinocytes than IL-17A or TNF-a, and these genes included multiple epithelial-mesenchymal transition-related genes. Differentially expressed genes in HGF-stimulated keratinocytes were involved in activation of epithelial-mesenchymal transition-related pathways. These HGF-induced genes were significantly upregulated in HS lesions compared with those in healthy skin and nonlesions and were more strongly associated with HS tunnels. In summary, HGF was highly expressed in HS and induced epithelial-mesenchymal transition-related genes in keratinocytes; HGF-induced genes were highly associated with gene profiling of HS with tunnels, suggesting that HGF may be involved in HS tunnel formation through epithelial-mesenchymal transition.

Division of labour (DoL) is of prime importance in the success of social insects in various ecosystems and benefits their colonies by increasing efficiency and productivity. This review summarizes more than three decades of experimental evidence collected towards understanding the emergence and maintenance of division of labour in the Indian tropical paper wasp Ropalidia marginata. This primitively eusocial species provides an interesting variation between newly founded colonies and mature colonies in terms of the behavioural mechanisms regulating division of labour. Newly founded colonies rely on physical dominance behaviour for establishing division of labour. Workers in mature post-emergence colonies continue to implement physical dominance as a way to regulate non-reproductive division of labour in a decentralized manner, while the queens switch to chemical regulation of worker reproduction. We discuss experiments that build evidence toward establishing R. marginata as an important model for understanding the origin and maintenance of division of labour.This article is part of the theme issue 'Division of labour as key driver of social evolution'.

Background/Objectives: Acne vulgaris is a skin disorder that affects millions worldwide, with Cutibacterium acnes playing a key role in its inflammation. Antibiotics reduce C. acnes and inflammation, but growing antibiotic resistance has limited their efficacy. Additionally, other common acne treatments with bactericidal activity, like benzoyl peroxide, cause irritation, dryness, and peeling. To fulfill the unmet need for alternative therapies, our strategy focused on identifying potent phage lysins and/or their derived cationic peptides. Methods: The C-terminal cationic antimicrobial peptide of the Prevotella intermedia phage lysin PlyPi01 was synthesized along with several sequence-engineered variants in an attempt to enhance their bactericidal efficacy. In vitro bacterial killing assays evaluated the potency of the lysin-derived peptide derivatives against C. acnes and Staphylococcus aureus, another skin bacterium associated with acne. Antibacterial activity was assessed both in conditions simulating the human skin and in combination with retinoids. Results: The variant peptide P156 was engineered by adding arginine residues at both the N- and C-terminal ends of the parental peptide PiP01. P156 was highly potent and eradicated all tested strains of C. acnes and S. aureus. P156 acted rapidly (>5-log kill in 10 min), further reducing the potential of resistance development. Additionally, P156 maintained its potency under conditions (e.g., temperature, pH, and salt concentration) observed on the skin surface and in hair follicles, as well as in combination with retinoid-all without being toxic to human cells. Conclusions: These collective findings position P156 as a promising topical drug for clinical applications to control acne vulgaris.

Gene expression in response to environmental stimuli is dependent on nuclear localization of key signaling components, which can be tightly regulated by phosphorylation. This is exemplified by the phosphate-sensing transcription factor Pho4, which requires phosphorylation for nuclear export by the yeast exportin Msn5. Here, we present a high resolution cryogenic-electron microscopy structure showing the phosphorylated 35-residue nuclear export signal of Pho4, which binds the concave surface of Msn5 through two Pho4 phospho-serines that align with two Msn5 basic patches. These findings characterize a mechanism of phosphate-specific recognition mediated by a non-classical signal distinct from that for Exportin-1. Furthermore, the discovery that unliganded Msn5 is autoinhibited explains the positive cooperativity of Pho4/Ran-binding and proposes a mechanism for Pho4's release in the cytoplasm. These findings advance our understanding of the diversity of signals that drive nuclear export and how cargo phosphorylation is crucial in regulating nuclear transport and controlling cellular signaling pathways.