Cell reports最新文献

Sex steroid hormones such as progesterone play a pivotal role in reproductive functions and maintaining pregnancy; however, the impact of progesterone on the interaction between mother and embryo is unclear. Here, we demonstrate that the relationship between maternal progesterone and membrane progesterone receptor epsilon (mPRε) in adipose tissue regulates embryonic nutritional environment and growth after birth in mice. The activation of adipose mPRε by increased progesterone during pregnancy enhances maternal insulin resistance via prostaglandin production, efficiently providing glucose to embryos. Correspondingly, the offspring of mPRε-deficient mothers exhibited metabolic dysfunction, whereas mPRε-deficient mothers with high-fat diet-induced obesity exhibited improved insulin sensitivity. These findings establish the importance of progesterone as a nutritional regulator between mother and embryo. Additionally, mPRε may represent a modulator for treating pregnant glycemic control disorders such as gestational diabetes mellitus, as well as metabolic syndrome in offspring.

Cancer-associated fibroblasts (CAFs) and immune cells make up two major components of the tumor microenvironment (TME), contributing to an ecosystem that can either support or restrain cancer progression. Metabolism is a key regulator of the TME, providing a means for cells to communicate with and influence each other, modulating tumor progression and anti-tumor immunity. Cells of the TME can metabolically interact directly through metabolite secretion and consumption or by influencing other aspects of the TME that, in turn, stimulate metabolic rewiring in target cells. Recent advances in understanding the subtypes and plasticity of cells in the TME both open up new avenues and create challenges for metabolically targeting the TME to hamper tumor growth and improve response to therapy. This perspective explores ways in which the CAF and immune components of the TME could metabolically influence each other, based on current knowledge of their metabolic states, interactions, and subpopulations.

N⁴-acetylcytidine (ac⁴C) is a novel mRNA modification that enhances RNA stability and translation in mammals and plants. We previously identified ac⁴C in Arabidopsis, introduced by two homologs of human N-acetyltransferase 10 (NAT10). While ac⁴C influences leaf development in Arabidopsis, its role in rice is unclear. In this study, we identify OsNAT10 as the ac⁴C writer in rice. osnat10 mutants show developmental defects, including shorter roots, fewer tillers, and lower yield. Compared with wild type, ac⁴C-modified genes are less abundant in osnat10, particularly those related to photosynthesis. Additionally, osnat10 exhibits decreased photosynthetic capacity and reduced RNA stability and translation efficiency of ac⁴C target genes, like LIGHT-INDUCED RICE 1 (LIR1). Overexpressing OsLIR1 partially rescues osnat10 defects, underscoring OsNAT10's role in photosynthesis regulation. Our findings highlight ac⁴C's crucial function in photosynthesis and plant development, offering insights into epitranscriptomic modifications for crop improvement.

In primary age-related tauopathy (PART) and Alzheimer's disease (AD), tau aggregates share a similar structure and anatomic distribution, which is distinct from tau pathology in other diseases. However, transcriptional similarities between PART and AD and gene expression changes within tau-pathology-bearing neurons are largely unknown. Using GeoMx spatial transcriptomics, mRNA was quantified in hippocampal neurons with and without tau pathology in PART and AD. Synaptic genes were down-regulated in disease overall but up-regulated in tau-pathology-positive neurons. Two transcriptional signatures were associated with intraneuronal tau, both validated in a cortical AD dataset. Genes in the up-regulated signature were enriched in calcium regulation and synaptic function. Notably, transcriptional changes associated with intraneuronal tau in PART and AD were similar, suggesting a possible mechanistic relationship. These findings highlight the power of molecular analysis stratified by pathology and provide insight into common pathways associated with tau pathology in PART and AD.

Methicillin-resistant Staphylococcus aureus (MRSA) is an opportunistic pathogen that colonizes various body sites, including the nares, skin, and vagina. During pregnancy,colonization can lead to dysbiosis, adverse pregnancy outcomes, and invasive disease. To identify genes contributing to MRSA vaginal fitness, we performed transposon sequencing (Tn-seq) using a murine model of vaginal colonization, identifying over 250 conditionally essential genes. Five genes were validated in our murine model, including those encoding the aerobic respiration protein QoxB, bacillithiol biosynthesis component BshB2, sialic acid catabolism enzyme NanE, and staphylococcal regulator of respiration SrrAB. RNA sequencing and comparative analysis identified over 30 SrrAB-regulated genes potentially important for fitness in vaginal-like conditions, particularly under oxygen stress. These findings highlight pathways such as aerobic respiration, bacillithiol biosynthesis, sialic acid catabolism, and transcriptional regulation that support MRSA's competitive fitness in the vaginal tract.

In cuttings, detached leaves or stems are exposed to many stresses during the root regeneration process. Here, we show that the detached Arabidopsis thaliana leaf can tolerate mild osmotic stress and still regenerate roots. Under stress conditions, wounding and stress upregulate the jasmonate (JA) signaling pathway transcription factor gene MYC2 and the abscisic acid (ABA) signaling pathway transcription factor gene ABA INSENSITIVE5 (ABI5). The MYC2-ABI5 complex upregulates the expression of β-GLUCOSIDASE18 (BGLU18), which releases ABA from ABA glucose ester, resulting in ABA accumulation in the detached leaf. Mutations in MYC2, ABI5, and BGLU18 lead to the loss of stress tolerance and defects in root regeneration under osmotic stress. The successive application of JA and ABA can enhance the root regeneration ability in Arabidopsis and poplar cuttings. Overall, the JA-mediated wound signaling pathway and the ABA-mediated stress signaling pathway collaboratively amplify ABA signals to protect root regeneration under stress conditions.

Conscious access is suggested to involve "ignition," an all-or-none activation across cortical areas. To elucidate this phenomenon, we carry out computer simulations of a detection task using a mesoscale connectome-based model for the multiregional macaque cortex. The model uncovers a dynamic bifurcation mechanism that gives rise to ignition in a network of associative regions. A hierarchical N-methyl-D-aspartate (NMDA)/α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor gradient plays a critical role: fast AMPA receptors drive feedforward signal propagation, while slow NMDA receptors in feedback pathways shape and sustain the ignited network. Intriguingly, the model suggests higher NMDA-to-AMPA receptor ratios in sensory areas compared to association areas, a prediction supported by in vitro autoradiography data. Furthermore, the model accounts for diverse behavioral and physiological phenomena linked to consciousness. This work sheds light on how receptor gradients along the cortical hierarchy enable distributed cognitive functions and provides a biologically constrained computational framework for investigating the neurophysiological basis of conscious access.

Piezo1, which maintains the integrity and function of the intestinal epithelial barrier, is essential for colonic epithelial homeostasis. However, whether and how Piezo1 regulates colon stem cell fate remains unclear. Here, we show that Piezo1 inhibition promotes colon stem cell proliferation. Mechanistically, stearoyl-CoA 9-desaturase 1 (SCD1) is downstream of Piezo1 to affect colon stem cell stemness by acting on the Wnt-β-catenin pathway. For mice, the altered colon stem cell stemness after Piezo1 knockdown and activation was accompanied by a reprogrammed fatty acid (FA) metabolism in colon crypts. Notably, we found that GsMTX4 protects injured colon stem cell stemness in mouse and human colitis organoids. Our results elucidated the role of Piezo1 in regulating normal and postinjury colon stem cell fates through SCD1-Wnt-β-catenin and the SCD1-mediated FA desaturation process. These results provide fresh perspectives on the mechanical factors regulating colon stem cell fate and therapeutic strategies for related intestinal diseases.

Glucose homeostasis is, in part, nutritionally programmed during early neonatal life, a critical window for synapse formation between hypothalamic glucoregulatory centers. Although microglia prune synapses throughout the brain, their role in refining hypothalamic glucoregulatory circuits remains unclear. Here, we show that the phagocytic activity of microglia in the mediobasal hypothalamus (MBH) is induced following birth, regresses upon weaning from maternal milk, and is exacerbated by feeding dams a high-fat diet while lactating. In addition to actively engulfing synapses, microglia are critical for refining perineuronal nets (PNNs) within the neonatal MBH. Remarkably, transiently depleting microglia before weaning (postnatal day [P]6-16) but not afterward (P21-31) induces glucose intolerance in adulthood due to impaired insulin responsiveness, which we link to PNN overabundance and reduced synaptic connectivity between hypothalamic glucoregulatory neurons and the pancreatic β cell compartment. Thus, microglia facilitate early-life synaptic plasticity in the MBH, including PNN refinement, to program hypothalamic circuits regulating adult glucose homeostasis.

Gut microbiota plays a crucial role in resisting the invasion of pathogens, particularly multidrug-resistant (MDR) bacteria, which pose a significant threat to public health. While exercise offers numerous health benefits, its impact on host colonization resistance remains largely unclear. In this study, we demonstrate that moderate exercise significantly reduces gut colonization by methicillin-resistant Staphylococcus aureus (MRSA), a clinically important MDR pathogen. Moreover, we identify an understudied strain of the intestinal probiotic Dubosiella newyorkensis (L8) as a critical factor in mediating exercise-induced colonization resistance against MRSA. Mechanistically, L8 enhances the deprivation of fucose, a crucial carbon source essential for MRSA growth and pathogenicity. This process relies on the high binding affinity of pyruvate to the ILE257 site of the lactate dehydrogenase in L8. Overall, our work highlights the importance of moderate exercise in maintaining host colonization resistance and demonstrates L8 as a probiotic in protecting against MRSA colonization.