A genomic compendium of cultivated human gut fungi characterizes the gut mycobiome and its relevance to common diseases.

The gut fungal community represents an essential element of human health, yet its functional and metabolic potential remains insufficiently elucidated, largely due to the limited availability of reference genomes. To address this gap, we presented the cultivated gut fungi (CGF) catalog, encompassing 760 fungal genomes derived from the feces of healthy individuals. This catalog comprises 206 species spanning 48 families, including 69 species previously unidentified. We explored the functional and metabolic attributes of the CGF species and utilized this catalog to construct a phylogenetic representation of the gut mycobiome by analyzing over 11,000 fecal metagenomes from Chinese and non-Chinese populations. Moreover, we identified significant common disease-related variations in gut mycobiome composition and corroborated the associations between fungal signatures and inflammatory bowel disease (IBD) through animal experimentation. These resources and findings substantially enrich our understanding of the biological diversity and disease relevance of the human gut mycobiome.

Mutational Landscape of Secondary Glioblastoma Guides MET-Targeted Trial in Brain Tumor.

Low-grade gliomas almost invariably progress into secondary glioblastoma (sGBM) with limited therapeutic option and poorly understood mechanism. By studying the mutational landscape of 188 sGBMs, we find significant enrichment of TP53 mutations, somatic hypermutation, MET-exon-14-skipping (METex14), PTPRZ1-MET (ZM) fusions, and MET amplification. Strikingly, METex14 frequently co-occurs with ZM fusion and is present in ∼14% of cases with significantly worse prognosis. Subsequent studies show that METex14 promotes glioma progression by prolonging MET activity. Furthermore, we describe a MET kinase inhibitor, PLB-1001, that demonstrates remarkable potency in selectively inhibiting MET-altered tumor cells in preclinical models. Importantly, this compound also shows blood-brain barrier permeability and is subsequently applied in a phase I clinical trial that enrolls MET-altered chemo-resistant glioma patients. Encouragingly, PLB-1001 achieves partial response in at least two advanced sGBM patients with rarely significant side effects, underscoring the clinical potential for precisely treating gliomas using this therapy.

Inhibition of fatty acid oxidation enables heart regeneration in adult mice.

Postnatal maturation of cardiomyocytes is characterized by a metabolic switch from glycolysis to fatty acid oxidation, chromatin reconfiguration and exit from the cell cycle, instating a barrier for adult heart regeneration1,2. Here, to explore whether metabolic reprogramming can overcome this barrier and enable heart regeneration, we abrogate fatty acid oxidation in cardiomyocytes by inactivation of Cpt1b. We find that disablement of fatty acid oxidation in cardiomyocytes improves resistance to hypoxia and stimulates cardiomyocyte proliferation, allowing heart regeneration after ischaemia-reperfusion injury. Metabolic studies reveal profound changes in energy metabolism and accumulation of α-ketoglutarate in Cpt1b-mutant cardiomyocytes, leading to activation of the α-ketoglutarate-dependent lysine demethylase KDM5 (ref. 3). Activated KDM5 demethylates broad H3K4me3 domains in genes that drive cardiomyocyte maturation, lowering their transcription levels and shifting cardiomyocytes into a less mature state, thereby promoting proliferation. We conclude that metabolic maturation shapes the epigenetic landscape of cardiomyocytes, creating a roadblock for further cell divisions. Reversal of this process allows repair of damaged hearts.

Vertical MoS2 transistors with sub-1-nm gate lengths.

Ultra-scaled transistors are of interest in the development of next-generation electronic devices1-3. Although atomically thin molybdenum disulfide (MoS2) transistors have been reported4, the fabrication of devices with gate lengths below 1 nm has been challenging5. Here we demonstrate side-wall MoS2 transistors with an atomically thin channel and a physical gate length of sub-1 nm using the edge of a graphene layer as the gate electrode. The approach uses large-area graphene and MoS2 films grown by chemical vapour deposition for the fabrication of side-wall transistors on a 2-inch wafer. These devices have On/Off ratios up to 1.02 × 105 and subthreshold swing values down to 117 mV dec-1. Simulation results indicate that the MoS2 side-wall effective channel length approaches 0.34 nm in the On state and 4.54 nm in the Off state. This work can promote Moore's law of the scaling down of transistors for next-generation electronics.

Unraveling dynamic protein structures by two-dimensional infrared spectra with a pretrained machine learning model.

Dynamic protein structures are crucial for deciphering their diverse biological functions. Two-dimensional infrared (2DIR) spectroscopy stands as an ideal tool for tracing rapid conformational evolutions in proteins. However, linking spectral characteristics to dynamic structures poses a formidable challenge. Here, we present a pretrained machine learning model based on 2DIR spectra analysis. This model has learned signal features from approximately 204,300 spectra to establish a "spectrum-structure" correlation, thereby tracing the dynamic conformations of proteins. It excels in accurately predicting the dynamic content changes of various secondary structures and demonstrates universal transferability on real folding trajectories spanning timescales from microseconds to milliseconds. Beyond exceptional predictive performance, the model offers attention-based spectral explanations of dynamic conformational changes. Our 2DIR-based pretrained model is anticipated to provide unique insights into the dynamic structural information of proteins in their native environments.

Ide-cel or Standard Regimens in Relapsed and Refractory Multiple Myeloma.

BACKGROUND: Survival is poor among patients with triple-class-exposed relapsed and refractory multiple myeloma. Idecabtagene vicleucel (ide-cel), a B-cell maturation antigen-directed chimeric antigen receptor (CAR) T-cell therapy, previously led to deep, durable responses in patients with heavily pretreated relapsed and refractory multiple myeloma. METHODS: In this international, open-label, phase 3 trial involving adults with relapsed and refractory multiple myeloma who had received two to four regimens previously (including immunomodulatory agents, proteasome inhibitors, and daratumumab) and who had disease refractory to the last regimen, we randomly assigned patients in a 2:1 ratio to receive either ide-cel (dose range, 150×106 to 450×106 CAR-positive T cells) or one of five standard regimens. The primary end point was progression-free survival. Key secondary end points were overall response (partial response or better) and overall survival. Safety was assessed. RESULTS: A total of 386 patients underwent randomization: 254 to ide-cel and 132 to a standard regimen. A total of 66% of the patients had triple-class-refractory disease, and 95% had daratumumab-refractory disease. At a median follow-up of 18.6 months, the median progression-free survival was 13.3 months in the ide-cel group, as compared with 4.4 months in the standard-regimen group (hazard ratio for disease progression or death, 0.49; 95% confidence interval, 0.38 to 0.65; P<0.001). A response occurred in 71% of the patients in the ide-cel group and in 42% of those in the standard-regimen group (P<0.001); a complete response occurred in 39% and 5%, respectively. Data on overall survival were immature. Adverse events of grade 3 or 4 occurred in 93% of the patients in the ide-cel group and in 75% of those in the standard-regimen group. Among the 225 patients who received ide-cel, cytokine release syndrome occurred in 88%, with 5% having an event of grade 3 or higher, and investigator-identified neurotoxic effects occurred in 15%, with 3% having an event of grade 3 or higher. CONCLUSIONS: Ide-cel therapy significantly prolonged progression-free survival and improved response as compared with standard regimens in patients with triple-class-exposed relapsed and refractory multiple myeloma who had received two to four regimens previously. The toxicity of ide-cel was consistent with previous reports. (Funded by 2seventy bio and Celgene, a Bristol-Myers Squibb company; KarMMa-3 ClinicalTrials.gov number, NCT03651128.).

Ide-cel vs standard regimens in triple-class-exposed relapsed and refractory multiple myeloma: updated KarMMa-3 analyses.

Outcomes are poor in triple-class-exposed (TCE) relapsed/refractory multiple myeloma (RRMM). In the phase 3 KarMMa-3 (clinicaltrials.gov; NCT03651128) trial, patients with TCE RRMM and 2-4 prior regimens were randomized 2:1 to idecabtagene vicleucel (ide-cel) or standard regimens (SRs). An interim analysis (IA) demonstrated significantly longer median progression-free survival (PFS; primary endpoint; 13.3 vs 4.4 months; P<.0001) and higher overall response rate (ORR) with ide-cel vs SRs. At final PFS analysis (median follow-up, 30.9 months), ide-cel further improved median PFS vs SRs (13.8 vs 4.4 months; hazard ratio (HR), 0.49; 95% confidence interval (CI), 0.38-0.63). PFS benefit with ide-cel vs SRs was observed regardless of number of prior lines of therapy, with greatest benefit after 2 prior lines (16.2 vs 4.8 months, respectively). ORR benefit was maintained with ide-cel vs SRs (71% vs 42%; complete response, 44% vs 5%). Patient-centric design allowed crossover from SRs (56%) to ide-cel upon progressive disease, confounding overall survival (OS) interpretation. At IA of OS, median (95% CI) was 41.4 (30.9-not reached [NR]) vs 37.9 (23.4-NR) months with ide-cel and SRs, respectively (HR, 1.01; 95% CI 0.73-1.40); median OS in both arms was longer than historical data (9-22 months). Two prespecified analyses adjusting for crossover showed OS favoring ide-cel. This trial highlighted the importance of individualized bridging therapy to ensure adequate disease control during ide-cel manufacturing. Ide-cel improved patient-reported outcomes vs SRs. No new safety signals were reported. These results demonstrate the continued favorable benefit-risk profile of ide-cel in early-line and TCE RRMM. NCT03651128.

Author Correction: A new coronavirus associated with human respiratory disease in China.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

A new coronavirus associated with human respiratory disease in China.

Emerging infectious diseases, such as severe acute respiratory syndrome (SARS) and Zika virus disease, present a major threat to public health1-3. Despite intense research efforts, how, when and where new diseases appear are still a source of considerable uncertainty. A severe respiratory disease was recently reported in Wuhan, Hubei province, China. As of 25 January 2020, at least 1,975 cases had been reported since the first patient was hospitalized on 12 December 2019. Epidemiological investigations have suggested that the outbreak was associated with a seafood market in Wuhan. Here we study a single patient who was a worker at the market and who was admitted to the Central Hospital of Wuhan on 26 December 2019 while experiencing a severe respiratory syndrome that included fever, dizziness and a cough. Metagenomic RNA sequencing4 of a sample of bronchoalveolar lavage fluid from the patient identified a new RNA virus strain from the family Coronaviridae, which is designated here 'WH-Human 1' coronavirus (and has also been referred to as '2019-nCoV'). Phylogenetic analysis of the complete viral genome (29,903 nucleotides) revealed that the virus was most closely related (89.1% nucleotide similarity) to a group of SARS-like coronaviruses (genus Betacoronavirus, subgenus Sarbecovirus) that had previously been found in bats in China5. This outbreak highlights the ongoing ability of viral spill-over from animals to cause severe disease in humans.

circRNADisease v2.0: an updated resource for high-quality experimentally supported circRNA-disease associations.

circRNADisease v2.0 is an enhanced and reliable database that offers experimentally verified relationships between circular RNAs (circRNAs) and various diseases. It is accessible at http://cgga.org.cn/circRNADisease/ or http://cgga.org.cn:9091/circRNADisease/. The database currently includes 6998 circRNA-disease entries across multiple species, representing a remarkable 19.77-fold increase compared to the previous version. This expansion consists of a substantial rise in the number of circRNAs (from 330 to 4246), types of diseases (from 48 to 330) and covered species (from human only to 12 species). Furthermore, a new section has been introduced in the database, which collects information on circRNA-associated factors (genes, proteins and microRNAs), molecular mechanisms (molecular pathways), biological functions (proliferation, migration, invasion, etc.), tumor and/or cell line and/or patient-derived xenograft (PDX) details, and prognostic evidence in diseases. In addition, we identified 7 159 865 relationships between mutations and circRNAs among 30 TCGA cancer types. Due to notable enhancements and extensive data expansions, the circRNADisease 2.0 database has become an invaluable asset for both clinical practice and fundamental research. It enables researchers to develop a more comprehensive understanding of how circRNAs impact complex diseases.

Bone Morphogenetic Protein 9 Protects Against Myocardial Infarction by Improving Lymphatic Drainage Function and Triggering DECR1-Mediated Mitochondrial Bioenergetics.

BACKGROUND: BMP9 (bone morphogenetic protein 9) is a member of the TGF-ß (transforming growth factor ß) family of cytokines with pleiotropic effects on glucose metabolism, fibrosis, and lymphatic development. However, the role of BMP9 in myocardial infarction (MI) remains elusive. METHODS: The expressional profiles of BMP9 in cardiac tissues and plasma samples of subjects with MI were determined by immunoassay or immunoblot. The role of BMP9 in MI was determined by evaluating the impact of BMP9 deficiency and replenishment with adeno-associated virus-mediated BMP9 expression or recombinant human BMP9 protein in mice. RESULTS: We show that circulating BMP9 and its cardiac levels are markedly increased in humans and mice with MI and are negatively associated with cardiac function. It is important to note that BMP9 deficiency exacerbates left ventricular dysfunction, increases infarct size, and augments cardiac fibrosis in mice with MI. In contrast, replenishment of BMP9 significantly attenuates these adverse effects. We further demonstrate that BMP9 improves lymphatic drainage function, thereby leading to a decrease of cardiac edema. In addition, BMP9 increases the expression of mitochondrial DECR1 (2,4-dienoyl-CoA reductase 1), a rate-limiting enzyme involved in ß-oxidation, which, in turn, promotes cardiac mitochondrial bioenergetics and mitigates MI-induced cardiomyocyte injury. Moreover, DECR1 deficiency exacerbates MI-induced cardiac damage in mice, whereas this adverse effect is restored by the treatment of adeno-associated virus-mediated DECR1. Consistently, DECR1 deletion abrogates the beneficial effect of BMP9 against MI-induced cardiomyopathy and cardiac damage in mice. CONCLUSIONS: These results suggest that BMP9 protects against MI by fine-tuning the multiorgan cross-talk among the liver, lymph, and the heart.

Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS.

BACKGROUND: The intrathecally administered antisense oligonucleotide tofersen reduces synthesis of the superoxide dismutase 1 (SOD1) protein and is being studied in patients with amyotrophic lateral sclerosis (ALS) associated with mutations in SOD1 (SOD1 ALS). METHODS: In this phase 3 trial, we randomly assigned adults with SOD1 ALS in a 2:1 ratio to receive eight doses of tofersen (100 mg) or placebo over a period of 24 weeks. The primary end point was the change from baseline to week 28 in the total score on the ALS Functional Rating Scale-Revised (ALSFRS-R; range, 0 to 48, with higher scores indicating better function) among participants predicted to have faster-progressing disease. Secondary end points included changes in the total concentration of SOD1 protein in cerebrospinal fluid (CSF), in the concentration of neurofilament light chains in plasma, in slow vital capacity, and in handheld dynamometry in 16 muscles. A combined analysis of the randomized component of the trial and its open-label extension at 52 weeks compared the results in participants who started tofersen at trial entry (early-start cohort) with those in participants who switched from placebo to the drug at week 28 (delayed-start cohort). RESULTS: A total of 72 participants received tofersen (39 predicted to have faster progression), and 36 received placebo (21 predicted to have faster progression). Tofersen led to greater reductions in concentrations of SOD1 in CSF and of neurofilament light chains in plasma than placebo. In the faster-progression subgroup (primary analysis), the change to week 28 in the ALSFRS-R score was -6.98 with tofersen and -8.14 with placebo (difference, 1.2 points; 95% confidence interval [CI], -3.2 to 5.5; P = 0.97). Results for secondary clinical end points did not differ significantly between the two groups. A total of 95 participants (88%) entered the open-label extension. At 52 weeks, the change in the ALSFRS-R score was -6.0 in the early-start cohort and -9.5 in the delayed-start cohort (difference, 3.5 points; 95% CI, 0.4 to 6.7); non-multiplicity-adjusted differences favoring early-start tofersen were seen for other end points. Lumbar puncture-related adverse events were common. Neurologic serious adverse events occurred in 7% of tofersen recipients. CONCLUSIONS: In persons with SOD1 ALS, tofersen reduced concentrations of SOD1 in CSF and of neurofilament light chains in plasma over 28 weeks but did not improve clinical end points and was associated with adverse events. The potential effects of earlier as compared with delayed initiation of tofersen are being further evaluated in the extension phase. (Funded by Biogen; VALOR and OLE ClinicalTrials.gov numbers, NCT02623699 and NCT03070119; EudraCT numbers, 2015-004098-33 and 2016-003225-41.).

PTBGRP: predicting phage-bacteria interactions with graph representation learning on microbial heterogeneous information network.

Identifying the potential bacteriophages (phage) candidate to treat bacterial infections plays an essential role in the research of human pathogens. Computational approaches are recognized as a valid way to predict bacteria and target phages. However, most of the current methods only utilize lower-order biological information without considering the higher-order connectivity patterns, which helps to improve the predictive accuracy. Therefore, we developed a novel microbial heterogeneous interaction network (MHIN)-based model called PTBGRP to predict new phages for bacterial hosts. Specifically, PTBGRP first constructs an MHIN by integrating phage-bacteria interaction (PBI) and six bacteria-bacteria interaction networks with their biological attributes. Then, different representation learning methods are deployed to extract higher-level biological features and lower-level topological features from MHIN. Finally, PTBGRP employs a deep neural network as the classifier to predict unknown PBI pairs based on the fused biological information. Experiment results demonstrated that PTBGRP achieves the best performance on the corresponding ESKAPE pathogens and PBI dataset when compared with state-of-art methods. In addition, case studies of Klebsiella pneumoniae and Staphylococcus aureus further indicate that the consideration of rich heterogeneous information enables PTBGRP to accurately predict PBI from a more comprehensive perspective. The webserver of the PTBGRP predictor is freely available at http://120.77.11.78/PTBGRP/.

A small molecule exerts selective antiviral activity by targeting the human cytomegalovirus nuclear egress complex.

Human cytomegalovirus (HCMV) is an important pathogen for which new antiviral drugs are needed. HCMV, like other herpesviruses, encodes a nuclear egress complex (NEC) composed of two subunits, UL50 and UL53, whose interaction is crucial for viral replication. To explore whether small molecules can exert selective antiviral activity by inhibiting NEC subunit interactions, we established a homogeneous time-resolved fluorescence (HTRF) assay of these interactions and used it to screen >200,000 compound-containing wells. Two compounds, designated GK1 and GK2, which selectively inhibited this interaction in the HTRF assay with GK1 also active in a co-immunoprecipitation assay, exhibited more potent anti-HCMV activity than cytotoxicity or activity against another herpesvirus. At doses that substantially reduced HCMV plaque formation, GK1 and GK2 had little or no effect on the expression of viral proteins and reduced the co-localization of UL53 with UL50 at the nuclear rim in a subset of cells. GK1 and GK2 contain an acrylamide moiety predicted to covalently interact with cysteines, and an analog without this potential lacked activity. Mass spectrometric analysis showed binding of GK2 to multiple cysteines on UL50 and UL53. Nevertheless, substitution of cysteine 214 of UL53 with serine (C214S) ablated detectable inhibitory activity of GK1 and GK2 in vitro, and the C214S substitution engineered into HCMV conferred resistance to GK1, the more potent of the two inhibitors. Thus, GK1 exerts selective antiviral activity by targeting the NEC. Docking studies suggest that the acrylamide tethers one end of GK1 or GK2 to C214 within a pocket of UL53, permitting the other end of the molecule to sterically hinder UL50 to prevent NEC formation. Our results prove the concept that targeting the NEC with small molecules can selectively block HCMV replication. Such compounds could serve as a foundation for development of anti-HCMV drugs and as chemical tools for studying HCMV.

The genome of Lespedeza potaninii reveals biased subgenome evolution and drought adaptation.

Lespedeza potaninii, a xerophytic subshrub belonging to the legume family, is native to the Tengger Desert and is highly adapted to drought. It has important ecological value due to its drought adaptability, but the underlying molecular mechanisms remain largely unknown. Here, we report a 1.24 Gb chromosome-scale assembly of the L. potaninii genome (contig N50 = 15.75 Mb). Our results indicate that L. potaninii underwent an allopolyploid event with 2 subgenomes, A and B, presenting asymmetric evolution and B subgenome dominance. We estimate that the 2 diploid progenitors of L. potaninii diverged around 3.6 million years ago (MYA) and merged around 1.0 MYA. We revealed that the expansion of hub genes associated with drought responses, such as the binding partner 1 of accelerated cell death 11 (ACD11) (BPA1), facilitated environmental adaptations of L. potaninii to desert habitats. We found a novel function of the BPA1 family in abiotic stress tolerance in addition to the known role in regulating the plant immune response, which could improve drought tolerance by positively regulating reactive oxygen species homeostasis in plants. We revealed that bZIP transcription factors could bind to the BPA1 promoter and activate its transcription. Our work fills the genomic data gap in the Lespedeza genus and the tribe Desmodieae, which should provide theoretical support both in the study of drought tolerance and in the molecular breeding of legume crops.

Identification of a CD4-Binding-Site Antibody to HIV that Evolved Near-Pan Neutralization Breadth.

Detailed studies of the broadly neutralizing antibodies (bNAbs) that underlie the best available examples of the humoral immune response to HIV are providing important information for the development of therapies and prophylaxis for HIV-1 infection. Here, we report a CD4-binding site (CD4bs) antibody, named N6, that potently neutralized 98% of HIV-1 isolates, including 16 of 20 that were resistant to other members of its class. N6 evolved a mode of recognition such that its binding was not impacted by the loss of individual contacts across the immunoglobulin heavy chain. In addition, structural analysis revealed that the orientation of N6 permitted it to avoid steric clashes with glycans, which is a common mechanism of resistance. Thus, an HIV-1-specific bNAb can achieve potent, near-pan neutralization of HIV-1, making it an attractive candidate for use in therapy and prophylaxis.

Caspase-11/GSDMD contributes to the progression of hyperuricemic nephropathy by promoting NETs formation.

Hyperuricemia is an independent risk factor for chronic kidney disease (CKD) and promotes renal fibrosis, but the underlying mechanism remains largely unknown. Unresolved inflammation is strongly associated with renal fibrosis and is a well-known significant contributor to the progression of CKD, including hyperuricemia nephropathy. In the current study, we elucidated the impact of Caspase-11/Gasdermin D (GSDMD)-dependent neutrophil extracellular traps (NETs) on progressive hyperuricemic nephropathy. We found that the Caspase-11/GSDMD signaling were markedly activated in the kidneys of hyperuricemic nephropathy. Deletion of Gsdmd or Caspase-11 protects against the progression of hyperuricemic nephropathy by reducing kidney inflammation, proinflammatory and profibrogenic factors expression, NETs generation, α-smooth muscle actin expression, and fibrosis. Furthermore, specific deletion of Gsdmd or Caspase-11 in hematopoietic cells showed a protective effect on renal fibrosis in hyperuricemic nephropathy. Additionally, in vitro studies unveiled the capability of uric acid in inducing Caspase-11/GSDMD-dependent NETs formation, consequently enhancing α-smooth muscle actin production in macrophages. In summary, this study demonstrated the contributory role of Caspase-11/GSDMD in the progression of hyperuricemic nephropathy by promoting NETs formation, which may shed new light on the therapeutic approach to treating and reversing hyperuricemic nephropathy.

Multidimensional profiling reveals GATA1-modulated stage-specific chromatin states and functional associations during human erythropoiesis.

Mammalian erythroid development can be divided into three stages: hematopoietic stem and progenitor cell (HSPC), erythroid progenitor (Ery-Pro), and erythroid precursor (Ery-Pre). However, the mechanisms by which the 3D genome changes to establish the stage-specific transcription programs that are critical for erythropoiesis remain unclear. Here, we analyze the chromatin landscape at multiple levels in defined populations from primary human erythroid culture. While compartments and topologically associating domains remain largely unchanged, ∼50% of H3K27Ac-marked enhancers are dynamic in HSPC versus Ery-Pre. The enhancer anchors of enhancer-promoter loops are enriched for occupancy of respective stage-specific transcription factors (TFs), indicating these TFs orchestrate the enhancer connectome rewiring. The master TF of erythropoiesis, GATA1, is found to occupy most erythroid gene promoters at the Ery-Pro stage, and mediate conspicuous local rewiring through acquiring binding at the distal regions in Ery-Pre, promoting productive erythroid transcription output. Knocking out GATA1 binding sites precisely abrogates local rewiring and corresponding gene expression. Interestingly, knocking down GATA1 can transiently revert the cell state to an earlier stage and prolong the window of progenitor state. This study reveals mechanistic insights underlying chromatin rearrangements during development by integrating multidimensional chromatin landscape analyses to associate with transcription output and cellular states.

Plant ESCRT protein ALIX coordinates with retromer complex in regulating receptor-mediated sorting of soluble vacuolar proteins.

Vacuolar proteins play essential roles in plant physiology and development, but the factors and the machinery regulating their vesicle trafficking through the endomembrane compartments remain largely unknown. We and others have recently identified an evolutionarily conserved plant endosomal sorting complex required for transport (ESCRT)-associated protein apoptosis-linked gene-2 interacting protein X (ALIX), which plays canonical functions in the biogenesis of the multivesicular body/prevacuolar compartment (MVB/PVC) and in the sorting of ubiquitinated membrane proteins. In this study, we elucidate the roles and underlying mechanism of ALIX in regulating vacuolar transport of soluble proteins, beyond its conventional ESCRT function in eukaryotic cells. We show that ALIX colocalizes and physically interacts with the retromer core subunits Vps26 and Vps29 in planta. Moreover, double-mutant analysis reveals the genetic interaction of ALIX with Vps26 and Vps29 for regulating trafficking of soluble vacuolar proteins. Interestingly, depletion of ALIX perturbs membrane recruitment of Vps26 and Vps29 and alters the endosomal localization of vacuolar sorting receptors (VSRs). Taken together, ALIX functions as a unique retromer core subcomplex regulator by orchestrating receptor-mediated vacuolar sorting of soluble proteins.

Crystallization of 2D TiO2 Nanosheets via Oriented Attachment of 1D Coordination Polymer.

Demystifying the molecular mechanism of growth is vital for the rational design, synthesis, and optimization of functional nanomaterials. Despite the promising perspectives and extensive efforts, the growth mechanism of atomically thin TiO2(B) nanosheets remains unclear, hence it is difficult to tune their band and surface structures. Herein, we report an oriented attachment-based crystallization mechanism of TiO2(B) nanosheets from a 1D titanium glycolate coordination polymer through hydrolysis and condensation. With time-tracking experiments, this 1D coordination polymer is found to be an intermediate in the synthesis of TiO2(B) nanosheets by using Ti alkoxides and chlorides as precursors, suggesting the universality of the 1D-to-2D growth mechanism. Such a side-to-side attachment pathway bridges the classical and nonclassical interpretations of crystallization, and meanwhile hints at the possibility of other 1D complexes as potential precursors for 2D materials.