Gene-specific somatic epigenetic mosaicism of FDFT1 underlies a non-hereditary localized form of porokeratosis.

Porokeratosis is a clonal keratinization disorder characterized by solitary, linearly arranged, or generally distributed multiple skin lesions. Previous studies showed that genetic alterations in MVK, PMVK, MVD, or FDPS-genes in the mevalonate pathway-cause hereditary porokeratosis, with skin lesions harboring germline and lesion-specific somatic variants on opposite alleles. Here, we identified non-hereditary porokeratosis associated with epigenetic silencing of FDFT1, another gene in the mevalonate pathway. Skin lesions of the generalized form had germline and lesion-specific somatic variants on opposite alleles in FDFT1, representing FDFT1-associated hereditary porokeratosis identified in this study. Conversely, lesions of the solitary or linearly arranged localized form had somatic bi-allelic promoter hypermethylation or mono-allelic promoter hypermethylation with somatic genetic alterations on opposite alleles in FDFT1, indicating non-hereditary porokeratosis. FDFT1 localization was uniformly diminished within the lesions, and lesion-derived keratinocytes showed cholesterol dependence for cell growth and altered expression of genes related to cell-cycle and epidermal development, confirming that lesions form by clonal expansion of FDFT1-deficient keratinocytes. In some individuals with the localized form, gene-specific promoter hypermethylation of FDFT1 was detected in morphologically normal epidermis adjacent to methylation-related lesions but not distal to these lesions, suggesting that asymptomatic somatic epigenetic mosaicism of FDFT1 predisposes certain skin areas to the disease. Finally, consistent with its genetic etiology, topical statin treatment ameliorated lesions in FDFT1-deficient porokeratosis. In conclusion, we identified bi-allelic genetic and/or epigenetic alterations of FDFT1 as a cause of porokeratosis and shed light on the pathogenesis of skin mosaicism involving clonal expansion of epigenetically altered cells.

Abdominal obesity and alcohol use modify the impact of genetic risk for incident advanced liver disease in the general population.

BACKGROUND & AIMS: Genetic variants, abdominal obesity and alcohol use are risk factors for incident liver disease (ILD). We aimed to study whether variants either alone or when aggregated into genetic risk scores (GRSs) associate with ILD, and whether waist-hip ratio (WHR) or alcohol use interacts with this risk. METHODS: Our study included 33 770 persons (mean age 50 years, 47% men) who participated in health-examination surveys (FINRISK 1992-2012 or Health 2000) with data on alcohol use, WHR and 63 genotypes associated with liver disease. Data were linked with national health registers for liver-related outcomes (hospitalizations, malignancies and death). Exclusions were baseline clinical liver disease. Mean follow-up time was 12.2 years. Cox regression analyses between variants and ILD were adjusted for age, sex and BMI. RESULTS: Variants in PNPLA3, IFNL4, TM6SF2, FDFT1, PPP1R3B, SERPINA1 and HSD17B13 were associated with ILD. GRSs calculated from these variants were not associated with WHR or alcohol use, but were exponentially associated with ILD (up to 25-fold higher risk in high versus low score). The risk of ILD in individuals with high GRS and high WHR or alcohol use compared with those with none of these risk factors was increased by up to 90-fold. GRSs provided new prognostic information particularly in individuals with high WHR. CONCLUSIONS: The effect of multiple genetic variants on the risk of ILD is potentiated by abdominal obesity and alcohol use. Simple GRSs may help to identify individuals with adverse lifestyle who are at a particularly high risk of ILD.

3ß-Hydroxy-12-oleanen-27-oic Acid Exerts an Antiproliferative Effect on Human Colon Carcinoma HCT116 Cells via Targeting FDFT1.

3ß-hydroxy-12-oleanen-27-oic acid (ATA), a cytotoxic oleanane triterpenoid with C14-COOH isolated from the rhizome of Astilbe chinensis, has been previously proven to possess antitumor activity and may be a promising antitumor agent. However, its molecular mechanisms of antitumor action were still unclear. This study explored the underlying mechanisms of cytotoxicity and potential target of ATA against human colorectal cancer HCT116 cells via integrative analysis of transcriptomics and network pharmacology in combination with in vitro and in vivo experimental validations. ATA significantly inhibited the proliferation of HCT116 cells in a concentration- and time-dependent manner and induced the cell cycle arrest at the G0/G1 phase, apoptosis, autophagy, and ferroptosis. Transcriptomic analysis manifested that ATA regulated mRNA expression of the genes related to cell proliferation, cell cycle, and cell death in HCT116 cells. The integrated analysis of transcriptomics, network pharmacology, and molecular docking revealed that ATA exerted cytotoxic activity via interactions with FDFT1, PPARA, and PPARG. Furthermore, FDFT1 was verified to be an upstream key target mediating the antiproliferative effect of ATA against HCT116 cells. Of note, ATA remarkably suppressed the growth of HCT116 xenografts in nude mice and displayed an apparent attenuation of FDFT1 in tumor tissues accompanied by the alteration of the biomarkers of autophagy, cell cycle, apoptosis, and ferroptosis. These results demonstrate that ATA exerted in vitro and in vivo antiproliferative effects against HCT116 cells through inducing cell apoptosis, autophagy, and ferroptosis via targeting FDFT1.

Raman spectroscopy biochemical characterisation of bladder cancer cisplatin resistance regulated by FDFT1: a review.

Bladder cancer is the fourth most common malignancy in males. It can present across the whole continuum of severity, from mild through well-differentiated disease to extremely malignant tumours with poor survival rates. As with other vital organ malignancies, proper clinical management involves accurate diagnosis and staging. Chemotherapy consisting of a cisplatin-based regimen is the mainstay in the management of muscle-invasive bladder cancers. Control via cisplatin-based chemotherapy is threatened by the development of chemoresistance. Intracellular cholesterol biosynthesis in bladder cancer cells is considered a contributory factor in determining the chemotherapy response. Farnesyl-diphosphate farnesyltransferase 1 (FDFT1), one of the main regulatory components in cholesterol biosynthesis, may play a role in determining sensitivity towards chemotherapy compounds in bladder cancer. FDFT1-associated molecular identification might serve as an alternative or appendage strategy for early prediction of potentially chemoresistant muscle-invasive bladder cancer tissues. This can be accomplished using Raman spectroscopy. Developments in the instrumentation have led to it becoming one of the most convenient forms of analysis, and there is a highly realistic chance that it will become an effective tool in the pathology lab. Chemosensitive bladder cancer tissues tend to have a higher lipid content, more protein genes and more cholesterol metabolites. These are believed to be associated with resistance towards bladder cancer chemotherapy. Herein, Raman peak assignments have been tabulated as an aid to indicating metabolic changes in bladder cancer tissues that are potentially correlated with FDFT1 expression.

Squalene Synthase Deficiency: Clinical, Biochemical, and Molecular Characterization of a Defect in Cholesterol Biosynthesis.

Mendelian disorders of cholesterol biosynthesis typically result in multi-system clinical phenotypes, underlining the importance of cholesterol in embryogenesis and development. FDFT1 encodes for an evolutionarily conserved enzyme, squalene synthase (SS, farnesyl-pyrophosphate farnesyl-transferase 1), which catalyzes the first committed step in cholesterol biosynthesis. We report three individuals with profound developmental delay, brain abnormalities, 2-3 syndactyly of the toes, and facial dysmorphisms, resembling Smith-Lemli-Opitz syndrome, the most common cholesterol biogenesis defect. The metabolite profile in plasma and urine suggested that their defect was at the level of squalene synthase. Whole-exome sequencing was used to identify recessive disease-causing variants in FDFT1. Functional characterization of one variant demonstrated a partial splicing defect and altered promoter and/or enhancer activity, reflecting essential mechanisms for regulating cholesterol biosynthesis/uptake in steady state.

Glucose starvation suppresses gastric cancer through targeting miR-216a-5p/Farnesyl-Diphosphate Farnesyltransferase 1 axis.

BACKGROUND: Fasting mimic diet is an effect approach for gastric cancer (GC) treatment. Exploring mechanisms of glucose deprivation-mediated GC suppression is required to develop novel therapeutic regimens. Farnesyltransferase 1 (FDFT1), as a novel target in basic research, has been reported to regulate malignant progression in some types of cancer. However, biological functions of FDFT1 in GC are still unclear. This study focused on biological functions of FDFT1 in GC and the association between glucose starvation (GS) and FDFT1. METHODS: The data derived from the Kaplan-Meier Plotter database were collected to identify the relationship between survival time and FDFT1 expression levels of GC patients. Bioinformatic analysis was performed to explore the biological functions of FDFT1. The expression levels of targeted genes and microRNAs (miRNAs) were detected with immunohistochemistry, quantitative real-time PCR and western blot. Malignant behaviors were measured using cell counting, cell counting kit-8, 5-ethynyl-2-deoxyuridine, wound healing, invasion transwell assays in vitro and constructions of subcutaneous and lung-metastatic tumors in vivo. The glycolysis of GC cells was determined by a series of metabolites, including lactate acid, pyruvic acid, ATP production, rates of glucose uptake, extracellular acidification rate and oxygen consumption rate. RESULTS: FDFT1 was downregulated in GC and negatively correlated with pathological T stage, pathological TNM stage and cancer differentiation. High expression of FDFT1 also indicated better prognosis of GC patients. FDFT1 upregulation attenuated proliferation, migration and invasion of GC. miR-216a-5p was identified as a critical suppressor of FDFT1 expression and miR-216a-5p/FDFT1 axis regulated malignant behaviors and glycolysis of GC cells. GS suppressed malignant behaviors of GC by targeting miR-216a-5p/FDFT1 axis both in vitro and in vivo. CONCLUSION: This study illustrated novel mechanisms by which GS effectively suppresses GC. FDFT1 may become a potential prognostic indicator and novel target of GC therapy.

20(S)-Rg3 upregulates FDFT1 via reducing miR-4425 to inhibit ovarian cancer progression.

We previously found that ginsenoside 20(S)-Rg3 diminishes the proliferative and invasive capacities of ovarian cancer cells by decreasing miR-4425 level. Yet the mechanism of action of miR-4425 in ovarian cancer remains unclear. Here we report that miR-4425 is upregulated in ovarian cancer tissues relative to normal ovarian tissues, and transfection of miR-4425 inhibitor impairs the proliferation, migration and invasion of SKOV3 and 3AO ovarian cancer cells. Further, miR-4425 antagomiR reduces cell proliferation in a subcutaneous SKOV3 xenograft model using BALB/c nude mice. We identifies farnesyl-diphosphate farnesyltransferase 1 (FDFT1) as a direct target of miR-4425 by Western blotting and a luciferase reporter assay. Forced expression of FDFT1 via transfection of an FDFT1-expressing plasmid into ovarian cancer cells not only retards cell proliferation, motility and invasiveness, but also negates the tumorigenic properties of a miR-4425 mimic. By contrast, silencing of FDFT1 by siRNAs abrogates suppression of the proliferation, migration and invasion of ovarian cancer cells treated with a miR-4425 inhibitor. Finally, transfection of either a miR-4425 mimic or FDFT1 siRNAs into 20(S)-Rg3-treated ovarian cancer cells counteracts the tumor-inhibitory activity of the ginsenoside. In conclusion, 20(S)-Rg3 exerts anti-ovarian cancer activity by downregulating oncogenic miR-4425 that inhibits the expression of the tumor suppressor gene FDFT1. These results expand our current understanding of the molecular pathways leading to ovarian cancer progression, and unveil the mechanism of action of 20(S)-Rg3 in ovarian cancer inhibition.

Role of FDFT1 polymorphism for fibrosis progression in patients with chronic hepatitis C.

BACKGROUND: In chronic hepatitis C (CHC), steatosis is associated with fibrosis and impaired response to antiviral therapy. Recently, a polymorphism of single nucleotide polymorphism SNP rs2645424 of farnesyl diphosphate farnesyl transferase 1 (FDFT1) was identified in NAFLD/NASH as a possible causal link to steatosis and fibrosis progression. SNP rs738409 in the adiponutrin gene (PNPLA3) is a well described factor for steatosis. This study evaluated the relation of these SNPs on steatosis, fibrosis and treatment response in CHC. METHODS: The SNPs rs738409478 and rs2645424 were determined by real-time PCR in 478 patients with CHC (m/f: 314/164; mean age: 44.9 ± 10.7; GT1: 387, GT4: 91) who completed treatment with peg-IFN-α-2a/ribavirin. All had a pretreatment liver biopsy. Steatosis and fibrosis were graded by board-certified pathologists according to Brunt and METAVIR respectively. RESULTS: The distribution of FDFT1 rs2645424 was GG: 186 (38.9%), AG: 222 (46.4%) and AA: 70 (14.6%) and of the rs738409 PNPLA3 allele: CC: 269 (56.3%), CG: 177 (37.0%) and GG: 32 (6.7%). Overall, FDTF1 polymorphism was not linked to the extent of steatosis or fibrosis. However, in patients without steatosis the AA genotype was associated with advanced fibrosis [AA: 8/20 (40.0%), AG: 6/70 (8.5%), GG: 9/57 (16.1%), P = 0.003]. In contrast, the minor PNPLA3 allele was associated with both steatosis and advanced fibrosis (P < 0.001). Both SNPs did not influence treatment response. CONCLUSION: The minor allele in FDFT1 was associated with advanced fibrosis in the non-steatotic but not in the steatotic subgroup. This may reflect different metabolic pathways in fibrosis progression for steatotic and non-steatotic patients with CHC.

Effects of ADSC-Derived Exosome LRRC75A-AS1 on Anti-inflammatory Function After SCI.

Spinal cord injury (SCI) is a highly debilitating disorder of the central nervous system that can severely impact an affected patient's quality of life. This study aimed to examine how adipose-derived mesenchymal stem cell exosomes (ADSC-exos) can be used to treat spinal cord injury. We analysed differentially expressed mRNAs in SCI using bioinformatics data, gene expression profiles in inflammatory cell models, RT-qPCR and WB. Apoptosis was detected with flow cytometry. Starbase provides the control mechanism for FDFT1. Target interactions were detected with dual-luciferase reporter and RIP assays. Exosomes were isolated from adipose tissue-derived mesenchymal stem cells and subsequently characterized with western blot analysis, transmission electron microscopy and nanoparticle tracking analysis. By analysing the GSE102964 database, we found that FDFT1 was significantly downregulated as SCI progressed. Overexpression of FDFT1 can significantly reverse the inflammatory response and apoptosis of BV2 cells induced by hemin. Mechanically, ADSC-exos can affect the expression of FDFT1 through the ceRNA mechanism mediated by LRRC75A-AS1 and in an RBP-dependent manner mediated by IGF2BP2. The overexpression of LRRC75A-AS1 significantly enhances BV2 apoptosis and can be reversed by FDFT1 knockdown. ADSC-exos LRRC75A-AS1 inhibits inflammation and reduces SCI by increasing the expression and stability of FDFT1 mRNA in a ceRNA and RBP-dependent manner.

FDFT1 repression by piR-39980 prevents oncogenesis by regulating proliferation and apoptosis through hypoxia in tongue squamous cell carcinoma.

AIM: Tongue squamous cell carcinoma (TSCC) is one of the most aggressive tumors whose underlying molecular mechanism remains elusive. Previous studies have identified piR-39980, a non-coding RNA, as a tumour suppressor or oncogene in different malignancies and the cholesterogenic protein, Farnesyl-Diphosphate Farnesyltransferase 1 (FDFT1) playing critical roles in cancer. The present study investigates the role of piR-39980, and its target FDFT1, in regulating the malignancy of TSCC. MAIN METHODS: We performed qRT-PCR to determine the expression of FDFT1, piR-39980 and validated FDFT1 as a target of piR-39980 by dual luciferase assay. Then, to investigate the role of FDFT1 overexpression and piR-39980's inhibitory effect on FDFT1 in TSCC oncogenesis, we carried out MTT, migration, ROS estimation, and flow cytometric cell cycle assays. In addition to the above experiments, we also carried out flow cytometric apoptosis assay, chromatin condensation, γ-H2AX accumulation, and phalloidin staining assays upon overexpression and silencing of piRNA to unveil its mechanism of actions in TSCC malignancy. KEY FINDINGS: FDFT1 promotes the oncogenesis of TSCC cells. Further, transient overexpression of piR-39980 significantly inhibited proliferation, migration, ROS generation, and colony formation and increased DNA damage and chromatin condensation causing cell death by repressing FDFT1. We conjectured that FDFT1 repression induces hypoxia, which slows DNA repair and accumulates damaged DNA, causing death of TSCC cells. SIGNIFICANCE: Our study showed FDFT1 acts as an oncogene in TSCC, unlike other cancers, whose repression by a piRNA could prevent oncogenesis by regulating proliferation and apoptosis through hypoxia. This study reveals novel gene-regulatory mechanistic insights into TSCC oncogenesis.

Genome-wide profiling of dysregulated piRNAs and their target genes implicated in oncogenicity of tongue squamous cell carcinoma.

PIWI-interacting RNAs (piRNAs) are single-stranded, 23-36 nucleotide long RNAs that regulate gene expression in the germline but are also detected in some cancers. However, there are no reports yet on piRNA expression in tongue squamous cell carcinoma (TSCC), the most common oral cancer (80-90% percent of all oral cancers). We performed small RNA and whole transcriptome sequencing in H357 tongue cancer and HOK cells (GEO database accession numbers: GSE196674 and GSE196688). We also examined nine published sets of gene expression array data of TSCC tissues from the GEO database to decode piRNAs and their putative targets that may be involved in tumorigenesis. We identified a pool of 16,058 and 25,677 piRNAs in H357 and HOK, respectively, among which 406 are differentially expressed. We also found that 2094 protein-coding genes are differentially expressed in either TSCC tissues or cell lines. We performed target predictions for these piRNAs, pathway and disease function (DF) analyses, as well as qRT-PCR validation of piRNA-target pairs. These experiments revealed one up-regulated (FDFT1) and four down-regulated (OGA, BDH1, TAT, HYAL4) target genes that are enriched in 11 canonical pathways (CPs), with postulated roles in the initiation and progression of TSCC. Downregulation of piR-33422 is predicted to upregulate the FDFT1 gene, which encodes a mevalonate/cholesterol-pathway related farnesyl-diphosphate farnesyltransferase. The FDFT1 appears to be involved in the largest number of oncogenesis-related processes and is interacting with statins, which is a classical cancer drug. This study provides the first evidence of the piRNome of TSCC, which could be investigated further to decode piRNA-mediated gene regulations in malignancy and potential drug targets, such as FDFT1.

FDFT1/FGFR2 rearrangement: A newly identified anlotinib-sensitive FGFR2 variant in cholangiocarcinoma.

According to previous reports,10-16% of patients with clinically advanced cholangiocarcinoma develop FGFR2 fusions or rearrangements. Treatment with FGFR2-specific inhibitors (tyrosine kinase inhibitors, TKIs) has proven effective for patients with cholangiocarcinoma. In this study, we report a case of advanced cholangiocarcinoma, in which the patient was unable to tolerate the adverse effects of standard first-line chemotherapy. Genetic testing suggested the presence of a novel variant resulting from FDFT1/FGFR2 rearrangement. Owing to poor accessibility and high price, only a limited number of patients with advanced cholangiocarcinoma have access to TKIs and precision targeted therapy in China. Anlotinib is a novel small-molecule multi-target TKI developed independently in China. It has a broad target spectrum, including FGFR, and can effectively inhibit tumor angiogenesis and tumor cell proliferation, thereby achieving an anti-tumor effect. Here, the patient was prescribed anlotinib. After treatment, the tumor size continued to shrink, and no significant adverse effects were reported. The finding suggested that anlotinib may be effective in patients with FDFT1/FGFR2 rearrangement and could serve as a novel treatment option for affected patients in future.

Identification of FDFT1 as a potential biomarker associated with ferroptosis in ccRCC.

Renal cell carcinoma (RCC) seriously threatens people's lives and health. The identification of some precise biomarkers during the process of RCC progression and the pathophysiologic procedure is critical for improving the diagnosis and management of RCC. Evidence suggests that ferroptosis may play a pivotal role in eradicating clear cell RCC (ccRCC, KIRC) tumor cells. We screened out the target prognostic ferroptosis-associated genes and examined the functions of farnesyl-diphosphate farnesyltransferase (FDFT1) in 786-O cells by plasmid transfection. In our study, we identified FDFT1 as a potential marker correlating with ferroptosis in KIRC. Upregulated FDFT1 inhibited cell proliferation, migration, and invasion, and the underlying antitumor effects may occur via the AKT signaling pathway. Our study provides helpful evidence to study the complex physiopathology of KIRC.

Effects of Fdft 1 gene silencing and VD3 intervention on lung injury in hypoxia-stressed rats.

BACKGROUND: Hypoxia can induce lung injury such as pulmonary arterial hypertension and pulmonary edema. And in the rat model of hypoxia-induced lung injury, the expression of Farnesyl diphosphate farnesyl transferase 1 (Fdft 1) was highly expressed and the steroid biosynthesis pathway was activated. However, the role of Fdft 1 and steroid biosynthesis pathway in hypoxia-induced lung injury remains unclear. OBJECTIVE: The study aimed to further investigate the relationship between Fdft1 and steroid biosynthesis pathway with hypoxia-induced lung injury. METHODS: A rat model of lung injury was constructed by hypobaric chamber with hypoxic stress, the adenovirus interference vector was used to silence the expression of Fdft 1, and the exogenous steroid biosynthesis metabolite Vitamin D3 (VD3) was used to treat acute hypoxia-induced lung injury in rats. RESULTS: Sh-Fdft 1 and exogenous VD3 significantly inhibited the expression of Fdft 1 and the activation of the steroid pathway in hypoxia-induced lung injury rats, which showed a synergistic effect on the steroid activation pathway. In addition, sh-Fdft 1 promoted the increase of pulmonary artery pressure and lung water content, the decrease of oxygen partial pressure and oxygen saturation, and leaded to the increase of lung cell apoptosis and the aggravation of mitochondrial damage in hypoxia-stressed rats. And VD3 could significantly improve the lung injury induced by hypoxia and sh-Fdft 1 in rats. CONCLUSIONS: Fdft 1 gene silencing can promote hypoxic-induced lung injury, and exogenous supplement of VD3 has an antagonistic effect on lung injury induced by Fdft 1 gene silencing and hypoxic in rats, suggesting that VD3 has a preventive and protective effect on the occurrence and development of hypoxia-induced lung injury.

Protective mechanism of fdft1 in steroid hormone synthesis pathway in SD rats with acute hypoxic injury.

BACKGROUND: The acute hypoxic injury caused by the plain population entering the plateau in a short period of time has become the main cause of endangering the health of the people who rush into the plateau. OBJECTIVE: The study aimed to identify the key genes which participate in resisting the acute hypoxic injury in SD Rats by transcriptomic profile analysis. METHODS: 48 Sprague Dawley (SD) male rats were enrolled and randomly divided into four groups (0h, 24h, 48h, 72h) and housed in hypobaric hypoxia chamber with altitude 6000m for different periods of time to make them acute hypoxic injury. The transcriptomic profile of the lung tissue of the rats was analysed by RNA second-generation sequencing combined with bioinformatics analysis. RESULTS: The results of GO and KEGG function classification analysis revealed that the differential expression genes enriched in steroid hormone synthesis pathway especially in 48h group compared to F0 group. Further analysis revealed that Farnesyl Diphosphate Farnesyl Transferase 1 (fdft1) gene encoding a rate-limiting enzyme in steroid hormone synthesis pathway was significant differently expressed between the groups. The expression levels of fdft1 gene were further verified by RT-PCR and Western-blot methods. CONCLUSIONS: The results suggest that fdft1 gene plays an important role in responding to acute hypoxic injury by regulating steroid hormone biosynthesis.

Bavachinin inhibits cholesterol synthesis enzyme FDFT1 expression via AKT/mTOR/SREBP-2 pathway.

Non-alcoholic fatty liver disease (NAFLD) is a progressive and chronic liver disease. No effective drug is currently approved for the treatment of NAFLD. Traditionally it is thought that pathogenesis of NAFLD develops from some imbalance in lipid control, thereby leading to hepatotoxicity and disease development. Squalene synthase (SQS), encoded by FDFT1, is a key regulator in cholesterol synthesis and thus a potential target for the treatment of NAFLD. Here we could identify bavachinin, a component from traditional Chinese medicine Fructus Psoraleae (FP), which apparently protects HepaRG cells from palmitic acid induced death, suppressing lipid accumulation and cholesterol synthesis through inhibition of FDFT1 through the AKT/mTOR/SREBP-2 pathway. Over-expression of FDFT1 abolished bavachinin (BVC) -induced inhibition of cholesterol synthesis. The data presented here suggest that bavachinin acts as a cholesterol synthesis enzyme inhibitor, and might serve as a drug for treating NAFLD in the future.

An Improved Genome Assembly of Azadirachta indica A. Juss.

Neem (Azadirachta indica A. Juss.), an evergreen tree of the Meliaceae family, is known for its medicinal, cosmetic, pesticidal and insecticidal properties. We had previously sequenced and published the draft genome of a neem plant, using mainly short read sequencing data. In this report, we present an improved genome assembly generated using additional short reads from Illumina and long reads from Pacific Biosciences SMRT sequencer. We assembled short reads and error-corrected long reads using Platanus, an assembler designed to perform well for heterozygous genomes. The updated genome assembly (v2.0) yielded 3- and 3.5-fold increase in N50 and N75, respectively; 2.6-fold decrease in the total number of scaffolds; 1.25-fold increase in the number of valid transcriptome alignments; 13.4-fold less misassembly and 1.85-fold increase in the percentage repeat, over the earlier assembly (v1.0). The current assembly also maps better to the genes known to be involved in the terpenoid biosynthesis pathway. Together, the data represent an improved assembly of the A. indica genome.

The Riddle of Nonalcoholic Fatty Liver Disease: Progression From Nonalcoholic Fatty Liver to Nonalcoholic Steatohepatitis.

Nonalcoholic fatty liver (NAFL) is an emerging global epidemic which progresses to nonalcoholic steatohepatitis (NASH) and cirrhosis in a subset of subjects. Various reviews have focused on the etiology, epidemiology, pathogenesis and treatment of NAFLD. This review highlights specifically the triggers implicated in disease progression from NAFL to NASH. The integrating role of genes, dietary factors, innate immunity, cytokines and gut microbiome have been discussed.