New insights into the unfolded protein response (UPR)-anterior gradient 2 (AGR2) pathway in the regulation of intestinal barrier function in weaned piglets.

Sustained dysfunction of the intestinal barrier caused by early weaning is a major factor that induces postweaning diarrhea in weaned piglets. In both healthy and diseased states, the intestinal barrier is regulated by goblet cells. Alterations in the characteristics of goblet cells are linked to intestinal barrier dysfunction and inflammatory conditions during pathogenic infections. In this review, we summarize the current understanding of the mechanisms of the unfolded protein response (UPR) and anterior gradient 2 (AGR2) in maintaining intestinal barrier function and how modifications to these systems affect mucus barrier characteristics and goblet cell dysregulation. We highlight a novel mechanism underlying the UPR-AGR2 pathway, which affects goblet cell differentiation and maturation and the synthesis and secretion of mucin by regulating epidermal growth factor receptor and mucin 2. This study provides a theoretical basis and new insights into the regulation of intestinal health in weaned piglets.

Driving axon regeneration by orchestrating neuronal and non-neuronal innate immune responses via the IFNγ-cGAS-STING axis.

The coordination mechanism of neural innate immune responses for axon regeneration is not well understood. Here, we showed that neuronal deletion of protein tyrosine phosphatase non-receptor type 2 sustains the IFNγ-STAT1 activity in retinal ganglion cells (RGCs) to promote axon regeneration after injury, independent of mTOR or STAT3. DNA-damage-induced cGAMP synthase (cGAS)-stimulator of interferon genes (STINGs) activation is the functional downstream signaling. Directly activating neuronal STING by cGAMP promotes axon regeneration. In contrast to the central axons, IFNγ is locally translated in the injured peripheral axons and upregulates cGAS expression in Schwann cells and infiltrating blood cells to produce cGAMP, which promotes spontaneous axon regeneration as an immunotransmitter. Our study demonstrates that injured peripheral nervous system (PNS) axons can direct the environmental innate immune response for self-repair and that the neural antiviral mechanism can be harnessed to promote axon regeneration in the central nervous system (CNS).

The m6 A Readers YTHDF1 and YTHDF2 Synergistically Control Cerebellar Parallel Fiber Growth by Regulating Local Translation of the Key Wnt5a Signaling Components in Axons.

Messenger RNA m6 A modification is shown to regulate local translation in axons. However, how the m6 A codes in axonal mRNAs are read and decoded by the m6 A reader proteins is still unknown. Here, it is found that the m6 A readers YTHDF1 and YTHDF2 are both expressed in cerebellar granule cells (GCs) and their axons. Knockdown (KD) of YTHDF1 or YTHDF2 significantly increases GC axon growth rates in vitro. By integrating anti-YTHDF1&2 RIP-Seq with the quantitative proteomic analysis or RNA-seq after KD of YTHDF1 or YTHDF2, a group of transcripts which may mediate the regulation of GC axon growth by YTHDFs is identified. Among them, Dvl1 and Wnt5a, encoding the key components of Wnt pathway, are further found to be locally translated in axons, which are controlled by YTHDF1 and YTHDF2, respectively. Specific ablation of Ythdf1 or Ythdf2 in GCs increases parallel fiber growth, promotes synapse formation in cerebellum in vivo, and improves motor coordination ability. Together, this study identifies a mechanism by which the m6 A readers YTHDF1 and YTHDF2 work synergistically on the Wnt5a pathway through regulating local translation in GC axons to control cerebellar parallel fiber development.

Degradation, adsorption and leaching of phenazine-1-carboxamide in agricultural soils.

Phenazines, a large group of nitrogen-containing heterocycles with promising bioactivities, can be widely used as medicines and pesticides. But phenazines also generate toxicity risks due to their non-selective DNA binding. The environmental fate of phenazines in soils is the key to assess their risks; however, hitherto, there have been very few related studies. Therefore in the present study, the degradation, adsorption and leaching behaviors of a typical natural phenazine-phenazine-1-carboxamide (PCN) in agricultural soils from three representative places in China with different physicochemical properties were, for the first time, systematically studied in laboratory simulation experiments. Our results indicated that the degradation of PCN in all the tested soils followed the first order kinetics, with half-lives ranging from 14.4 to 57.8 d under different conditions. Soil anaerobic microorganisms, organic matter content and pH conditions are important factors that regulating PCN degradation. The adsorption data of PCN were found to be well fitted using the Freundlich model, with the r2 values above 0.978. Freundlich adsorption coefficient Kf of PCN ranged from 5.75 to 12.8 [(mg/kg)/(mg/L)1/n] in soils. The retention factor Rf values ranged from 0.0833 to 0.354, which means that the mobility of PCN in the three types of soil is between immobile to moderately mobile. Our results demonstrate that PCN is easily degraded, has high adsorption affinity and low mobility in high organic matter content and clay soils, thus resulting in lower risks of contamination to groundwater systems. In contrast, it degraded slowly, has low adsorption affinity and moderately mobile in soils with low organic matter and clay content, therefore it has higher polluting potential to groundwater systems. Overall, these findings provide useful insights into the future evaluation of environmental as well as health risks of PCN.

The m6A reader YTHDF1 regulates axon guidance through translational control of Robo3.1 expression.

N 6-Methyladenosine (m6A) is a dynamic mRNA modification which regulates protein expression in various posttranscriptional levels. Functional studies of m6A in nervous system have focused on its writers and erasers so far, whether and how m6A readers mediate m6A functions through recognizing and binding their target mRNA remains poorly understood. Here, we find that the expression of axon guidance receptor Robo3.1 which plays important roles in midline crossing of spinal commissural axons is regulated precisely at translational level. The m6A reader YTHDF1 binds to and positively regulates translation of m6A-modified Robo3.1 mRNA. Either mutation of m6A sites in Robo3.1 mRNA or YTHDF1 knockdown or knockout leads to dramatic reduction of Robo3.1 protein without affecting Robo3.1 mRNA level. Specific ablation of Ythdf1 in spinal commissural neurons results in pre-crossing axon guidance defects. Our findings identify a mechanism that YTHDF1-mediated translation of m6A-modified Robo3.1 mRNA controls pre-crossing axon guidance in spinal cord.

Dynamic m6A modification regulates local translation of mRNA in axons.

N6-methyladenosine (m6A) is a reversible modification in mRNA and has been shown to regulate processing, translation and decay of mRNA. However, the roles of m6A modification in neuronal development are still not known. Here, we found that the m6A eraser FTO is enriched in axons and can be locally translated. Axon-specific inhibition of FTO by rhein, or compartmentalized siRNA knockdown of Fto in axons led to increases of m6A levels. GAP-43 mRNA is modified by m6A and is a substrate of FTO in axons. Loss-of-function of this non-nuclear pool of FTO resulted in increased m6A modification and decreased local translation of axonal GAP-43 mRNA, which eventually repressed axon elongation. Mutation of a predicted m6A site in GAP-43 mRNA eliminated its m6A modification and exempted regulation of its local translation by axonal FTO. This work showed an example of dynamic internal m6A demethylation of non-nuclear localized mRNA by the demethylase FTO. Regulation of m6A modification of axonal mRNA by axonal FTO might be a general mechanism to control their local translation in neuronal development.