In bone remodeling, osteogenesis is closely coupled to angiogenesis. Bone tissue engineering using multifunctional bioactive materials is a promising technique which has the ability to simultaneously stimulate osteogenesis and angiogenesis for repair of bone defects. We developed mesoporous bioactive glass (MBG)-doped poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) (PHBHHx) composite scaffolds as delivery vehicle. Two bioactive molecules, dimethyloxalylglycine (DMOG), a small-molecule angiogenic drug, and recombinant human bone morphogenetic protein-2 (rhBMP-2), an osteoinductive growth factor, were co-incorporated into the scaffold. The synergistic effects of DMOG and rhBMP-2 released in the composite scaffolds on osteogenic and angiogenic differentiation of hBMSCs were investigated using real-time quantitative polymerase chain reaction and western blotting. Moreover, in vivo studies were conducted to observe bone regeneration and vascular formation of critical-sized bone defects in rats using micro-computed tomography, histological analyses, Microfil® perfusion, fluorescence labeling, and immunohistochemical analysis. The results showed that DMOG and rhBMP-2 released in the MBG-PHBHHx scaffolds did exert synergistic effects on the osteogenic and angiogenic differentiation of hBMSCs. Moreover, DMOG and rhBMP-2 produced significant increases in newly-formed bone and neovascularization of calvarial bone defects in rats. It is concluded that the co-delivery strategy of both rhBMP-2 and DMOG can significantly improve the critical-sized bone regeneration.

The responses of broiler chickens to dietary protein reduction were investigated in the presence of glycine and cysteine inclusion at the marginal deficiency of sulfur-containing amino acids. A total of 432 broiler chickens were allotted to six dietary treatments; SP1 is standard protein diet with 100% total sulfur amino acids (TSAA), SP2 is standard protein diet with 85% TSAA, RP is reduced protein diet without glycine and cysteine supplementation, RPC is reduced protein diet with cysteine supplementation at 0.1%, and RPG is reduced protein diet with 1% glycine supplementation, while RPGC is reduced protein diet with 0.1% cysteine and 1% glycine supplementation. In this study, 4.5% protein is reduced in diets-thus, 17.5% CP (crude protein) for starter phase and 15.5% CP for the grower phase. Reduced protein diets contained 85% TSAA. Broiler chickens fed standard protein diet SP2 had superior bodyweight (BW) (p ≤ 0.05) in the starter and grower phase, average daily gain (ADG) (p ≤ 0.05) in the starter and entire feeding period, average daily feed intake (ADFI) (p ≤ 0.05) in the starter phase, and better feed conversion ratio (FCR) (p ≤ 0.05) in the starter, grower and entire feeding period; however, RPGC showed higher ADG (p ≤ 0.05) in the grower phase, and ADFI (p ≤ 0.05) in the grower and entire feeding period. RPC and RPG diet improved BW (p ≤ 0.05), ADG (p ≤ 0.05), ADFI (p ≤ 0.05), and better FCR (p ≤ 0.05) in starter, grower, entire feeding period compared to RP. The RPGC group had higher BW (p ≤ 0.05), ADG (p ≤ 0.05), ADFI (p ≤ 0.05) and better FCR (p ≤ 0.05) compared to the RPC group. Blood biochemical parameters showed that Broiler chickens fed on the SP2 diet had higher levels of total protein (TP) (p ≤ 0.05), albumin (ALB) (p ≤ 0.05), creatinine (CRE) (p ≤ 0.05), and aspartate aminotransferase (AST) (p ≤ 0.05) and, lower level of uric acid (UA) (p ≤ 0.05), blood urea nitrogen (BUN) (p ≤ 0.05), glucose (GLU) (p ≤ 0.05), and alanine aminotransferase (ALT) (p ≤ 0.05) in the starter phase; however, higher level of TP (p ≤ 0.05), GLU (p ≤ 0.05), CRE (p ≤ 0.05), and AST (p ≤ 0.05), and lower level of ALB (p ≤ 0.05), UA (p ≤ 0.05), and ALT (p ≤ 0.05) in the grower phase; RPGC had higher level of TP (p ≤ 0.05), UA (p ≤ 0.05), GLU (p ≤ 0.05), ALT (p ≤ 0.05) and AST (p ≤ 0.05), and lower level of ALB (p ≤ 0.05), BUN (p ≤ 0.05), and CRE (p ≤ 0.05) in the starter phase; however, in grower phase, RPGC had higher level of TP (p ≤ 0.05), and ALB (p ≤ 0.05), and lower level of UA (p ≤ 0.05), CRE (p ≤ 0.05), ALT (p ≤ 0.05), and AST (p ≤ 0.05). Free amino acids profile showed that broiler fed on standard protein diet SP2 had reduced the methionine (p ≤ 0.05) concentration; RPC increased the concentrations of taurine (p ≤ 0.05), phosphoethanolamine (p ≤ 0.05), threonine (p ≤ 0.05), valine (p ≤ 0.05), isoleucine (p ≤ 0.05), phenylalanine (p ≤ 0.05), ornithine (p ≤ 0.05), and lysine (p ≤ 0.05) and reduced the citrulline (p ≤ 0.05) concentration; RPG increased the concentration of glutamate (p ≤ 0.05), glycine (p ≤ 0.05), cysteine (p ≤ 0.05), and arginine (p ≤ 0.05), and decreased the concentration of tyrosine (p ≤ 0.05); and RPGC increased the concentration of serine (p ≤ 0.05) and reduced the concentration of hydroxyproline (p ≤ 0.05). Serum metabolites analysis showed that reduced protein downregulated the 54 metabolites; however, glycine fortification up-regulated the Benzamide, Pro-Ser, N-Carbamylglutamate, D-gluconate, and Gamma-Glutamylcysteine. Carcass quality showed that SP2 decreased the abdominal fat percentage (p ≤ 0.05). Nitrogen digestibility was higher by the diet RP (p ≤ 0.05). This study demonstrated that protein content could be reduced up to 4.5% with 1% glycine and 0.1% cysteine fortification in diet, which has the potential to inhibit the adverse effect of reduced protein and attain the standard growth performance.

Glycosylphosphatidylinositol (GPI) anchoring of proteins is a conserved posttranslational modification in eukaryotes. GPI-anchored proteins are widely distributed in fungal plant pathogens, but the specific roles of the GPI-anchored proteins in the pathogenicity of Sclerotinia sclerotiorum, a devastating necrotrophic plant pathogen with a worldwide distribution, remain largely unknown. This research addresses SsGSR1, which encodes an S. sclerotiorum glycine- and serine-rich protein named SsGsr1 with an N-terminal secretory signal and a C-terminal GPI-anchor signal. SsGsr1 is located at the cell wall of hyphae, and deletion of SsGSR1 leads to abnormal cell wall architecture and impaired cell wall integrity of hyphae. The transcription levels of SsGSR1 were maximal in the initial stage of infection, and SsGSR1-deletion strains showed impaired virulence in multiple hosts, indicating that SsGSR1 is critical for the pathogenicity. Interestingly, SsGsr1 targeted the apoplast of host plants to induce cell death that relies on the glycine-rich 11-amino-acid repeats arranged in tandem. The homologs of SsGsr1 in Sclerotinia, Botrytis, and Monilinia species contain fewer repeat units and have lost their cell death activity. Moreover, allelic variants of SsGSR1 exist in field isolates of S. sclerotiorum from rapeseed, and one of the variants lacking one repeat unit results in a protein that exhibits loss of function relative to the cell death-inducing activity and the virulence of S. sclerotiorum. Taken together, our results demonstrate that a variation in tandem repeats provides the functional diversity of GPI-anchored cell wall protein that, in S. sclerotiorum and other necrotrophic pathogens, allows successful colonization of the host plants. IMPORTANCE Sclerotinia sclerotiorum is an economically important necrotrophic plant pathogen and mainly applies cell wall-degrading enzymes and oxalic acid to kill plant cells before colonization. In this research, we characterized a glycosylphosphatidylinositol (GPI)-anchored cell wall protein named SsGsr1, which is critical for the cell wall architecture and the pathogenicity of S. sclerotiorum. Additionally, SsGsr1 induces rapid cell death of host plants that is dependent on glycine-rich tandem repeats. Interestingly, the number of repeat units varies among homologs and alleles of SsGsr1, and such a variation creates alterations in the cell death-inducing activity and the role in pathogenicity. This work advances our understanding of the variation of tandem repeats in accelerating the evolution of a GPI-anchored cell wall protein associated with the pathogenicity of necrotrophic fungal pathogens and prepares the way toward a fuller understanding of the interaction between S. sclerotiorum and host plants.

Spondyloepiphyseal dysplasia congenita (SEDC) is an extremely rare autosomal dominant chondrodysplasia that is usually caused by substitution of glycine with another amino acid in the triple helical region of COL2A1. Herein, we describe a case of SEDC in a Chinese family with a novel de novo mutation in the COL2A1 gene, c.1150G>A (p.Gly384Ser), which may impair protein stability and lead to dysfunction of type II collagen.

The mammalian SWItch/Sucrose Non-Fermentable (SWI/SNF) helicase SMARCA4 is frequently mutated in cancer and inactivation results in a cellular dependence on its paralog, SMARCA2, thus making SMARCA2 an attractive synthetic lethal target. However, published data indicates that achieving a high degree of selective SMARCA2 inhibition is likely essential to afford an acceptable therapeutic index, and realizing this objective is challenging due to the homology with the SMARCA4 paralog. Herein we report the discovery of a potent and selective SMARCA2 proteolysis-targeting chimera molecule (PROTAC), A947. Selective SMARCA2 degradation is achieved in the absence of selective SMARCA2/4 PROTAC binding and translates to potent in vitro growth inhibition and in vivo efficacy in SMARCA4 mutant models, compared to wild type models. Global ubiquitin mapping and proteome profiling reveal no unexpected off-target degradation related to A947 treatment. Our study thus highlights the ability to transform a non-selective SMARCA2/4-binding ligand into a selective and efficacious in vivo SMARCA2-targeting PROTAC, and thereby provides a potential new therapeutic opportunity for patients whose tumors contain SMARCA4 mutations.

This paper reports studies of two patients proven by a variety of studies to have mitochondrial depletion syndromes due to mutations in either their MPV17 or DGUOK genes. Each was initially investigated metabolically because of plasma methionine concentrations as high as 15-21-fold above the upper limit of the reference range, then found also to have plasma levels of S-adenosylmethionine (AdoMet) 4.4-8.6-fold above the upper limit of the reference range. Assays of S-adenosylhomocysteine, total homocysteine, cystathionine, sarcosine, and other relevant metabolites and studies of their gene encoding glycine N-methyltransferase produced evidence suggesting they had none of the known causes of elevated methionine with or without elevated AdoMet. Patient 1 grew slowly and intermittently, but was cognitively normal. At age 7 years he was found to have hepatocellular carcinoma, underwent a liver transplant and died of progressive liver and renal failure at age almost 9 years. Patient 2 had a clinical course typical of DGUOK deficiency and died at age 8 ½ months. Although each patient had liver abnormalities, evidence is presented that such abnormalities are very unlikely to explain their elevations of AdoMet or the extent of their hypermethioninemias. A working hypothesis is presented suggesting that with mitochondrial depletion the normal usage of AdoMet by mitochondria is impaired, AdoMet accumulates in the cytoplasm of affected cells poor in glycine N-methyltransferase activity, the accumulated AdoMet causes methionine to accumulate by inhibiting activity of methionine adenosyltransferase II, and that both AdoMet and methionine consequently leak abnormally into the plasma.

Serine metabolism promotes tumor oncogenesis and regulates immune cell functions, but whether it also contributes to antiviral innate immunity is unknown. Here, we demonstrate that virus-infected macrophages display decreased expression of serine synthesis pathway (SSP) enzymes. Suppressing the SSP key enzyme phosphoglycerate dehydrogenase (PHGDH) by genetic approaches or by treatment with the pharmaceutical inhibitor CBR-5884 and by exogenous serine restriction enhanced IFN-β-mediated antiviral innate immunity in vitro and in vivo. Mechanistic experiments showed that virus infection or serine metabolism deficiency increased the expression of the V-ATPase subunit ATP6V0d2 by inhibiting S-adenosyl methionine-dependent H3K27me3 occupancy at the promoter. ATP6V0d2 promoted YAP lysosomal degradation to relieve YAP-mediated blockade of the TBK1-IRF3 axis and, thus, enhance IFN-β production. These findings implicate critical functions of PHGDH and the key immunometabolite serine in blunting antiviral innate immunity and also suggest manipulation of serine metabolism as a therapeutic strategy against virus infection.

Peptides containing the asparagines-glycine-arginine (NGR) motif have been identified as specific ligands binding to CD13/aminopeptidase N (APN) receptor, a tumor neovascular biomarker. In this study, we synthesized a novel NGR-containing peptide (NOTA-G3-NGR), and labeled NOTA-G3-NGR with (68)Ga (t1/2 = 67.7 min). The resulting (68)Ga-NOTA-G3-NGR peptide was subject to in vitro and in vivo characterization. The microPET imaging results revealed that the (68)Ga-NOTA-G3-NGR peptide exhibits rapid and specific tumor uptake, and high tumor-to-background contrast in a subcutaneous HT-1080 fibrosarcoma mouse model. We concluded that the (68)Ga-NOTA-G3-NGR peptide has potential in the diagnosis of CD13-targeted tumor angiogenesis.

Mepiquat (Mep) is a contaminant produced by Maillard reaction with reducing sugar, free lysine and an alkylating agent under typical roasting conditions, particularly in the range of 200-240 °C. It has been reported that exposure to Mep is harmful to rats. However, its metabolic mechanism is still not clear. In this study, untargeted metabolomics was used to reveal the effect of Mep on the metabolic profile of adipose tissue in Sprague-Dawley rats. Twenty-six differential metabolites were screened out. Eight major perturbed metabolic pathways were found, which were linoleic acid metabolism, Phenylalanine, tyrosine, and tryptophan biosynthesis, phenylalanine metabolism, arachidonic acid metabolism, Glycine, serine, and threonine metabolism, glycerolipid metabolism, Alanine, aspartate, and glutamate metabolism, and glyoxylate and dicarboxylic acid metabolism. This study lays a solid foundation for clarifying the toxic mechanism of Mep.

Arginine regulates growth performance, nutrient metabolism and health effects, but the underlying mechanism remains unknown. This study aims to investigate the effect of dietary arginine supplementation on rat growth performance and urinary metabolome through ¹H-NMR spectroscopy. Twenty rats were randomly assigned to two groups supplemented with 0% or 1.0% l-arginine for 4 weeks. Urine samples were analyzed through NMR-based metabolomics. Arginine supplementation significantly increased the urine levels of 4-aminohippurate, acetate, creatine, creatinine, ethanolamine, formate, hippurate, homogentisate, indoxyl sulfate, and phenylacetyglycine. Conversely, arginine decreased the urine levels of acetamide, β-glucose, cirtulline, ethanol, glycine, isobutyrate, lactate, malonate, methymalonate, N-acetylglutamate, N-methylnicotinamide, and propionate. Results suggested that arginine can alter common systemic metabolic processes, including energy metabolism, amino acid metabolism, and gut microbiota metabolism. Moreover, the results also imply a possible physiological role of the metabolism in mediating the arginine supplementation-supported growth of rats.

Metabolic reprogramming is a vital factor in the development of many types of cancer, including colon cancer. Serine metabolic reprogramming is a major feature of tumor metabolism. Yes-associated protein (YAP) participates in organ size control and tumorigenesis. However, the relationship between YAP and serine metabolism in colon cancer is unclear. In this study, RNA sequencing and metabolomics analyses indicated significant enrichment of the glycine, serine, and threonine metabolism pathways in serine starvation-resistant cells. Short-term serine deficiency inhibited YAP activation, whereas a prolonged response dephosphorylated YAP and promoted its activity. Mechanistically, USP7 increases YAP stability under increased serine conditions by regulating deubiquitination. Verteporfin (VP) effectively inhibited the proliferation of colon cancer cells and organoids and could even modulate serine metabolism by inhibiting USP7 expression. Clinically, YAP was significantly activated in colon tumor tissues and positively correlated with the expression of phosphoglycerate dehydrogenase (PHGDH) and USP7. Generally, our study uncovered the mechanism by which serine metabolism regulates YAP via USP7 and identified the crucial role of YAP in the regulation of cell proliferation and tumor growth; thus, VP may be a new treatment for colon cancer.

Nonylphenol (NP) was quantified using liquid chromatography tandem mass spectrometry (LC-MS/MS) in the urine and plasma of rats treated with 0, 50, and 250 mg/kg/day of NP for four consecutive days. A urinary metabolomic strategy was originally implemented by high performance liquid chromatography time of flight mass spectrometry (HPLC-QTOF-MS) to explore the toxicological effects of NP and determine the overall alterations in the metabolite profiles so as to find potential biomarkers. It is essential to point out that from the observation, the metabolic data were clearly clustered and separated for the three groups. To further identify differentiated metabolites, multivariate analysis, including principal component analysis (PCA), orthogonal partial least-squares discriminant analysis (OPLS-DA), high-resolution MS/MS analysis, as well as searches of Metlin and Massbank databases, were conducted on a series of metabolites between the control and dose groups. Finally, five metabolites, including glycine, glycerophosphocholine, 5-hydroxytryptamine, malonaldehyde (showing an upward trend), and tryptophan (showing a downward trend), were identified as the potential urinary biomarkers of NP-induced toxicity. In order to validate the reliability of these potential biomarkers, an independent validation was performed by using the multiple reaction monitoring (MRM)-based targeted approach. The oxidative stress reflected by urinary 8-oxo-deoxyguanosine (8-oxodG) levels was elevated in individuals highly exposed to NP, supporting the hypothesis that mitochondrial dysfunction was a result of xenoestrogen accumulation. This study reveals a promising approach to find biomarkers to assist researchers in monitoring NP.

Previous studies have demonstrated that glutamate plays an important role in the development of pathological pain. This study investigates the expression changes of glutamate and the roles of different types of glutamate receptors in the red nucleus (RN) in the development of neuropathic allodynia induced by spared nerve injury (SNI). Immunohistochemistry indicated that glutamate was constitutively expressed in the RN of normal rats. After SNI, the expression levels of glutamate were significantly increased in the RN at 1 week and reached the highest level at 2 weeks postinjury compared with sham-operated and normal rats. The RN glutamate was colocalized with neurons, oligodendrocytes, and astrocytes but not microglia under physiological and neuropathic pain conditions. To elucidate further the roles of the RN glutamate and different types of glutamate receptors in the development of neuropathic allodynia, antagonists to N-methyl-D-aspartate (NMDA), non-NMDA, or metabotropic glutamate receptors (mGluRs) were microinjected into the RN contralateral to the nerve-injury side of rats with SNI, and the paw withdrawal threshold (PWT) was dynamically assessed with von Frey filaments. Microinjection of the NMDA receptor antagonist MK-801 into the RN did not show any effect on SNI-induced mechanical allodynia. However, microinjection of the non-NMDA receptor antagonist 6,7-dinitroquinoxaline-2,3(1H,4H)-dione or the mGluR antagonist (±)-α-methyl-(4-carboxyphenyl) glycine into the RN significantly increased the PWT and alleviated SNI-induced mechanical allodynia. These findings suggest that RN glutamate is involved in regulating neuropathic pain and facilitates the development of SNI-induced neuropathic allodynia. The algesic effect of glutamate is transmitted by the non-NMDA glutamate receptor and mGluRs.

Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer (TC). Considering the important association between cellular immunity and PTC progression, it is worth exploring the biological significance of immune-related signaling in PTC.

NMDA receptors (NMDARs) populate the complex between inner hair cell (IHC) and spiral ganglion neurons (SGNs) in the developing and mature cochlea. However, in the mature cochlea, activation of NMDARs is thought to mainly occur under pathological conditions such as excitotoxicity. Ototoxic drugs such as aspirin enable cochlear arachidonic-acid-sensitive NMDAR responses, and induced chronic tinnitus was blocked by local application of NMDAR antagonists into the cochlear fluids. We largely ignore if other modulators are also engaged. In the brain, D-serine is the primary physiological co-agonist of synaptic NMDARs. Whether D-serine plays a role in the cochlea had remained unexplored. We now reveal the presence of D-serine and its metabolic enzymes prior to, and at hearing onset, in the sensory and non-neuronal cells of the cochlea of several vertebrate species. In vivo intracochlear perfusion of D-serine in guinea pigs reduces sound-evoked activity of auditory nerve fibers without affecting the receptor potentials, suggesting that D-serine acts specifically on the postsynaptic auditory neurons without altering the functional state of IHC or of the stria vascularis. Indeed, we demonstrate in vitro that agonist-induced activation of NMDARs produces robust calcium responses in rat SGN somata only in the presence of D-serine, but not of glycine. Surprisingly, genetic deletion in mice of serine racemase (SR), the enzyme that catalyzes D-serine, does not affect hearing function, but offers protection against noise-induced permanent hearing loss as measured 3 months after exposure. However, the mechanisms of activation of NMDA receptors in newborn rats may be different from those in adult guinea pigs. Taken together, these results demonstrate for the first time that the neuro-messenger D-serine has a pivotal role in the cochlea by promoting the activation of silent cochlear NMDAR in pathological situations. Thus, D-serine and its signaling pathway may represent a new druggable target for treating sensorineural hearing disorders (i.e., hearing loss, tinnitus).

Cotton is the most important crop for the production of natural fibres used in the textile industry. High salinity, drought, cold and high temperature represent serious abiotic stresses, which seriously threaten cotton production. Phospholipase AS has an irreplaceable role in lipid signal transmission, growth and development and stress events. Phospholipase A can be divided into three families: PLA1, PLA2 and pPLA. Among them, the PLA1 family is rarely studied in plants. In order to study the potential functions of the PLA1 family in cotton, the bioinformatics analysis of the PLA1 family was correlated with cotton adversity, and tissue-specific analysis was performed. Explore the structure-function relationship of PLA1 members. It is found that the expression of GbPLA1-32 gene is affected by a variety of environmental stimuli, indicating that it plays a very important role in stress and hormone response, and closely associates the cotton adversity with this family. Through further functional verification, we found that virus-induced GbPLA1-32 gene silencing (VIGS) caused Gossypium barbadense to be sensitive to salt stress. This research provides an important basis for further research on the molecular mechanism of cotton resistance to abiotic stress.

Osimertinib is the first-line therapeutic option for the T790M-mutant non-small-cell lung cancer and the acquired resistance obstructs its application. It is an urgent challenge to identify the potential mechanisms of osimertinib resistance for uncovering some novel therapeutic approaches.

Choline kinase (CK) gene plays an important role in plants growth, development and resistance to stress. It mainly regulates the biosynthesis of phosphatidylcholine. This study aims to explore the structure-function relationship, and to provide a framework for functional validation and biochemical characterization of various CK genes. Our analysis showed that 87 CK genes were identified in cotton and 7 diploid plants, of which 43 genes encode CK proteins in 4 cotton species, and 13 genes were identified in Gossypium hirsutum. Most of GhCK genes are affected by the abiotic stress conditions, indicating the importance of CK proteins for plant development and response to abiotic stress. RT-qPCR analysis showed the tissue specificity of GhCK genes in response to Cd2+ and other abiotic stresses. Under Cd2+ stress, the expression level of GhCK gene family members has undergone different changes. The expression level of GhCK5 was enhanced, indicating that Cd2+ stress caused the increase of phosphatidylcholine content, which in turn reacted on the plant cell membrane, finally reached the absorption of Cd2+ into plant cells to repair Cd2+ the purpose of contaminated soil. This study will further broaden our understanding of the association between evolution and function of the GhCK gene family.

Long non-coding RNAs (lncRNAs), microRNAs (miRNAs or miRs), and genes are emerging players in cancer progression. In the present study, we explored the roles and interactions of oncogenic lncRNA small nucleolar RNA host gene 1 (SNHG1), miR-376, forkhead box protein K1 (FOXK1), and Snail in hepatocellular carcinoma (HCC). Expression of SNHG1, miR-376, and FOXK1 in HCC was characterized in clinical HCC tissues of 75 patients with HCC. The interactions between SNHG1 and miR-376 and between miR-376 and FOXK1 were predicted and confirmed by dual-luciferase reporter gene and RNA immunoprecipitation assays. Overexpression and knockdown experiments were performed in HCC cells to examine the effects of the SNHG1/miR-376/FOXK1/Snail axis on viability, apoptosis, invasiveness, and migrating abilities. Their effects on tumor growth and metastasis were validated in nude mouse models. SNHG1 and FOXK1 were upregulated, and miR-376a was downregulated in HCC. SNHG1 knockdown contributed to suppression of HCC cell viability, invasion, and migration properties and promotion of apoptosis. SNHG1 could competitively bind to miR-376a to upregulate its target gene FOXK1, which upregulated Snail. SNHG1 knockdown delayed cancer progression both in vitro and in vivo by upregulating miR-376a and downregulating FOXK1 and Snail. SNHG1 knockdown exerts anti-tumor activity in HCC, suggesting a therapeutic target.

Misfolding and aggregation of disease-specific proteins, resulting in the formation of filamentous cellular inclusions, is a hallmark of neurodegenerative disease with characteristic filament structures, or conformers, defining each proteinopathy. Here we show that a previously unsolved amyloid fibril composed of a 135 amino acid C-terminal fragment of TMEM106B is a common finding in distinct human neurodegenerative diseases, including cases characterized by abnormal aggregation of TDP-43, tau, or α-synuclein protein. A combination of cryoelectron microscopy and mass spectrometry was used to solve the structures of TMEM106B fibrils at a resolution of 2.7 Å from postmortem human brain tissue afflicted with frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP, n = 8), progressive supranuclear palsy (PSP, n = 2), or dementia with Lewy bodies (DLB, n = 1). The commonality of abundant amyloid fibrils composed of TMEM106B, a lysosomal/endosomal protein, to a broad range of debilitating human disorders indicates a shared fibrillization pathway that may initiate or accelerate neurodegeneration.