Cell reports最新文献

Invariant object recognition-the ability to recognize objects across size, rotation, or context-is fundamental for making sense of a dynamic visual world. Though traditionally studied in primates, emerging evidence suggests rodents recognize objects across a range of identity-preserving transformations. We demonstrate that rats robustly perform visual object recognition and explore a neural pathway that may underlie this capacity by developing a pipeline from high-throughput behavior training to cellular resolution imaging in awake, head-fixed animals. Leveraging our optical approach, we systematically profile neurons in primary and higher-order visual areas and their spatial organization. We find that rat visual cortex exhibits several features similar to those observed in the primate ventral stream but also marked deviations, suggesting species-specific differences in how brains solve visual object recognition. This work reinforces the sophisticated visual abilities of rats and offers the technical foundation to use them as a powerful model for mechanistic perception.

FANCA is one of the 23 genes whose deficiencies lead to defective DNA interstrand crosslink repair and cancer-prone Fanconi anemia disease. Beyond its functions in DNA repair and tumor suppression, we report that high FANCA expression is strongly associated with breast cancer development. Overexpression of WT-FANCA significantly promotes breast cancer cell proliferation and tumor growth both in vitro and in vivo, while FANCA deficiency severely compromises the proliferation of breast cancer cells, but not non-tumorigenic breast epithelial cells. Heterozygous knockout of FANCA in breast cancer mouse models is sufficient to cause significant reduction of breast tumor growth in vivo. Furthermore, we have shown that high FANCA expression in breast cancer correlates with promoter hypomethylation in a TET-dependent manner, and TET inhibition recapitulates the proliferation defects caused by FANCA deficiency. Our study identifies the oncogenic properties of WT-FANCA and shows that FANCA is a promising target for breast cancer intervention.

Dysregulated lipid metabolism plays an important role in prostate cancer, although the understanding of the essential regulatory processes in tumorigenesis is incomplete. We employ a CRISPR-Cas9 screen using a custom human lipid metabolism knockout library to identify essential genes for prostate cancer survival. Screening in three prostate cancer cell lines reveals 63 shared dependencies, with enrichment in terpenoid backbone synthesis and N-glycan biosynthesis. Independent knockout of key genes of the mevalonate pathway reduces cell proliferation. Further investigation focuses on NUS1, a subunit of cis-prenyltransferase required for dolichol synthesis. NUS1 knockout decreases tumor growth in vivo and viability in patient-derived xenograft (PDX)-derived organoids. Mechanistic studies reveal that loss of NUS1 promotes oxidative stress, lipid peroxidation and ferroptosis sensitivity, endoplasmic reticulum (ER) stress, and G1 cell-cycle arrest, and it dampens androgen receptor (AR) signaling, collectively leading to growth arrest. This study highlights the critical role of the mevalonate-dolichol-N-glycan biosynthesis pathway, particularly NUS1, in prostate cancer survival and growth.

Nuclear pore complexes (NPCs) are channels that control access to the genome. The number of NPCs that cells assemble varies between different cell types and in disease. However, the mechanisms regulating NPC formation in mammalian cells remain unclear. Using a genome-wide small interfering RNA (siRNA) screen, we identify translation-related factors, proteasome components, and the CCR4-NOT complex as top regulators of NPC assembly and numbers. While inhibition of ribosomal function and protein translation reduces NPC formation, blocking protein degradation or CCR4-NOT function increases NPC numbers. We demonstrate that CCR4-NOT inhibition raises global mRNA levels, increasing the pool of nucleoporin mRNAs available for translation. Upregulation of nucleoporin complexes in CCR4-NOT-inhibited cells allows for higher NPC formation, increasing total NPC numbers in normal and cancer cells. Our findings uncover that nucleoporin mRNA stability and protein homeostasis are major determinants of NPC formation and highlight a role for the CCR4-NOT complex in negatively regulating NPC assembly.

In many forms of sexual reproduction, only the most robust spermatozoa, which overcome multiple physiological challenges, reach the oocyte. However, the exact mechanisms of gamete recognition and fusion are unknown. In the present study, we demonstrated that with the onset of gamete recognition, oocyte microvilli form lamellipodium-like structures, activate actin polymerization, and subsequently engulf spermatozoa to initiate gamete fusion. Gamete fusion occurred via a phagocytosis-like process we termed "sperm engulfment activated by IZUMO1-JUNO linkage and gamete fusion-related factors" (SEAL). Gamete adhesion was strictly regulated by binding of sperm IZUMO1 to oocyte JUNO, while SEAL was primarily mediated by sperm DCST1/2, SPACA6, TMEM95, FIMP, and TMEM81, the essential factors for gamete fusion. Interestingly, JUNO was almost depleted from oocyte surfaces in the region where SEAL enveloped spermatozoa by microvilli without actin polymerization. SEAL formation was recapitulated using JUNO-expressing K562 lymphocytic cells rather than oocytes. Together, these findings suggest that dynamic rearrangement of membrane components facilitates SEAL prior to successful fertilization.

Here, we report significant changes in the composition of the lung microbiome and metabolome of mice under immune suppression, infection of immunosuppressed mice with virulent and avirulent strains of the clinically important human-pathogenic fungus Aspergillus fumigatus, and treatment with the clinically used antifungal drug voriconazole. Our data also indicate the important role of the gut microbiome for lung homeostasis mediated by the plasma metabolome. In the lung microbiome, DNA sequencing indicates that infection by A. fumigatus leads to a significant increase of anaerobic bacteria, most prominently of Ligilactobacillus murinus; the latter has been confirmed by qPCR analyses. We also isolated live bacteria, including L. murinus, from the murine lower respiratory tract. Co-cultivation of L. murinus and A. fumigatus leads to a reduction in oxygen concentration accompanied by an increase of L. murinus cells, suggesting that A. fumigatus establishes a microaerophilic niche, thereby promoting growth of anaerobic bacteria.

Classical models of efficient coding in neurons assume simple mean responses-"tuning curves"- such as bell-shaped or monotonic functions of a stimulus feature. Real neurons, however, can be more complex: grid cells, for example, exhibit periodic responses that impart the neural population code with high accuracy. But do highly accurate codes require fine-tuning of the response properties? We address this question with the use of a simple model: a population of neurons with random, spatially extended, and irregular tuning curves. Irregularity enhances the local resolution of the code but gives rise to catastrophic, global errors. For optimal smoothness of the tuning curves, when local and global errors balance out, the neural population compresses information about a continuous stimulus into a low-dimensional representation, and the resulting distributed code achieves exponential accuracy. An analysis of recordings from monkey motor cortex points to such "compressed efficient coding." Efficient codes do not require a finely tuned design-they emerge robustly from irregularity or randomness.

Neutrophilic asthma is a vexing disease, but mechanistic and therapeutic advancements will require better models of allergy-induced airway neutrophilia. Here, we find that periodic ovalbumin (OVA) inhalation in sensitized mice elicits rapid allergic airway inflammation and pathophysiology mimicking neutrophilic asthma. OVA-experienced murine lungs harbor diverse clusters of CD4⁺ resident memory T (T_RM) cells, including unconventional RORγt^negative/low T helper 17 (T_H17) cells. Acute OVA challenge instigates interleukin (IL)-17A secretion from these T_RM cells, driving CXCL5 production from Muc5ac^high airway secretory cells, leading to destructive airway neutrophilia. The T_RM and epithelial cell signals discovered herein are also observed in adult human asthmatic airways. Epithelial antigen presentation regulates this biology by skewing T_RM cells toward T_H2 and T_H1 fates so that T_H1-related interferon (IFN)-γ suppresses IL-17A-driven, CXCL5-mediated airway neutrophilia. Concordantly, in vivo IFN-γ supplementation improves disease outcomes. Thus, using our model of neutrophilic asthma, we identify lung epithelial-CD4⁺ T_RM cell crosstalk as a key rheostat of allergic airway neutrophilia.

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.

Excessive activation of effector-triggered immunity (ETI) in plants inhibits plant growth and activates cell death. ETI mediated by intracellular Toll/interleukin-1 receptor/resistance protein (TIR) nucleotide-binding, leucine-rich repeat receptors (NLRs) involves two partially redundant signaling nodes in Arabidopsis, ENHANCED DISEASE SUSCEPTIBILITY 1-PHYTOALEXIN DEFICIENT 4-ACTIVATED DISEASE RESISTANCE 1 (EDS1-PAD4-ADR1) and EDS1-SENESCENCE-ASSOCIATED GENE 101-N REQUIREMENT GENE 1 (EDS1-SAG101-NRG1). Genetic and transcriptomic analyses show that EDS1-PAD4-ADR1 primarily enhances immune component abundance and is critical for limiting pathogen growth, whereas EDS1-SAG101-NRG1 mainly activates the hypersensitive response (HR) cell death but is dispensable for immune priming. This study enhances our understanding of the distinct contributions of these two signaling modules to ETI and suggests molecular principles and potential strategies for improving disease resistance in crops without compromising yield.