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Programmable RNA sensing for cell monitoring and manipulation
No full textRNA is a central and universal mediator of genetic information underlying the diversity of cell types and cell states, which together shape tissue organization and organismal function across species and lifespans. Despite numerous advances in RNA sequencing technologies and the massive accumulation of transcriptome datasets across the life sciences1,2, the dearth of technologies that use RNAs to observe and manipulate cell types remains a bottleneck in biology and medicine. Here we describe CellREADR (Cell access through RNA sensing by Endogenous ADAR), a programmable RNA-sensing technology that leverages RNA editing mediated by ADAR to couple the detection of cell-defining RNAs with the translation of effector proteins. Viral delivery of CellREADR conferred specific cell-type access in mouse and rat brains and in ex vivo human brain tissues. Furthermore, CellREADR enabled the recording and control of specific types of neurons in behaving mice. CellREADR thus highlights the potential for RNA-based monitoring and editing of animal cells in ways that are specific, versatile, simple and generalizable across organ systems and species, with wide applications in biology, biotechnology and programmable RNA medicine
Endogenous DOPA inhibits melanoma through suppression of CHRM1 signaling
Full text linkMelanoma risk is 30 times higher in people with lightly pigmented skin versus darkly pigmented skin. Using primary human melanocytes representing the full human skin pigment continuum and preclinical melanoma models, we show that cell-intrinsic differences between dark and light melanocytes regulate melanocyte proliferative capacity and susceptibility to malignant transformation, independent of melanin and ultraviolet exposure. These differences result from dihydroxyphenylalanine (DOPA), a melanin precursor synthesized at higher levels in melanocytes from darkly pigmented skin. We used both high-throughput pharmacologic and genetic in vivo CRISPR screens to determine that DOPA limits melanocyte and melanoma cell proliferation by inhibiting the muscarinic acetylcholine receptor M1 (CHRM1) signaling. Pharmacologic CHRM1 antagonism in melanoma leads to depletion of c-Myc and FOXM1, both of which are proliferation drivers associated with aggressive melanoma. In preclinical mouse melanoma models, pharmacologic inhibition of CHRM1 or FOXM1 inhibited tumor growth. CHRM1 and FOXM1 may be new therapeutic targets for melanoma
Solid-basaloid variant of adenoid cystic carcinoma of the breast with near complete response to neoadjuvant chemotherapy
Full text linkBreast adenoid cystic carcinoma (AdCC) is a rare subtype of triple negative breast cancer. Two morphologic variants are described, namely classic AdCC (C-AdCC) and solid basaloid (SB-AdCC). Recent studies have shown that the SB-AdCC variant has significantly worse prognosis than C-AdCC. Due to the rarity of SB-AdCC, no standard recommendations are available for its management. Data on the use and benefit of chemotherapy in patients with SB-AdCC are sparse and the response to neoadjuvant chemotherapy has not been reported. We present the clinical and pathologic findings of a patient with SB-AdCC treated with neoadjuvant chemotherapy who achieved a remarkable pathologic response
ΔNp63α in cancer: importance and therapeutic opportunities
No full textOur understanding of cancer and the key pathways that drive cancer survival has expanded rapidly over the past several decades. However, there are still important challenges that continue to impair patient survival, including our inability to target cancer stem cells (CSCs), metastasis, and drug resistance. The transcription factor p63 is a p53 family member with multiple isoforms that carry out a wide array of functions. Here, we discuss the critical importance of the ΔNp63α isoform in cancer and potential therapeutic strategies to target ΔNp63α expression to impair the CSC population, as well as to prevent metastasis and drug resistance to improve patient survival
MCRS1 modulates the heterogeneity of microtubule minus-end morphologies in mitotic spindles
No full textFaithful chromosome segregation requires the assembly of a bipolar spindle, consisting of two antiparallel microtubule (MT) arrays having most of their minus ends focused at the spindle poles and their plus ends overlapping in the spindle midzone. Spindle assembly, chromosome alignment and segregation require highly dynamic MTs. The plus ends of MTs have been extensively investigated; instead, their minus end structure remains poorly characterized. Here, we used large-scale electron tomography to study the morphology of the MT minus ends in 3D-reconstructed metaphase spindles in HeLa cells. In contrast to the homogeneous open morphology of the MT plus ends at the kinetochores, we found that MT minus ends are heterogeneous showing either open or closed morphologies. Silencing the minus-end specific stabilizer, MCRS1 increased the proportion of open MT minus ends. Altogether, these data suggest a correlation between the morphology and the dynamic state of the MT ends. Taking this heterogeneity of the MT minus end morphologies into account, our work indicates an unsynchronized behavior of MTs at the spindle poles, thus laying the ground for further studies on the complexity of MT dynamics regulation. [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text]
A conserved superlocus regulates above- and belowground root initiation
No full textPlants continuously form new organs in different developmental contexts in response to environmental cues. Underground lateral roots initiate from prepatterned cells in the main root, but cells can also bypass the root-shoot trajectory separation and generate shoot-borne roots through an unknown mechanism. We mapped tomato (Solanum lycopersicum) shoot-borne root development at single-cell resolution and showed that these roots initiate from phloem-associated cells through a unique transition state. This state requires the activity of a transcription factor that we named SHOOTBORNE ROOTLESS (SBRL). Evolutionary analysis reveals that SBRL's function and cis regulation are conserved in angiosperms and that it arose as an ancient duplication, with paralogs controlling wound-induced and lateral root initiation. We propose that the activation of a common transition state by context-specific regulators underlies the plasticity of plant root systems
A feedback control principle common to several biological and engineered systems
Full text linkFeedback control is used by many distributed systems to optimize behaviour. Traditional feedback control algorithms spend significant resources to constantly sense and stabilize a continuous control variable of interest, such as vehicle speed for implementing cruise control, or body temperature for maintaining homeostasis. By contrast, discrete-event feedback (e.g. a server acknowledging when data are successfully transmitted, or a brief antennal interaction when an ant returns to the nest after successful foraging) can reduce costs associated with monitoring a continuous variable; however, optimizing behaviour in this setting requires alternative strategies. Here, we studied parallels between discrete-event feedback control strategies in biological and engineered systems. We found that two common engineering rules-additive-increase, upon positive feedback, and multiplicative-decrease, upon negative feedback, and multiplicative-increase multiplicative-decrease-are used by diverse biological systems, including for regulating foraging by harvester ant colonies, for maintaining cell-size homeostasis, and for synaptic learning and adaptation in neural circuits. These rules support several goals of these systems, including optimizing efficiency (i.e. using all available resources); splitting resources fairly among cooperating agents, or conversely, acquiring resources quickly among competing agents; and minimizing the latency of responses, especially when conditions change. We hypothesize that theoretical frameworks from distributed computing may offer new ways to analyse adaptation behaviour of biology systems, and in return, biological strategies may inspire new algorithms for discrete-event feedback control in engineering
Precise and pervasive phasic bursting in locus coeruleus during maternal behavior in mice
No full textThe noradrenergic locus coeruleus (LC) mediates key aspects of arousal, memory, and cognition in structured tasks, but its contribution to naturalistic behavior remains unclear. LC activity is thought to multiplex distinct signals by superimposing sustained ('tonic') firing patterns reflecting global brain states, such as arousal and anxiety, and rapidly fluctuating ('phasic') bursts signaling discrete behaviorally significant events. Manipulations of the LC noradrenergic system broadly impair social behavior, but the temporal structure of LC firing and its relationship to social interaction is unknown. One possibility is that tonic firing may increase in the presence of social partners; it is also possible that phasic bursts may accompany specific social events. We used chronic in vivo electrophysiology and fiber photometry to measure single unit and population neural activity in LC of freely behaving mice during their interactions with pups. We find that pup retrieval elicits remarkably precise phasic activity in LC that can't be attributed merely to sensory stimuli, motor activity, or reward. Correlation of LC activity with retrieval events shows that phasic events are most closely related to specific subsequent behaviors. The reliability and magnitude of phasic responses strongly suggest that these events are coordinated across LC and broadcast NA release throughout the brain. We also observed slow changes in tonic firing when females performed distinct maternal behaviors such as nest building and pup grooming. We therefore propose that LC signals state changes during sustained interactions and contributes to goal-directed action selection during social behavior with globally-broadcast NA release.SIGNIFICANCE STATEMENTLocus coeruleus (LC) releases noradrenaline (NA) brain-wide influencing many cognitive, emotional, and physiological processes. Multifunctionality of LC is maintained by multiplexing NA signaling via brief 'phasic' patterns of bursting and slowly changing 'tonic' firing. Manipulations of NA impair social behavior, yet the structure of LC activity with respect to specific social events is unknown. We measured LC activity in mice freely interacting with pups. We find that pup retrieval elicits precisely timed and pervasive phasic activation of LC that anticipates specific behaviors. We also found that LC neurons exhibited slow fluctuations in firing during sustained behaviors. We propose that LC simultaneously contributes to goal-directed social action selection with globally-broadcast NA release, and signals social state changes with increased tonic firing
Interpreting Potts and Transformer Protein Models Through the Lens of Simplified Attention
Full text linkThe established approach to unsupervised protein contact prediction estimates coevolving positions using undirected graphical models. This approach trains a Potts model on a Multiple Sequence Alignment. Increasingly large Transformers are being pretrained on unlabeled, unaligned protein sequence databases and showing competitive performance on protein contact prediction. We argue that attention is a principled model of protein interactions, grounded in real properties of protein family data. We introduce an energy-based attention layer, factored attention, which, in a certain limit, recovers a Potts model, and use it to contrast Potts and Transformers. We show that the Transformer leverages hierarchical signal in protein family databases not captured by single-layer models. This raises the exciting possibility for the development of powerful structured models of protein family databases