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Fibrolamellar carcinoma (FLC) is a rare, lethal, early-onset liver cancer with a critical need for new therapeutics. The primary driver in FLC is the fusion oncoprotein, DNAJ-PKAc, which remains challenging to target therapeutically. It is critical, therefore, to expand understanding of the FLC molecular landscape to identify druggable pathways/targets. Here, we perform the most comprehensive integrative proteo-metabolomic analysis of FLC. We also conduct nutrient manipulation, respirometry analyses, as well as key loss-of-function assays in FLC tumor tissue slices from patients. We propose a model of cellular energetics in FLC pointing to proline anabolism being mediated by ornithine aminotransferase hyperactivity and ornithine transcarbamylase hypoactivity with serine and glutamine catabolism fueling the process. We highlight FLCs potential dependency on voltage-dependent anion channel (VDAC), a mitochondrial gatekeeper for anions including pyruvate. The metabolic rewiring in FLC that we propose in our model, with an emphasis on mitochondria, can be exploited for therapeutic vulnerabilities.

Purpose: Non-obstructive azoospermia (NOA) represents the persistent absence of sperm in ejaculate without obstruction, stemming from diverse disease processes. This survey explores global practices in NOA diagnosis, comparing them with guidelines and offering expert recommendations. Materials and Methods:Materials and Methods: A 56-item questionnaire survey on NOA diagnosis and management was conducted globally from July to September 2022. This paper focuses on part 1, evaluating NOA diagnosis. Data from 367 participants across 49 coun-tries were analyzed descriptively, with a Delphi process used for expert recommendations. Results:Results: Of 336 eligible responses, most participants were experienced attending physicians (70.93%). To diagnose azoosper-mia definitively, 81.7% requested two semen samples. Commonly ordered hormone tests included serum follicle-stimulating hormone (FSH) (97.0%), total testosterone (92.9%), and luteinizing hormone (86.9%). Genetic testing was requested by 66.6%, with karyotype analysis (86.2%) and Y chromosome microdeletions (88.3%) prevalent. Diagnostic testicular biopsy, distinguishing obstructive azoospermia (OA) from NOA, was not performed by 45.1%, while 34.6% did it selectively. Differ-entiation relied on physical examination (76.1%), serum hormone profiles (69.6%), and semen tests (68.1%). Expectations of finding sperm surgically were higher in men with normal FSH, larger testes, and a history of sperm in ejaculate. Conclusions:Conclusions: This expert survey, encompassing 367 participants from 49 countries, unveils congruence with recommended guidelines in NOA diagnosis. However, noteworthy disparities in practices suggest a need for evidence-based, international consensus guidelines to standardize NOA evaluation, addressing existing gaps in professional recommendations.

Abstract Aging is a consequence of complex molecular changes, but whether a single microRNA (miRNA) can drive aging remains unclear. A miRNA known to be upregulated during both normal and premature aging is miR-29. We find miR-29 to also be among the top miRNAs predicted to drive aging-related gene expression changes. We show that partial loss of miR-29 extends the lifespan of Zmpste24 -/- mice, an established model of progeria, indicating that miR-29 is functionally important in this accelerated aging model. To examine whether miR-29 alone is sufficient to promote aging-related phenotypes, we generated mice in which miR-29 can be conditionally overexpressed (miR-29TG). miR-29 overexpression is sufficient to drive many aging-related phenotypes and led to early lethality. Transcriptomic analysis of both young miR-29TG and old WT mice reveals shared downregulation of genes associated with extracellular matrix organization and fatty acid metabolism, and shared upregulation of genes in pathways linked to inflammation. These results highlight the functional importance of miR-29 in controlling a gene expression program that drives aging-related phenotypes.

Background and Aims: Artificial intelligence (AI) chatbots like Conversational Generative Pre-trained Transformer (ChatGPT) have recently created much buzz, especially regarding patient education. Such informed patients understand and adhere to the management and get involved in shared decision making. The accuracy and understandability of the generated educational material are prime concerns. Thus, we compared ChatGPT with traditional patient information leaflets (PILs) about chronic pain medications. Methods: Patients' frequently asked questions were generated from PILs available on the official websites of the British Pain Society (BPS) and the Faculty of Pain Medicine. Eight blinded annexures were prepared for evaluation, consisting of traditional PILs from the BPS and AI-generated patient information materials structured similar to PILs by ChatGPT. The authors performed a comparative analysis to assess materials’ readability, emotional tone, accuracy, actionability, and understandability. Readability was measured using Flesch Reading Ease (FRE), Gunning Fog Index (GFI), and Flesch-Kincaid Grade Level (FKGL). Sentiment analysis determined emotional tone. An expert panel evaluated accuracy and completeness. Actionability and understandability were assessed with the Patient Education Materials Assessment Tool. Results: Traditional PILs generally exhibited higher readability (P values < 0.05), with [mean (standard deviation)] FRE [62.25 (1.6) versus 48 (3.7)], GFI [11.85 (0.9) versus 13.65 (0.7)], and FKGL [8.33 (0.5) versus 10.23 (0.5)] but varied emotional tones, often negative, compared to more positive sentiments in ChatGPT-generated texts. Accuracy and completeness did not significantly differ between the two. Actionability and understandability scores were comparable. Conclusion: While AI chatbots offer efficient information delivery, ensuring accuracy and readability, patient-centeredness remains crucial. It is imperative to balance innovation with evidence-based practice.

Summary: Fibrolamellar carcinoma (FLC) is a rare, lethal, early-onset liver cancer with a critical need for new therapeutics. The primary driver in FLC is the fusion oncoprotein, DNAJ-PKAc, which remains challenging to target therapeutically. It is critical, therefore, to expand understanding of the FLC molecular landscape to identify druggable pathways/targets. Here, we perform the most comprehensive integrative proteo-metabolomic analysis of FLC. We also conduct nutrient manipulation, respirometry analyses, as well as key loss-of-function assays in FLC tumor tissue slices from patients. We propose a model of cellular energetics in FLC pointing to proline anabolism being mediated by ornithine aminotransferase hyperactivity and ornithine transcarbamylase hypoactivity with serine and glutamine catabolism fueling the process. We highlight FLC’s potential dependency on voltage-dependent anion channel (VDAC), a mitochondrial gatekeeper for anions including pyruvate. The metabolic rewiring in FLC that we propose in our model, with an emphasis on mitochondria, can be exploited for therapeutic vulnerabilities.

Genetic alterations that activate protein kinase A (PKA) are found in many tumor types. Yet, their downstream oncogenic signaling mechanisms are poorly understood. We used global phosphoproteomics and kinase activity profiling to map conserved signaling outputs driven by a range of genetic changes that activate PKA in human cancer. Two signaling networks were identified downstream of PKA: RAS/MAPK components and an Aurora Kinase A (AURKA)/glycogen synthase kinase (GSK3) sub-network with activity toward MYC oncoproteins. Findings were validated in two PKA-dependent cancer models: a novel, patient-derived fibrolamellar carcinoma (FLC) line that expresses a DNAJ-PKAc fusion and a PKA-addicted melanoma model with a mutant type I PKA regulatory subunit. We identify PKA signals that can influence both de novo translation and stability of the proto-oncogene c-MYC. However, the primary mechanism of PKA effects on MYC in our cell models was translation and could be blocked with the eIF4A inhibitor zotatifin. This compound dramatically reduced c-MYC expression and inhibited FLC cell line growth in vitro. Thus, targeting PKA effects on translation is a potential treatment strategy for FLC and other PKA-driven cancers.

Fibrolamellar carcinoma (FLC) is a rare liver cancer that disproportionately affects adolescents and young adults. Currently, no standard of care is available and there remains a dire need for new therapeutics. Most patients harbor the fusion oncogene DNAJB1-PRKACA (DP fusion), but clinical inhibitors are not yet developed and it is critical to identify downstream mediators of FLC pathogenesis. Here, we identify long noncoding RNA LINC00473 among the most highly upregulated genes in FLC tumors and determine that it is strongly suppressed by RNAi-mediated inhibition of the DP fusion in FLC tumor epithelial cells. We show by loss- and gain-of-function studies that LINC00473 suppresses apoptosis, increases the expression of FLC marker genes, and promotes FLC growth in cell-based and in vivo disease models. Mechanistically, LINC00473 plays an important role in promoting glycolysis and altering mitochondrial activity. Specifically, LINC00473 knockdown leads to increased spare respiratory capacity, which indicates mitochondrial fitness. Overall, we propose that LINC00473 could be a viable target for this devastating disease.

Abstract Background MicroRNAs (miRNAs) are important post-transcriptional gene regulators controlling cellular lineage specification and differentiation during embryonic development, including the gastrointestinal system. However, miRNA-mediated regulatory mechanisms involved in early embryonic development of human small intestine (SI) remains underexplored. To explore candidate roles for miRNAs in prenatal SI lineage specification in humans, we used a multi-omic analysis strategy in a directed differentiation model that programs human pluripotent stem cells toward the SI lineage. Results We leveraged small RNA-seq to define the changing miRNA landscape, and integrated chromatin run-on sequencing (ChRO-seq) and RNA-seq to define genes subject to significant post-transcriptional regulation across the different stages of differentiation. Small RNA-seq profiling revealed temporal dynamics of miRNA signatures across different developmental events of the model, including definitive endoderm formation, SI lineage specification and SI regional patterning. Our multi-omic, integrative analyses showed further that the elevation of miR-182 and reduction of miR-375 are key events during SI lineage specification. We demonstrated that loss of miR-182 leads to an increase in the foregut master marker SOX2. We also used single-cell analyses in murine adult intestinal crypts to support a life-long role for miR-375 in the regulation of Zfp36l2. Finally, we uncovered opposing roles of SMAD4 and WNT signaling in regulating miR-375 expression during SI lineage specification. Beyond the mechanisms highlighted in this study, we also present a web-based application for exploration of post-transcriptional regulation and miRNA-mediated control in the context of early human SI development. Conclusion The present study uncovers a novel facet of miRNAs in regulating prenatal SI development. We leveraged multi-omic, systems biology approaches to discover candidate miRNA regulators associated with early SI developmental events in a human organoid model. In this study, we highlighted miRNA-mediated post-transcriptional regulation relevant to the event of SI lineage specification. The candidate miRNA regulators that we identified for the other stages of SI development also warrant detailed characterization in the future.

Abstract Mammary cancer incidence varies greatly across species and underlying mechanisms remain elusive. We previously showed that mammosphere-derived epithelial cells from species with low mammary cancer incidence, such as horses, respond to carcinogen 7, 12-Dimethylbenz(a)anthracene-induced DNA damage by undergoing apoptosis, a postulated anti-cancer mechanism. Additionally, we found that miR-214-3p expression in mammosphere-derived epithelial cells is lower in mammary cancer-resistant as compared to mammary cancer-susceptible species. Here we show that increasing miR-214 expression and decreasing expression of its target gene nuclear factor kappa B subunit 1 in mammosphere-derived epithelial cells from horses abolishes 7,12-Dimethylbenz(a)anthracene-induced apoptosis. A direct interaction of miR-214-3p with another target gene, unc-5 netrin receptor A, is also demonstrated. We propose that relatively low levels of miR-214 in mammosphere-derived epithelial cells from mammals with low mammary cancer incidence, allow for constitutive gene nuclear factor kappa B subunit 1 expression and apoptosis in response to 7, 12-Dimethylbenz(a)anthracene. Better understanding of the mechanisms regulating cellular responses to carcinogens improves our overall understanding of mammary cancer resistance mechanisms.

Abstract A network of co-hepato/pancreatic stem/progenitors exists in pigs and humans in Brunner’s Glands in the submucosa of the duodenum, in peribiliary glands (PBGs) of intrahepatic and extrahepatic biliary trees, and in pancreatic duct glands (PDGs) of intrapancreatic biliary trees, collectively supporting hepatic and pancreatic regeneration postnatally. The network is found in humans postnatally throughout life and, so far, has been demonstrated in pigs postnatally at least through to young adulthood. These stem/progenitors in vivo in pigs are in highest numbers in Brunner’s Glands and in PDGs nearest the duodenum, and in humans are in Brunner’s Glands and in PBGs in the hepato/pancreatic common duct, a duct missing postnatally in pigs. Elsewhere in PDGs in pigs and in all PDGs in humans are only committed unipotent or bipotent progenitors. Stem/progenitors have genetic signatures in liver/pancreas-related RNA-seq data based on correlation, hierarchical clustering, differential gene expression and principal component analyses (PCA). Gene expression includes representative traits of pluripotency genes (SOX2, OCT4), endodermal transcription factors (e.g. SOX9, SOX17, PDX1), other stem cell traits (e.g. NCAM, CD44, sodium iodide symporter or NIS), and proliferation biomarkers (Ki67). Hepato/pancreatic multipotentiality was demonstrated by the stem/progenitors’ responses under distinct ex vivo conditions or in vivo when patch grafted as organoids onto the liver versus the pancreas. Therefore, pigs are logical hosts for translational/preclinical studies for cell therapies with these stem/progenitors for hepatic and pancreatic dysfunctions.

In the past decade, insect meal has gained popularity in the animal feed industry, particularly in aquafeed, due to rising costs and decreased availability of fish meal (FM) and fish oil. Initially met with skepticism, insect meal is now seen as a promising ingredient because of its high nutrient profile. Research worldwide is exploring its potential as a FM replacement. Insects are abundant, nutritious, and environmentally friendly, as they can be reared on organic waste, minimizing the need for land, water, and energy. This research aims at obtaining a comprehensive and in-depth understanding of the current status and research trend patterns in this research field. To achieve this goal, this study conducts a mini systematic review and scientometric analysis of the global research published from 2013 to 2022 on the usage of insect meal in aquaculture. In the scientometric analysis, a total of 354 papers published by 1800 authors in 124 different journals from the Web of Science (WoS) core collection were analyzed, evaluating the number of publications, most relevant authors, organizations, top cited countries, most globally cited publications, and trending research themes in this field. The result showed that the University of Turin was the leading organization in insect meal research, whereas aquaculture was the leading journal, and author Laura Gasco was the prominent researcher in this field in the studied time frame (2013–2022). Italy was the leading country in Europe, while China dominated Asia in terms of the number of publications. The annual growth rate in insect meal research was found to be positive (23.11%), with 36.95 average citations per document. This study helps practitioners and scholars understand the current state of insect meal in aquaculture and identifies research requirements that can benefit both academia and industry.

Abstract Somatic mutations drive colorectal cancer (CRC) by disrupting gene regulatory mechanisms. Distinct combinations of mutations can result in unique changes to regulatory mechanisms leading to variability in the efficacy of therapeutics. MicroRNAs are important regulators of gene expression, and their activity can be altered by oncogenic mutations. However, it is unknown how distinct combinations of CRC-risk mutations differentially affect microRNAs. Here, using genetically-modified mouse intestinal organoid (enteroid) models, we identify 12 different modules of microRNA expression patterns across different combinations of mutations common in CRC. We also show that miR-24-3p is aberrantly upregulated in genetically-modified mouse enteroids irrespective of mutational context. Furthermore, we identify an enrichment of miR-24-3p predicted targets in downregulated gene lists from various mutational contexts compared to WT. In follow-up experiments, we demonstrate that miR-24-3p promotes CRC cell survival in multiple cell contexts. Our novel characterization of genotype-specific patterns of miRNA expression offer insight into the mechanisms that drive inter-tumor heterogeneity and highlight candidate microRNA therapeutic targets for the advancement of precision medicine for CRC.

This review delves into the mesmerizing technology of nano-agrochemicals, specifically pesticides and herbicides, and their potential to aid in the achievement of UN SDG 17, which aims to reduce hunger and poverty globally. The global market for conventional pesticides and herbicides is expected to reach USD 82.9 billion by 2027, growing 2.7% annually, with North America, Europe, and the Asia–Pacific region being the biggest markets. However, the extensive use of chemical pesticides has proven adverse effects on human health as well as the ecosystem. Therefore, the efficacy, mechanisms, and environmental impacts of conventional pesticides require sustainable alternatives for effective pest management. Undoubtedly, nano-agrochemicals have the potential to completely transform agriculture by increasing crop yields with reduced environmental contamination. The present review discusses the effectiveness and environmental impact of nanopesticides as promising strategies for sustainable agriculture. It provides a concise overview of green nano-agrochemical synthesis and agricultural applications, and the efficacy of nano-agrochemicals against pests including insects and weeds. Nano-agrochemical pesticides are investigated due to their unique size and exceptional performance advantages over conventional ones. Here, we have focused on the environmental risks and current state of nano-agrochemicals, emphasizing the need for further investigations. The review also draws the attention of agriculturists and stakeholders to the current trends of nanomaterial use in agriculture especially for reducing plant diseases and pests. A discussion of the pros and cons of nano-agrochemicals is paramount for their application in sustainable agriculture.

Objectives: Patients with ST elevation myocardial infarction (STEMI) without standard modifiable cardiovascular risk factors (SMuRFs; dyslipidaemia, hypertension, diabetes mellitus and smoking) are reported to have a worse clinical outcome compared to those with SMuRFs. However, robust prospective data and low-and middle-income country perspective are lacking. We aimed to study the patients with first STEMI and assess the influence of SMuRFs on clinical outcomes by comparing the patients with and without SMuRFs. Methods: We included all consecutive STEMI patients without prior coronary artery disease enrolled in the Madras Medical College STEMI Registry from September 2018 to October 2019. We collected baseline clinical characteristics, revascularisation strategies and clinical outcome. We analysed suboptimal self-reported sleep duration as a 5th extended SMuRF (eSMuRF). Primary outcome was in-hospital mortality. Secondary outcomes included in-hospital complications and one-year all-cause mortality. Results: Among 2,379 patients, 605 patients (25.4%) were SMuRF-less. More women were SMuRF-less than men (27.1% vs 22.1%; P = 0.012). SMuRF-less patients were older (57.44 ± 13.95 vs 55.68 ± 11.74; P < 0.001), more often former tobacco users (10.4% vs 5.0%; P < 0.001), with more anterior wall MI (62.6% vs 52.1%; P = 0.032). The primary outcome [in-hospital mortality (10.7% vs 11.3%; P = 0.72)] and secondary outcomes [in-hospital complications (29.1% vs 31.7%; P = 0.23) and one-year all-cause mortality (22.3% vs 22.7%; P = 0.85)] were similar in both groups. Addition of suboptimal self-reported sleep duration as a 5th eSMuRF yielded similar results. Conclusions: 25% of first STEMI patients were SMuRF-less. Clinical outcomes of patients without SMuRFs were similar to those with SMuRFs. Suboptimal sleep duration did not account for the risk associated with the SMuRF-less status.

Oral verapamil lowers inflammatory markers and daily insulin needs in subjects with type 1 diabetes and helps preserve pancreatic beta cell function for at least two years. In this context, serum chromogranin A provides a promising therapy marker.

Epigenetic modifications, mainly aberrant DNA methylation, have been shown to silence the expression of genes involved in epigenetic diseases, including cancer suppression genes. Almost all conventional cancer therapeutic agents, such as the DNA hypomethylation drug 5-aza-2-deoxycytidine, have insurmountable side effects. To investigate the role of the well-known DNA protectant (ectoine) in skin cell DNA methylation and cancer cell proliferation, comprehensive methylome sequence analysis, 5-methyl cytosine (5mC) analysis, proliferation and tumorigenicity assays, and DNA epigenetic modifications-related gene analysis were performed. The results showed that extended ectoine treatment globally hypomethylated DNA in skin cells, especially in the CpG island (CGIs) element, and 5mC percentage was significantly reduced. Moreover, ectoine mildly inhibited skin cell proliferation and did not induce tumorigenicity in HaCaT cells injected into athymic nude mice. HaCaT cells treated with ectoine for 24 weeks modulated the mRNA expression levels of Dnmt1, Dnmt3a, Dnmt3b, Dnmt3l, Hdac1, Hdac2, Kdm3a, Mettl3, Mettl14, Snrpn, and Mest. Overall, ectoine mildly demethylates DNA in skin cells, modulates the expression of epigenetic modification-related genes, and reduces cell proliferation. This evidence suggests that ectoine is a potential anti-aging agent that prevents DNA hypermethylation and subsequently activates cancer-suppressing genes.

Background & Aims: The intestinal barrier comprises a monolayer of specialized intestinal epithelial cells (IECs) that are critical in maintaining mucosal homeostasis. Dysfunction within various IEC fractions can alter intestinal permeability in a genetically susceptible host, resulting in a chronic and debilitating condition known as Crohn’s disease (CD). Defining the molecular changes in each IEC type in CD will contribute to an improved understanding of the pathogenic processes and the identification of cell type–specific therapeutic targets. We performed, at single-cell resolution, a direct comparison of the colonic epithelial cellular and molecular landscape between treatment-naïve adult CD and non–inflammatory bowel disease control patients. Methods: Colonic epithelial-enriched, single-cell sequencing from treatment-naïve adult CD and non–inflammatory bowel disease patients was investigated to identify disease-induced differences in IEC types. Results: Our analysis showed that in CD patients there is a significant skew in the colonic epithelial cellular distribution away from canonical LGR5+ stem cells, located at the crypt bottom, and toward one specific subtype of mature colonocytes, located at the crypt top. Further analysis showed unique changes to gene expression programs in every major cell type, including a previously undescribed suppression in CD of most enteroendocrine driver genes as well as L-cell markers including GCG. We also dissect an incompletely understood SPIB+ cell cluster, revealing at least 4 subclusters that likely represent different stages of a maturational trajectory. One of these SPIB+ subclusters expresses crypt-top colonocyte markers and is up-regulated significantly in CD, whereas another subcluster strongly expresses and stains positive for lysozyme (albeit no other canonical Paneth cell marker), which surprisingly is greatly reduced in expression in CD. In addition, we also discovered transposable element markers of colonic epithelial cell types as well as transposable element families that are altered significantly in CD in a cell type–specific manner. Finally, through integration with data from genome-wide association studies, we show that genes implicated in CD risk show heretofore unknown cell type–specific patterns of aberrant expression in CD, providing unprecedented insight into the potential biological functions of these genes. Conclusions: Single-cell analysis shows a number of unexpected cellular and molecular features, including transposable element expression signatures, in the colonic epithelium of treatment-naïve adult CD.

Genetic alterations that activate protein kinase A (PKA) are found in many tumor types. Yet, their downstream oncogenic signaling mechanisms are poorly understood. We used global phosphoproteomics and kinase activity profiling to map conserved signaling outputs driven by a range of genetic changes that activate PKA in human cancer. Two signaling networks were identified downstream of PKA: RAS/MAPK components and an Aurora Kinase A (AURKA)/glycogen synthase kinase (GSK3) sub-network with activity toward MYC oncoproteins. Findings were validated in two PKA-dependent cancer models: a novel, patient-derived fibrolamellar carcinoma (FLC) line that expresses a DNAJ-PKAc fusion and a PKA-addicted melanoma model with a mutant type I PKA regulatory subunit. We identify PKA signals that can influence both de novo translation and stability of the proto-oncogene c-MYC. However, the primary mechanism of PKA effects on MYC in our cell models was translation and could be blocked with the eIF4A inhibitor zotatifin. This compound dramatically reduced c-MYC expression and inhibited FLC cell line growth in vitro. Thus, targeting PKA effects on translation is a potential treatment strategy for FLC and other PKA-driven cancers.

Lignin is essential for plant growth, structural integrity, biotic/abiotic stress resistance, and water transport. Besides, lignin constitutes 10–30% of lignocellulosic biomass and is difficult to utilize for biofuel production. Over the past few decades, extensive research has uncovered numerous metabolic pathways and genes involved in lignin biosynthesis, several of which have been highlighted as the primary targets for genetic manipulation. However, direct manipulation of lignin biosynthesis is often associated with unexpected abnormalities in plant growth and development for unknown causes, thus limiting the usefulness of genetic engineering for biomass production and utilization. Recent advances in understanding the complex regulatory mechanisms of lignin biosynthesis have revealed new avenues for spatial and temporal modification of lignin in lignocellulosic plants that avoid growth abnormalities. This review explores recent work on utilizing specific transcriptional regulators to modify lignin biosynthesis at both tissue and cellular levels, focusing on using specific promoters paired with functional or regulatory genes to precisely control lignin synthesis and achieve biomass production with desired properties. Further advances in designing more appropriate promoters and other regulators will increase our capacity to modulate lignin content and structure in plants, thus setting the stage for high-value utilization of lignin in the future.

Vertical sleeve gastrectomy (VSG) results in an increase in the number of hormone-secreting enteroendocrine cells (EECs) in the intestinal epithelium; however, the mechanism remains unclear. Notably, the beneficial effects of VSG are lost in a mouse model lacking the nuclear bile acid receptor farnesoid X receptor (FXR). FXR is a nuclear transcription factor that has been shown to regulate intestinal stem cell (ISC) function in cancer models. Therefore, we hypothesized that the VSG-induced increase in EECs is due to changes in intestinal differentiation driven by an increase in bile acid signaling through FXR. To test this, we performed VSG in mice that express EGFP in ISC/progenitor cells and performed RNA-Seq on GFP-positive cells sorted from the intestinal epithelia. We also assessed changes in EEC number (marked by glucagon-like peptide-1, GLP-1) in mouse intestinal organoids following treatment with bile acids, an FXR agonist, and an FXR antagonist. RNA-Seq of ISCs revealed that bile acid receptors are expressed in ISCs and that VSG explicitly alters expression of several genes that regulate EEC differentiation. Mouse intestinal organoids treated with bile acids and 2 different FXR agonists increased GLP-1–positive cell numbers, and administration of an FXR antagonist blocked these effects. Taken together, these data indicate that VSG drives ISC fate toward EEC differentiation through bile acid signaling.

Fibrolamellar carcinoma (FLC) is an aggressive liver cancer primarily afflicting adolescents and young adults. Most patients with FLC harbor a heterozygous deletion on chromosome 19 that leads to the oncogenic gene fusion, DNAJB1-PRKACA. There are currently no effective therapeutics for FLC. To address that, it is critical to gain deeper mechanistic insight into FLC pathogenesis. We assembled a large sample set of FLC and nonmalignant liver tissue (n = 52) and performed integrative multiomic analysis. Specifically, we carried out small RNA sequencing to define altered microRNA expression patterns in tumor samples and then coupled this analysis with RNA sequencing and chromatin run-on sequencing data to identify candidate master microRNA regulators of gene expression in FLC. We also evaluated the relationship between DNAJB1-PRKACA and microRNAs of interest in several human and mouse cell models. Finally, we performed loss-of-function experiments for a specific microRNA in cells established from a patient-derived xenograft (PDX) model. We identified miR-10b-5p as the top candidate pro-proliferative microRNA in FLC. In multiple human cell models, overexpression of DNAJB1-PRKACA led to significant upregulation of miR-10b-5p. Inhibition of miR-10b in PDX-derived cells increased the expression of several potentially novel target genes, concomitant with a significant reduction in metabolic activity, proliferation, and anchorage-independent growth. This study highlights a potentially novel proliferative axis in FLC and provides a rich resource for further investigation of FLC etiology.

In current history, adding nanoscale and micron-sized filler materials to composite materials for fabrication has been a popular approach for improving the composite’s mechanical characteristics. Due to their lower friction coefficient, excellent mechanical strength modulus, and low moisture uptake, filler-based hybrid composite materials are replacing metallic materials. Glass/Dharbai hybrid composites with nano-SiO2 fillers have been created in this study. After manufacture, the composite materials were treated with liquid nitrogen at 177 K for various durations. Every sample material was cut according to ASTM standards to investigate mechanical features such as ILSS, impact test, and flexural strength. The broken composite specimen was studied using a scanning electron microscope. Water retention studies have been conducted under two distinct liquid solutions: tab or regular water and seawater. ILSS, flexural strength, and water retention were all greater in 4 wt.% of nanofiller-rich composites than in ordinary composites. Compared to 30 minutes, the 15-minute cryo-treated specimens provide the highest mechanical strength. On the other hand, the automobile, aviation, and shipbuilding sectors would benefit from a nanofiller-based composite.

Exploration has shifted from traditional materials and alloys to composite materials in recent years to develop lightweight, high-effective materials for specific purposes. Natural fibres are less costly, biodegradable, and nonflammable than glass fibres. This study explores how titanium oxide affects woven polyester reinforced composite’s mechanical and physical characteristics. Nanocomposites were created by hand utilizing the following terms: (i) TiO2 nanoparticle filler weight ratio, (ii) fibre content, and (iii) fibre diameter, all at three unique levels. Using the L9 (33) orthogonal design, nine composite samples are generated and tested according to the ASTM standard. According to the research, hybrid composites containing 4% titanium oxide powder and 15 mm length of bamboo fibre with 0.24 mm of bamboo fibre diameter have high mechanical strength. Adding fibre to pristine polyester increased its mechanical properties. As the fibre and filler percentages grew, more effort was required to break the fragments between the matrix and its resin. The verification test, which uses the optimal processing value and grey relational analysis, outperforms the real test results by a wide margin. Tensile strength increased by 14.76%, flexural strength increased by 14.07%, and hardness increased by 25.55%.

Due to their high mechanical and physical properties, natural fibre-based composite materials have been important in many fields of application for four to five years. The chief intention of the current study is to determine the mechanical and water retention features of composite materials under ambient conditions. Coir and pineapple leaf fibre were used as a reinforcement, aluminium oxide as additives, and polyester as a matrix. The hybrid resources were laminated by the manual hand lay-up method. The mechanical characteristics like tensile, flexural, and fracture toughness properties were tested as per the ASTM standard. Nanoparticle weight ratio and its size variation significantly impact mechanical qualities. The hybrid composite’s water retention behaviour was tested for two types of water levels: ordinary tab water and nanofluid. The moisture uptake of the composites rose as the fibre volume increased, and after 640 hours, all of the composites had reached equilibrium. According to the results, the following combinations have the maximum mechanical strength: 15% wt.% coir, 15% wt.% pineapple, 10% wt.% nanofiller, and 60% wt.% polyester resin. The combinations mentioned above withstand the most load during the tests. Compared to 20% filler, 10% Al2O3 filler produces good interfacial adhesion in the current study. The fractured specimens were analyzed using scanning electron microscopic (SEM) pictures to recognize better the failure process of composites during mechanical testing.