As the primary source of norepinephrine (NE) in the brain, the locus coeruleus (LC) regulates both arousal and stress responses. However, how local neuromodulatory inputs contribute to LC function remains unresolved. Here we identify a network of transcriptionally and functionally diverse GABAergic neurons in the LC dendritic field that integrate distant inputs and modulate modes of LC firing to control arousal. We define peri-LC anatomy using viral tracing and combine single-cell RNA sequencing and spatial transcriptomics to molecularly define both LC and peri-LC cell types. We identify several cell types which underlie peri-LC functional diversity using a series of complementary approaches in behaving mice. Our findings indicate that LC and peri-LC neurons comprise transcriptionally and functionally heterogenous neuronal populations, alongside anatomically segregated features which coordinate specific influences on behavioral arousal and avoidance states. Defining the molecular, cellular and functional diversity in the LC provides a road map for understanding the neurobiological basis of arousal alongside hyperarousal-related neuropsychiatric phenotypes.
Catecholamine signaling is thought to modulate cognition in an inverted-U relationship, but the mechanisms are unclear. We measured norepinephrine and dopamine release, postsynaptic calcium responses, and interactions between tonic and phasic firing modes under various stimuli and conditions. High tonic activity in vivo depleted catecholamine stores, desensitized postsynaptic responses, and decreased phasic transmission. Together this provides a clearer understanding of the inverted-U relationship, offering insights into psychiatric disorders and neurodegenerative diseases with impaired catecholamine signaling.
Transduction frequency with phage P1 had been observed to be very low in Escherichia coli K-12 mutants lacking the operon (ppk1-ppx) responsible for the synthesis of inorganic polyphosphate (poly P). We now find that these mutants, for lack of poly P, are lysogenic for P1 and when infected with phage P1 produce only Ϸ1% the number of infective centers compared with the WT host. Both phage adsorption and release were unaffected. The hostencoded P1 late-gene transcriptional activator, SspA, failed to show the transcriptional increase in the mutant, observed in the WT. UV induction of a P1-infected mutant resulted in a 200-fold increase in the production of infectious phage particles. The lysogenized P1 (P1mut) and P1 progeny from the mutant host (⌬ppk1-ppx) produced plaques of differing morphologies, whereas P1 progeny from the WT yielded only small, clear plaques. Two discernable variants, one producing small and clear plaques (P1small) and the other large plaques with turbid rims (P1large), had broader host range and produced larger burst sizes in WT compared with P1. Transmission electron microscopy showed P1mut had contractile sheath defects. Thus, the lack of poly P/PPK1 in the mutant host resulted in the formation of defective P1 particles during intracellular growth. A filamentous phage, fd, also failed to produce plaques on a mutant lawn. Although fd adsorbed to the F-pilus, its DNA failed to enter the mutant host.contractile sheath ͉ lysogeny ͉ lytic replication ͉ Stringent Starvation protein A I norganic polyphosphate (poly P), a linear polymer of orthophosphate residues linked by high-energy phosphoanhydride bonds, ranges in length from tens to hundreds of residues. Poly P is evolutionarily conserved and has been found in all organisms (1, 2). Poly P accumulation may be very high in many bacteria and fungi, accounting for as much as 10-20% of dry weight (3, 4). Intracellular accumulation of poly P in these organisms is an essential response to stress and for survival (4, 5). The principal poly P-synthesizing enzyme in several prokaryotic species, including Escherichia coli, is polyphosphate kinase 1 (PPK1), which catalyzes the transfer of the terminal phosphate group of ATP to a growing chain of poly P (6). A null mutant of PPK1 is defective in transcription, cell motility, quorum sensing, biofilm formation, and survival (7-9). In E. coli infected with the temperate bacteriophage , the p R promoter is negatively regulated by guanosine 3Ј,5Ј-bisdiphosphate (ppGpp), at the level of transcription (10). Phage P1 is a temperate phage like , but the P1 prophage exists as an episome (11). Although its replication in E. coli under stringent response has not been specifically examined, mutants in the stringent starvation protein A (sspA) are defective in P1 lytic replication (12). Previously, we observed a very low transduction frequency (Ͻ10 Ϫ6 ) when we attempted to transfer the ppk1-ppx mutation into E. coli and Shigella spp. (4, 5). To understand how the cell physiology of the ppk1-ppx null mutant affected P...
Neuraxial anesthesia, as the standard of care for Cesarean deliveries, is associated with decreased blood loss. However, parturients with inherited bleeding disorders are at increased risk for epidural hematomas. A small retrospective study has shown that parturients with known factor deficiencies can safely undergo neuraxial anesthesia once the specific factors are replenished. We present a patient who had a considerably increased risk of peripartum bleeding from an unspecified inherited bleeding disorder and was provided a successful neuraxial anesthetic without complications. We discuss the multidisciplinary approach among the surgeons, anesthesiologists, hematologist, and nursing staff to maximize patient safety and comfort.
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