Non-canonical autophagy functions of ATG16L1 in epithelial cells limit lethal infection by influenza A virus.

Influenza A virus (IAV) and SARS-CoV-2 (COVID-19) cause pandemic infections where cytokine storm syndrome and lung inflammation lead to high mortality. Given the high social and economic cost of respiratory viruses, there is an urgent need to understand how the airways defend against virus infection. Here we use mice lacking the WD and linker domains of ATG16L1 to demonstrate that ATG16L1-dependent targeting of LC3 to single-membrane, non-autophagosome compartments - referred to as non-canonical autophagy - protects mice from lethal IAV infection. Mice with systemic loss of non-canonical autophagy are exquisitely sensitive to low-pathogenicity IAV where extensive viral replication throughout the lungs, coupled with cytokine amplification mediated by plasmacytoid dendritic cells, leads to fulminant pneumonia, lung inflammation and high mortality. IAV was controlled within epithelial barriers where non-canonical autophagy reduced IAV fusion with endosomes and activation of interferon signalling. Conditional mouse models and ex vivo analysis showed that protection against IAV infection of lung was independent of phagocytes and other leucocytes. This establishes non-canonical autophagy in airway epithelial cells as a novel innate defence that restricts IAV infection and lethal inflammation at respiratory surfaces.

Fine mapping of powdery mildew resistance gene PmXNM in a Chinese wheat landrace Xiaonanmai.

KEY MESSAGE: Powdery mildew resistance gene PmXNM, originated from the Chinese wheat landrace Xiaonanmai, was delimited to a 300.7-kb interval enriched with resistance genes. Powdery mildew, caused by Blumeria graminis f. sp. tritici (Bgt), is a globally devastating disease threatening the yield and quality of wheat worldwide. The use of broad-spectrum disease resistance genes from wheat landraces is an effective strategy to prevent this pathogen. Chinese wheat landrace Xiaonanmai (XNM) was immune to 23 tested Bgt isolates at the seedling stage. The F1, F2, and F2:4 progenies derived from the cross between XNM and Chinese Spring (CS) were used in this study. Genetic analysis revealed that powdery mildew resistance in XNM was controlled by a single dominant gene, temporarily designated PmXNM. Bulked segregant analysis and molecular mapping delimited PmXNM to the distal terminal region of chromosome 4AL flanked by markers caps213923 and kasp511718. The region carrying the PmXNM locus was approximately 300.7 kb and contained nine high-confidence genes according to the reference genome sequence of CS. Five of these genes, annotated as disease resistance RPP13-like proteins 1, were clustered in the target region. Haplotype analysis using the candidate gene-specific markers indicated that the majority of 267 common wheat accessions (75.3%) exhibited extensive gene losses at the PmXNM locus, as confirmed by aligning the targeted genome sequences of CS with those of other sequenced wheat cultivars. Seven candidate gene-specific markers have proven effective for marker-assisted introgression of PmXNM into modern elite cultivars.

Neutrophilic dermatoses as a manifestation of a systemic lupus erythematosus flare.

Neutrophilic dermatoses (NDs) refer to a group of cutaneous conditions histologically characterized by the dense accumulation of neutrophils in the skin in the absence of infection. NDs have been associated with underlying autoimmune connective tissue disorders (CTDs) such as systemic lupus erythematosus (SLE), Sjogren's syndrome, and dermatomyositis. We describe a case of neutrophilic dermatoses as a manifestation of a SLE flare.

Periodontal ligament fibroblasts-derived exosomes induced by PGE2 inhibit human periodontal ligament stem cells osteogenic differentiation via activating miR-34c-5p/SATB2/ERK.

Several studies have confirmed that exosomes containing microRNAs (miRNAs) from the aseptic inflammatory microenvironment play an important role in bone remodeling. But the mechanism that induces changes in the osteogenic ability of periodontal ligament stem cells (PDLSCs) is still unclear. In the present study, the osteogenic function of periodontal ligament fibroblasts-derived exosomes induced by PGE2 on PDLSCs was detected by real-time PCR, alizarin red assay and alkaline phosphatase staining. High-throughput miRNAs sequencing was used to reveal that miR-34c-5p in exosomes-PGE2 was upregulated compared it in exosomes-normal. Real-time PCR and western blotting assay verified that overexpression of miR-34c-5p inhibited osteogenic differentiation, and reduced phosphorylation of ERK1/2. In addition, dual-luciferase reporter assay revealed that miR-34c-5p targeted special AT-rich sequence-binding protein 2 (SATB2). It was shown that exosomal miR-34c-5p inhibited osteogenic differentiation of PDLSCs via SATB2/ERK pathway.

Cell Profiling of Acute Kidney Injury to Chronic Kidney Disease Reveals Novel Oxidative Stress Characteristics in the Failed Repair of Proximal Tubule Cells.

Chronic kidney disease (CKD) is a major public health issue around the world. A significant number of CKD patients originates from acute kidney injury (AKI) patients, namely "AKI-CKD". CKD is significantly related to the consequences of AKI. Damaged renal proximal tubular (PT) cell repair has been widely confirmed to indicate the renal prognosis of AKI. Oxidative stress is a key damage-associated factor and plays a significant role throughout the development of AKI and CKD. However, the relationships between AKI-CKD progression and oxidative stress are not totally clear and the underlying mechanisms in "AKI-CKD" remain indistinct. In this research, we constructed unilateral ischemia-reperfusion injury (UIRI)-model mice and performed single-nucleus RNA sequencing (snRNA-seq) of the kidney samples from UIRI and sham mice. We obtained our snRNA-seq data and validated the findings based on the joint analysis of public databases, as well as a series of fundamental experiments. Proximal tubular cells associated with failed repair express more complete senescence and oxidative stress characteristics compared to other subgroups. Furthermore, oxidative stress-related transcription factors, including Stat3 and Dnmt3a, are significantly more active under the circumstance of failed repair. What is more, we identified abnormally active intercellular communication between PT cells associated with failed repair and macrophages through the APP-CD74 pathway. More notably, we observed that the significantly increased expression of CD74 in hypoxia-treated TECs (tubular epithelial cells) was dependent on adjacently infiltrated macrophages, which was essential for the further deterioration of failed repair in PT cells. This research provides a novel understanding of the process of AKI to CKD progression, and the oxidative stress-related characteristics that we identified might represent a potentially novel therapeutic strategy against AKI.

[Clinical and genetic characteristics of children with primary dilated cardiomyopathy]. / å„¿ç«¥åŽŸå‘æ€§æ‰©å¼ åž‹å¿ƒè‚Œç— çš„ä¸´åºŠç‰¹å¾åŠé—ä¼ å­¦åˆ†æž.

OBJECTIVES: To study the genetic characteristics, clinical characteristics, and prognosis of children with primary dilated cardiomyopathy (DCM). METHODS: A retrospective analysis was performed on the medical data of 44 children who were diagnosed with DCM in Hebei Children's Hospital from July 2018 to February 2023. According to the genetic testing results, they were divided into two groups: gene mutation-positive group (n=17) and gene mutation-negative group (n=27). The two groups were compared in terms of clinical data at initial diagnosis and follow-up data. RESULTS: Among the 44 children with DCM, there were 21 boys (48%) and 23 girls (52%). Respiratory symptoms including cough and shortness of breath were the most common symptom at initial diagnosis (34%, 15/44). The detection rate of gene mutations was 39% (17/44). There were no significant differences between the two groups in clinical characteristics, proportion of children with cardiac function grade Ⅲ or Ⅳ, brain natriuretic peptide levels, left ventricular ejection fraction, and left ventricular fractional shortening at initial diagnosis (P>0.05). The median follow-up time was 23 months, and 9 children (20%) died, including 8 children from the gene mutation-positive group, among whom 3 had TTN gene mutation, 2 had LMNA gene mutation, 2 had TAZ gene mutation, and 1 had ATAD3A gene mutation. The gene mutation-positive group had a significantly higher mortality rate than the gene mutation-negative group (P<0.05). CONCLUSIONS: There is no correlation between the severity of DCM at initial diagnosis and gene mutations in children. However, children with gene mutations may have a poorer prognosis.

Fine mapping of Pm58 from Aegilops tauschii conferring powdery mildew resistance.

KEY MESSAGE: The powdery mildew resistance gene Pm58 was traced to a 141.3-kb interval with the co-segregating marker Xkasp68500 in wheat breeding. Pm58 is a powdery mildew resistance gene identified in Aegilops tauschii accession TA1662 and effective in a common wheat background. To finely map Pm58, an F2 population of 676 plants derived from the cross T093 × TA1662 was used for recombinant screening. We obtained 13 recombinants that occurred between the flanking markers Xhnu670 and Xhnu186. Genotyping and phenotyping these recombinant F2:3 families delimited Pm58 to a 0.22-cM interval (Xsts20220-Xkasp61553) on chromosome arm 2DS. The region carrying the Pm58 locus was approximately 141.3-kb, which contained eight annotated genes according to the reference genome sequence of Ae. tauschii AL8/78. Haplotype analysis of 178 Ae. tauschii accessions using the candidate gene-specific markers identified a disease resistance gene AET2Gv20068500 as a candidate for Pm58. Comparative mapping of the Pm58-containing interval revealed two presence/absence variations (PAVs) between AL8/78 and common wheat Chinese Spring. PAV-1 resides in the 3'-end of AET2Gv20068500. The majority of 158 common wheat cultivars (84.8%) displayed the absence of a 14.1-kb fragment in the PAV-1 region, which was confirmed by aligning the targeted genome sequences of the other sequenced Ae. tauschii accessions and common wheat cultivars. A co-segregating marker Xkasp68500 developed from AET2Gv20068500 can distinguish TA1662 from all randomly selected common wheat cultivars and will be instrumental for tracking Pm58 in breeding programs.

Clinical effects of maxillary protraction in different stages of dentition in skeletal class III children: A systematic review and meta-analysis.

OBJECTIVES: This systematic review and meta-analysis aimed to evaluate the effectiveness of using maxillary protraction during different stages of the dentition by assessing changes in the jaws and inclination of incisors. MATERIALS AND METHODS: MEDLINE (PubMed), Embase, Cochrane, Web Of Science, China National Knowledge Infrastructure and Wanfang Databases were searched without time limitations up to 15 January 2022. Google Scholar was used to search grey literature. We included cohort studies that compared the effect of maxillary protraction by analysing primary outcomes and were grouped in age-related conditions. Mean differences and 95% confidence intervals were used for statistical analysis, followed by Grading of Recommendations Assessment, Development and Evaluation analysis. RESULTS: Six studies were finally included. The heterogeneity test showed P ≥ .1 and I2  ≤ 50%, and a fixed-effect model was applied. Patients in the early treatment group (ETG) were mainly in the early-mixed dentition stage, while patients in the late treatment group (LTG) were in the late-mixed and early-permanent dentition stage. Meta-analysis showed that there were no statistical differences (P > .05) between the ETG and LTG groups in terms of SNA (the angle composed by point Sella-Nasion-Subspinale), SNB (the angle composed by point Sella-Nasion-Supramentale), ANB (the angle composed by point Subspinale-Nasion-Supramentale), Wits, U1/SN (the angle composed by the axis of upper incisors and Sella-Nasion plane) and L1/MP (the angle composed by the axis of lower incisors and the mandibular plane). CONCLUSION: Our analysis showed that maxillary protraction applied in the late-mixed or early-permanent dentition stage did not cause different effects on the maxillary growth, the correction of the intermaxillary relationship, the inhibition of mandibular growth and dental tipping of skeletal class III patients when compared to that in the early-mixed dentition stage. Collectively, these data provide a theoretical basis for widening the applicable age period of maxillary protraction and choosing the best treatment opportunity for children patients after a comprehensive assessment.

MiR-125a-3p inhibits cell proliferation and inflammation responses in fibroblast-like synovial cells in rheumatoid arthritis by mediating the Wnt/ß-catenin and NF-κB pathways via targeting MAST3.

OBJECTIVES: To explore the role and mechanism of miR-125a-3p in rheumatoid arthritis (RA) progression. METHODS: The RA-tissues and fibroblast-like synovial cells in rheumatoid arthritis (RA-FLS) were used in this study. qRT-PCR, western blot and ELISA assay were performed to detect the expression levels of IL-6, IL-ß and ΤΝF-α. Dual-luciferase reporter gene assay was used to observe the binding effect of miR-125a-3p and MAST3, and CCK-8 was used to observe the effect of miR-125a-3p on the proliferation of RA-FLS. RESULTS: miR-125a-3p was significantly downregulated in the RA-tissues and RA-FLS, and miR-125a-3p could inhibit the proliferation and reduce the inflammation response of RA-FLS. Besides, MAST3 was found as a target of miR-125a-3p, and increased MAST3 could reverse the effects of miR-125a-3p on RA-FLS including decreased proliferation, reduced inflammation level and the inactivation of Wnt/ß-catenin and NF-κB pathways. CONCLUSIONS: This study suggests that miR-125a-3p could inactivate the Wnt/ß-catenin and NF-κB pathways to reduce the proliferation and inflammation response of RA-FLS via targeting MAST3.

Karyotyping of circulating tumor cells for predicting chemotherapeutic sensitivity and efficacy in patients with esophageal cancer.

BACKGROUND: Aneuploidy of chromosome 8 in circulating tumor cells (CTCs) has been reported correlates with therapeutic efficacy and prognosis in patients with advanced gastric cancer. However, it is not clear whether it is also appropriate for other cancer. Therefore, in this study, we evaluate the clinical application aneuploidy of CTCs for esophageal cancer. METHODS: Peripheral blood were collected for karyotyping analysis before and after first 4-cycles chemotherapy from seventy nine patients with newly diagnosed esophageal cancer. Karyotyping of chromosome 8 in CTCs detected by SET-iFISH (Subtraction Enrichment-Immunostaining fluorescence in situ hybridizatio) in those patients were grouped into two categories according to CTC number: triploid group and non-triploid group. Pearson Chi-Square were used to compare the association between different aneuploidy type and chemotherapeutic sensitivity and efficacy. RESULTS: Among the 16 patients with triploid of chromosome 8, 4 patients benefit, and of the 63 patients with non-triploid, 54 patients benefit. Chi-square test analysis found that clinical benefit of non-triploid patients was significantly higher than triploid patients, suggesting non-triploid patients were more sensitive to chemotherapy than triploid patients. After 4-cycles chemotherapy, it is found that chemotherapeutic efficacy was positively correlated with non-triploid proportion. These results suggest that non-triploid proportion could be used as a candidate maker for assessing chemotherapeutic efficacy. CONCLUSIONS: Monitoring aneuploidy of chromosome 8 in CTCs before and after chemotherapy may help predict sensitivity and efficacy of chemotherapy in patients with esophageal cancer.

Propionate-induced changes in cardiac metabolism, notably CoA trapping, are not altered by l-carnitine.

High concentrations of propionate and its metabolites are found in several diseases that are often associated with the development of cardiac dysfunction, such as obesity, diabetes, propionic acidemia, and methylmalonic acidemia. In the present work, we employed a stable isotope-based metabolic flux approach to understand propionate-mediated perturbation of cardiac energy metabolism. Propionate led to accumulation of propionyl-CoA (increased by ~101-fold) and methylmalonyl-CoA (increased by 36-fold). This accumulation caused significant mitochondrial CoA trapping and inhibited fatty acid oxidation. The reduced energy contribution from fatty acid oxidation was associated with increased glucose oxidation. The enhanced anaplerosis of propionate and CoA trapping altered the pool sizes of tricarboxylic acid cycle (TCA) metabolites. In addition to being an anaplerotic substrate, the accumulation of proprionate-derived malate increased the recycling of malate to pyruvate and acetyl-CoA, which can enter the TCA for energy production. Supplementation of 3 mM l-carnitine did not relieve CoA trapping and did not reverse the propionate-mediated fuel switch. This is due to new findings that the heart appears to lack the specific enzyme catalyzing the conversion of short-chain (C3 and C4) dicarboxylyl-CoAs to dicarboxylylcarnitines. The discovery of this work warrants further investigation on the relevance of dicarboxylylcarnitines, especially C3 and C4 dicarboxylylcarnitines, in cardiac conditions such as heart failure.

Oscillatory patterns in hippocampus under light and deep isoflurane anesthesia closely mirror prominent brain states in awake animals.

The hippocampus exhibits a variety of distinct states of activity under different conditions. For instance the rhythmic patterns of activity orchestrated by the theta oscillation during running and REM sleep are markedly different from the large irregular activity (LIA) observed during awake resting and slow wave sleep. We found that under different levels of isoflurane anesthesia activity in the hippocampus of rats displays two distinct states, which have several qualities that mirror the theta and LIA states. These data provide further evidence that the two states are intrinsic modes of the hippocampus; while also characterizing a preparation that could be useful for studying the natural activity states in hippocampus.

The long non-coding RNA HOTAIR affects the radiosensitivity of pancreatic ductal adenocarcinoma by regulating the expression of Wnt inhibitory factor 1.

Pancreatic ductal adenocarcinoma (PDAC) is seriously resistant to radiotherapy and the mechanism is largely unknown. HOX transcript antisense intergenic RNA (HOTAIR) is overexpressed in PDAC. However, the function of HOTAIR has never been related to the radiosensitivity of PDAC. In this present study, the expression of HOTAIR in the PDAC cell lines and tissues was measured by quantitative real-time PCR (qRT-PCR), and the association between HOTAIR expression levels and X-ray treatment in PDAC cell lines was investigated. Additionally, the influence of HOTAIR knockdown on radiosensitivity, proliferation, and apoptosis of PDAC cells after radiation was evaluated by colony formation assays, Cell Counting Kit-8 (CCK-8) assays, and flow cytometry, respectively. Furthermore, the correlation between HOTAIR and Wnt inhibitory factor 1 (WIF-1) expression in PDAC cell lines and tissues was studied to assess the role of HOTAIR and WIF-1 in the radiosensitivity of PDAC. The results confirmed that HOTAIR expression was significantly increased in the PDAC cell lines and tissues (n = 90) compared with human normal pancreatic ductal epithelial cell line (HPDE) and matched adjacent normal tissues (n = 90). Functionally, HOTAIR knockdown enhanced the radiosensitivity of PDAC cells, reduced the proliferation, and increased the apoptosis of cells after radiation. And HOTAIR silencing increased the expression of WIF-1. Furthermore, the overexpression of WIF-1 revealed that HOTAIR modulated the radiosensitivity of PDAC cells by regulating the expression of WIF-1. These data reveals that HOTAIR can affect the radiosensitivity of PDAC cells partly via regulating the expression of WIF-1, and HOTAIR-WIF-1 axis is a potential target for PDAC radiotherapy.

High expression of AFAP1-AS1 is associated with poor survival and short-term recurrence in pancreatic ductal adenocarcinoma.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is still a lethal malignancy. Long noncoding RNAs (lncRNAs) have been shown to play a critical role in cancer development and progression. Here we identified overexpression of the lncRNA AFAP1-AS1 in PDAC patients and evaluated its prognostic and functional relevance. METHODS: The global lncRNA expression profile in PDAC was measured by lncRNA microarray. Expression of AFAP1-AS1 was evaluated by reverse-transcriptase quantitative polymerase chain reaction (RT-qPCR) in 90 PDAC tissue samples and adjacent normal tissues. The impact of AFAP1-AS1 expression on cell proliferation, migration, and invasion were evaluated in vitro using knockdown and ectopic expression strategies. RESULTS: Microarray analysis revealed that up-regulation of AFAP1-AS1 expression in PDAC tissues compared with normal adjacent tissues, which was confirmed by RT-qPCR in 69/90 cases (76.7%). Its overexpression was associated with lymph node metastasis, perineural invasion, and poor survival. When using AFAP1-AS1 as a prognostic marker, the areas under ROC curves were 0.8669 and 0.9370 for predicting tumor progression within 6 months and 1 year, respectively. In vitro functional experiments involving knockdown of AFAP1-AS1 resulted in attenuated PDAC cell proliferation, migration, and invasion. Ectopic expression of AFAP1-AS1 promoted cell proliferation, migration, and invasion. CONCLUSIONS: AFAP1-AS1 is a potential novel prognostic marker to predict the clinical outcome of PDAC patients after surgery and may be a rational target for therapy.

Long non-coding RNA HOTTIP is correlated with progression and prognosis in tongue squamous cell carcinoma.

Long non-coding RNAs (lncRNAs) have been demonstrated to be a critical role in cancer progression and prognosis. However, little is known about the pathological role of lncRNA HOXA transcript at the distal tip (HOTTIP) in tongue squamous cell carcinoma (TSCC) patients. The aim of this study is to measure the expression of lncRNA HOTTIP in TSCC patients and to explore the clinical significance of the lncRNA HOTTIP. The expression of lncRNA HOTTIP was measured in 86 TSCC tissues and 14 adjacent non-malignant tissues using qRT-PCR. In our study, results indicated that lncRNA HOTTIP was highly expressed in TSCC compared with adjacent non-malignant tissues (P < 0.001) and positively correlated with T stage (T1-2 vs. T3-4, P = 0.023), clinical stage (I-II stages vs. III-IV stages, P = 0.018), and distant metastasis (absent vs. present, P = 0.031) in TSCC patients. Furthermore, we also found that lncRNA HOTTIP overexpression was an unfavorable prognostic factor in TSCC patients (P < 0.001), regardless of T stage, distant metastasis, and clinical stage. Finally, overexpression of lncRNA HOTTIP was supposed to be an independent poor prognostic factor for TSCC patients through multivariate analysis (P = 0.023). In conclusion, increased lncRNA HOTTIP expression may be serve as an unfavorable prognosis predictor for TSCC patients. Nevertheless, further investigation with a larger sample size is needed to support our results.

Periodontal ligament cells-derived exosomes promote osteoclast differentiation via modulating macrophage polarization.

Several studies have demonstrated that exosomes (Exos) are involved in the regulation of macrophage polarization and osteoclast differentiation. However, the characteristics as well as roles of exosomes from human periodontal ligament cells (hPDLCs-Exos) in M1/M2 macrophage polarization and osteoclast differentiation remain unclear. Here, periodontal ligament cells were successfully extracted by method of improved Type-I collagen enzyme digestion. hPDLCs-Exos were extracted by ultracentrifugation. hPDLCs-Exos were identified by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA) and western blotting (WB). Osteoclast differentiation was evaluated by real-time quantitative polymerase chain reaction (RT-qPCR), WB and tartrate-resistant acid phosphatase (TRAP) staining. M1/M2 macrophage polarization were evaluated by RT-qPCR and WB. The results showed hPDLCs-Exos promoted osteoclast differentiation and M2 macrophage polarization, but inhibited M1 macrophage polarization. Moreover, M1 macrophages inhibited osteoclast differentiation, whereas M2 macrophages promoted osteoclast differentiation. It has shown that hPDLCs-Exos promoted osteoclast differentiation by inhibiting M1 and promoting M2 macrophage polarization.

Erratum: miR-181a, delivered by hypoxic PTC-secreted exosomes, inhibits DACT2 by downregulating MLL3, leading to YAP-VEGF-mediated angiogenesis.

[This corrects the article DOI: 10.1016/j.omtn.2021.02.027.].

Rapid High-Temperature Liquid Shock Synthesis of High-Entropy Alloys for Hydrogen Evolution Reaction.

High-entropy-alloy nanoparticles (HEA-NPs) show great potential as electrocatalysts for water splitting, fuel cells, CO2 conversion, etc. However, fine-tuning the surface, morphology, structure, and crystal phase of HEA remains a great challenge. Here, the high-temperature liquid shock (HTLS) technique is applied to produce HEA-NPs, e.g., PtCoNiRuIr HEA-NPs, with tunable elemental components, ultrafine particle size, controlled crystal phases, and lattice strains. HTLS directly applied Joule heating on the liquid mixture of metal precursors, capping agents, and reducing agents, which is feasible for controlling the morphology and structure such as the atomic arrangement of the resulting products, thereby facilitating the rationally designed nanocatalysts. Impressively, the as-obtained PtCoNiRuIr HEA-NPs delivered superior activity and long-term stability for the hydrogen evolution reaction (HER), with low overpotentials at 10 mA cm-2 and 1 A cm-2 of only 18 and 408 mV, respectively, and 10000 CV stable cycles in 0.5 M H2SO4. Furthermore, in the near future, by combining the HTLS method with artificial intelligence (AI) and theoretical calculations, it is promising to provide an advanced platform for the high-throughput synthesis of HEA nanocatalysts with optimized performance for various energy applications, which is of great significance for achieving a carbon-neutral society with an effective and environmentally friendly energy system.

The V-ATPase-ATG16L1 axis recruits LRRK2 to facilitate the lysosomal stress response.

Leucine-rich repeat kinase 2 (LRRK2), a Rab kinase associated with Parkinson's disease and several inflammatory diseases, has been shown to localize to stressed lysosomes and get activated to regulate lysosomal homeostasis. However, the mechanisms of LRRK2 recruitment and activation have not been well understood. Here, we found that the ATG8 conjugation system regulates the recruitment of LRRK2 as well as LC3 onto single membranes of stressed lysosomes/phagosomes. This recruitment did not require FIP200-containing autophagy initiation complex, nor did it occur on double-membrane autophagosomes, suggesting independence from canonical autophagy. Consistently, LRRK2 recruitment was regulated by the V-ATPase-ATG16L1 axis, which requires the WD40 domain of ATG16L1 and specifically mediates ATG8 lipidation on single membranes. This mechanism was also responsible for the lysosomal stress-induced activation of LRRK2 and the resultant regulation of lysosomal secretion and enlargement. These results indicate that the V-ATPase-ATG16L1 axis serves a novel non-autophagic role in the maintenance of lysosomal homeostasis by recruiting LRRK2.

A CA1 circuit motif that signals the start of information integration.

Integrating information from the recent past is critical for guiding predictions and shaping behavior. The process of integrating information, such as tracking distance traveled or time elapsed, begins with establishing a starting point. Yet, the mechanisms by which neural circuits utilize relevant cues to initiate integration remain unknown. Our study sheds light on this question by identifying a subpopulation of CA1 pyramidal neurons called PyrDown. These neurons shut down their activity at the beginning of distance or time integration and then gradually ramp up their firing as the animal approaches the reward. PyrDown neurons provide a mechanism for representing integrated information through ramping activity, complementing the well-known place/time cells that respond to specific distances or time points. Our findings also reveal that parvalbumin inhibitory interneurons mediate the shutdown of PyrDown neurons, uncovering a circuit motif that enables the initiation of subsequent information integration to improve future predictions.