Cell reports最新文献

Preterm birth is a major concern in neonatal care, significantly impacting infant survival and long-term health. The gut microbiome, essential for infant development, often becomes imbalanced in preterm infants, making it crucial to understand the effects of antibiotics on its development. Our study analyzed weekly, 6-month, and 1-year stool samples from 100 preterm infants, correlating clinical data on antibiotic use and feeding patterns. Comparing infants who received no antibiotics with those given empirical post-birth treatment, we observed notable alterations in the gut microbiome's composition and an increase in antibiotic resistance gene abundance early in life. Although these effects diminished over time, their long-term clinical impacts remain unclear. Human milk feeding was associated with beneficial microbiota like Actinobacteriota and reduced antibiotic resistance genes, underscoring its protective role. This highlights the importance of judicious antibiotic use and promoting human milk to foster a healthy gut microbiome in preterm infants.

Impaired neuronal and synaptic function are hallmarks of early Alzheimer's disease (AD), preceding other neuropathological traits and cognitive decline. We previously showed that SFRP1, a glial-derived protein elevated in AD brains from preclinical stages, contributes to disease progression, implicating glial factors in early pathogenesis. Here, we generate and analyze transgenic mice overexpressing astrocytic SFRP1. SFRP1 accumulation causes early dendritic and synaptic defects in adult mice, followed by impaired synaptic long-term potentiation and cognitive decline, evident only when the animals age, thereby mimicking AD's structural-functional temporal distinction. This phenotype correlates with proteomic changes, including increased structural synaptic proteins like neurexin, which localizes in close proximity with SFRP1 in cultured hippocampal neurons. We conclude that excessive SFRP1 hinders synaptic protein turnover, reducing synaptic plasticity-a mechanism that may underlie the synaptopathy observed in the brains of prodromal AD patients.

Tight junctions (TJs) control the paracellular transport of ions, solutes, and macromolecules across epithelial barriers. There is evidence that claudin-based ion transport (the pore pathway) and the paracellular transport of macromolecules (the leak pathway) are controlled independently. However, how leak pathway flux is regulated is unclear. Here, we have identified the Cdc42/Rac GTPase-activating protein ARHGAP12 as a specific activator of the leak pathway. ARHGAP12 is recruited to TJs via an interaction between its Src homology (SH3) domain and the TJ protein ZO-2 to suppress N-WASP-mediated F-actin assembly. This dampens junctional tension and promotes the paracellular transport of macromolecules without affecting ion flux. Mechanistically, we demonstrate that the ARHGAP12 tandem WW domain interacts directly with PPxR motifs in the proline-rich domain of N-WASP and thereby attenuates SH3-domain-mediated N-WASP oligomerization and Arp2/3-driven F-actin assembly. Collectively, our data indicate that branched F-actin networks regulate junctional tension to fine-tune the TJ leak pathway.

The progression of traumatic brain injury (TBI) pathology is significantly influenced by age and involves a complex interplay of glial cells. However, the influence of age on the glial dynamics and their TBI responses remains mostly unexplored. Here, we obtain a comprehensive single-cell transcriptome atlas of three major glial types under the physiological and TBI conditions across four post-embryonic life stages in the zebrafish midbrain optic tectum. We identify a library of glial subtypes and states with specific age-dependent patterns that respond distinctly to TBI. Combining the glial interactome analysis and CRISPR-Cas9-mediated gene disruption, we reveal the essential roles of dla-notch3 and cxcl12a-cxcr4b interactions in the early-larval-stage-specific unresponsiveness of radial astrocytes to TBI and the TBI-induced age-independent recruitment of microglia to injury sites, respectively. Overall, our findings provide the molecular and cellular framework of TBI-induced age-related glial dynamics in vertebrate brains.

Eukaryotes exhibit a complex and dynamic internal meshwork of membranes-the endomembrane system-used to insert membrane proteins and ingest food. Verbal models explaining the origin of endomembranes abound, but quantitative considerations of fitness are lacking. Drawing on quantitative data on endomembranes allows for the derivation of two biologically grounded analytical models of endomembrane evolution that quantify organismal fitness: (1) vesicle-based uptake of small nutrient molecules, pinocytosis, and (2) vesicle-based insertion of membrane proteins, proto-endoplasmic reticulum. Surprisingly, pinocytosis of small-molecule nutrients does not provide a net fitness gain under biologically sensible parameter ranges, explaining why pinocytosis is primarily used for protein uptake in contemporary organisms. The proto-endoplasmic reticulum does provide net fitness gains, making it the more likely candidate for initiating the endomembrane system. With modifications, the approach developed here can be used more generally to understand the present-day endomembrane system and illuminate the origin of the eukaryotic cell.

Metabolic reprogramming is a hallmark of malignant transformation. While initial studies in the field of cancer metabolism focused on central carbon metabolism, the field has expanded to metabolism beyond glucose and glutamine and uncovered the important role of amino acids in tumorigenesis and tumor immunity as energy sources, signaling molecules, and precursors for (epi)genetic modification. As a result of the development and application of new technologies, a multifaceted picture has emerged, showing that context-dependent heterogeneity in amino acid metabolism exists between tumors and even within distinct regions of solid tumors. Understanding the complexity and flexibility of amino acid metabolism in cancer is critical because it can influence therapeutic responses and predict clinical outcomes. This overview discusses the current findings on the heterogeneity in amino acid metabolism in cancer and how understanding the metabolic diversity of amino acids can be translated into more clinically relevant therapeutic interventions.

Despite constitutive Ras/Raf/MAPK pathway activation in most pancreatic ductal adenocarcinomas (PDACs), treatment approaches targeting this pathway have primarily been unsuccessful. We conduct a drug library screen on an MEK inhibitor (MEKi)-resistant PDAC model and perform complementary pathway analysis to identify cellular resistance phenotypes. We use syngeneic models to investigate the molecular determinants of identified drug synergism. Our study reveals an enrichment for the hallmarks of G2/M checkpoints in MEKi-resistant phenotypes from all investigated models. We find overexpression of Polo-like kinase 1 (PLK1) and other G2/M checkpoint-related proteins in MEKi-resistant cells. We identify synergistic activity between MEK and PLK1 inhibition both in vitro and in vivo and mechanistically show that dual inhibition of the PLK1 and MEK pathways activates the JNK/c-JUN pathway. This causes the accumulation of DNA damage, ultimately leading to apoptotic cell death. Dual PLK1/MEK inhibition emerges as a promising targeted approach in PDAC.

Huntington's disease (HD) is a fatal neurodegenerative disease characterized by the selective loss of neostriatal medium spiny neurons (MSNs). We previously found that intraventricular delivery of viral vectors expressing brain-derived neurotrophic factor (BDNF) and Noggin induced heterotopic recruitment of new MSNs to the adult neostriatum and slowed disease progression in the R6/2 mouse model of HD. Nonetheless, the extent to which newly generated neurons integrate into adult striatal circuits has remained unclear. Here, using wild-type (WT) and R6/2 mice, we follow the fate of genetically tagged new neurons recruited to the striatum after intraventricular infusion of BDNF and Noggin. Using rabies tract tracing, optogenetics, and calcium imaging, we find that new neurons functionally assimilate into the cortico-striato-pallidal motor circuitry, and chemogenetic stimulation of these new neurons confirms their contribution to motor behavior. Together, these data indicate that induced neurogenesis may restore multi-synaptic circuits in the adult brain, offering a regenerative strategy for the treatment of HD.

Signal transducer and activator of transcription (STAT)3 signaling has been studied extensively using mouse embryonic stem cells. Zygotic deletion of Stat3 enables embryo implantation, but thereafter, mutants resemble non-affected littermates from the previous day until around mid-gestation. This probably results from the loss of serine-phosphorylated STAT3, the predominant form in early postimplantation embryonic tissues associated with mitochondrial activity. Bulk RNA sequencing of isolated mouse epiblasts confirmed developmental delay transcriptionally. Single-cell RNA sequencing revealed the exclusion of derivatives of Stat3 null embryonic stem cells exclusively from the erythroid lineage of mid-gestation chimeras. We show that Stat3 null embryonic stem cells can differentiate into erythroid and hematopoietic lineages in vitro but become outcompeted when mixed with wild-type cells. Our results implicate a role for STAT3 in the temporal control of embryonic progression, particularly in tissues requiring rapid cell division, such as postimplantation epiblast and hematopoietic lineages. Interestingly, mutations in STAT3 are associated with short stature in humans.

Salmonella causes ∼1 million cases of gastroenteritis annually in the United States. Critical to virulence are secreted effectors that reprogram host functions. We previously discovered the effector SarA facilitates phosphorylation of STAT3, inducing expression of the anti-inflammatory cytokine interleukin-10 (IL-10). This STAT3 activation requires a region of homology with the host cytokine receptor gp130. Here, we demonstrate that a single amino acid difference is critical for the anti-inflammatory bias of SarA-STAT3 signaling. An isoleucine at pY+1 of the YxxQ motif in SarA (which binds the STAT3 SH2 domain) causes increased STAT3 recruitment and phosphorylation, biasing toward anti-inflammatory targets. This isoleucine renders SarA a better substrate for tyrosine phosphorylation by GSK-3. GSK-3 is canonically a serine/threonine kinase that nonetheless undergoes tyrosine autophosphorylation at a motif with isoleucine at the pY+1 position. Our results provide a molecular basis for how a Salmonella effector achieves supraphysiological levels of STAT3 activation to control host genes.