A Deep-Red Emissive Sulfur-Doped Double [7]Helicene Photosensitizer: Synthesis, Structure and Chiral Optical Properties.

Doping of polycyclic conjugated hydrocarbons (PCHs) with sulfur atoms is becoming more and more important as a means of creating unique functional materials. Recently, thiophene-containing multiple helicenes have garnered enormous attention due to their intriguing electronic and (chir)optical properties compared with carbohelicenes. However, the efficient synthesis of thiopyran-containing multiple helicenes and the underlying sulfur doping mechanisms are rather unexplored. Herein, the synthesis and structural analysis of a thiopyran-containing double [7]helicene 3 are reported. X-ray crystallographic analysis reveals 3 and its dication with C2-symmetric propeller-shape structure and compact p-p interaction in the solid state. 3 exhibits deep-red to near-infrared (NIR) fluorescence emission. Tunable aromaticity of the central benzene ring and thiopyran rings is found by chemical oxidation, which is further confirmed by nucleus-independent chemical shift (NICS), anisotropy of the induced current density (AICD) and harmonic oscillator model of aromaticity (HOMA) analysis. Furthermore, the chiral and photosensitizing characters of 3 are investigated. The excellent deep-red to NIR fluorescence, circularly polarized luminescence (CPL) and photosensitizing activities suggest that 3 can be used as an outstanding photosensitizer in photodynamic therapy (PDT) and bioimaging, especially paving the way for future CPL-PDT and CPL-bio-probe applications.

Nanopore sequencing of forensic short tandem repeats using QNome of Qitan Technology.

Devices of nanopore sequencing can be highly portable and of low cost. Thus, nanopore sequencing is promising in in-field forensic applications. Previous investigations have demonstrated that nanopore sequencing is feasible for genotyping forensic short tandem repeats (STRs) by using sequencers of Oxford Nanopore Technologies. Recently, Qitan Technology launched a new portable nanopore sequencer and became the second supplier in the world. Here, for the first time, we assess the QNome (QNome-3841) for its accuracy in nanopore sequencing of STRs and compare with MinION (MinION Mk1B). We profile 54 STRs of 21 unrelated individuals and 2800M standard DNA. The overall accuracy for diploid STRs and haploid STRs were 53.5% (378 of 706) and 82.7% (134 of 162), respectively, by using QNome. The accuracies were remarkably lower than those of MinION (diploid STRs, 84.5%; haploid, 90.7%), with a similar amount of sequencing data and identical bioinformatics analysis. Although it was not reliable for diploid STRs typing by using QNome, the haploid STRs were consistently correctly typed. The majority of errors (58.8%) in QNome-based STR typing were one-repeat deviations of repeat units in the error from true allele, related with homopolymers in repeats of STRs.

[Application of optical genome mapping technology for the detection of chromosomal structural variations].

OBJECTIVE: To assess the value of optical genome mapping (OGM) for the detection of chromosomal structural abnormalities including ring chromosomes, balanced translocations, and insertional translocations. METHODS: Clinical data of four patients who underwent pre-implantation genetic testing concurrently with OGM and chromosomal microarray analysis at the Center of Reproductive Medicine of the Sixth Affiliated Hospital of Sun Yat-sen University from January to October 2022 due to chromosomal structural abnormalities were selected as the study subjects. Some of the results were verified by multi-color fluorescence in situ hybridization. RESULTS: The OGM has successfully detected a balanced translocation and fine mapped the breakpoints in a patient. Among two patients with insertional translocations, OGM has provided more refined breakpoint locations than karyotyping analysis in a patient who had chromosome 3 inserted into chromosome 6 and determined the direction of the inserted fragment. However, OGM has failed to detect the chromosomal abnormality in a patient with chromosome 8 inserted into the Y chromosome. It has also failed to detect circular signals in a patient with ring chromosome mosaicism. CONCLUSION: OGM has successfully detected chromosomal structural variations in the four patients and provided assistance for their diagnosis.

Computed tomography-guided percutaneous cryoablation and microwave ablation in the treatment of perivascular hepatocellular carcinoma: A comparative study with propensity score matching.

OBJECTIVE: To evaluate the safety and efficacy of cryoablation (CYA) and microwave ablation (MWA) in the treatment of patients with perivascular hepatocellular carcinoma (HCC). METHODS: Patients with perivascular HCC who underwent computed tomography (CT)-guided percutaneous CYA or MVA treatment in our hospital from August 2009 to March 2019 were included. Propensity score matching (PSM) was performed to adjust for potential baseline differences in the two groups. The technical success rate (TS), complications, and visual analog scale (VAS) were analyzed. The overall survival (OS) was evaluated using Kaplan-Meier curves and Cox proportional hazards models. RESULTS: After PSM, 32 patients from each group were selected. The technical success rate was 94 % for CYA and 91 % for MWA, and 13 patients developed recurrence (CYA, n = 5, 2 local, 3 distant; MWA, n = 8, 6 local, 2 distant). There were no significant differences in OS (36-months OS: CYA 53.1 % vs, MWA 40.6 %; P = 0.191). No intraoperative deaths or complication-related deaths were observed, and 19 patients (CYA, n = 8; MWA, n = 11) experienced complications (P = 0.435). The VAS in the MWA group (5.38 ± 1.21) was significantly higher than that in the CYA group (2.22 ± 0.87; P < 0.001). CONCLUSIONS: While CYA has equal safety and high primary efficacy as MWA in the treatment of perivascular HCC, it is associated with less periprocedural pain.

Association of COVID-19 and Lung Cancer: Short-Term and Long-Term Interactions.

Background: COVID-19 has been ravaging the globe for more than three years. Due to systemic immunosuppression of anti-tumor therapy, application of chemotherapy and adverse effects of surgery, the short- and long-term prognosis of cancer patients to COVID-19 are of significant concern. Method: This research included three parts of data. The first part of the data came from the public database that covered Veneto residents. The second part of the data included participants in Guangzhou. The third part of the data was used for MR analysis. We assessed the associations by logistic, linear or Cox regression when appropriate. Result: Lung cancer patients with COVID-19 had shorter progression-free survival (PFS) after COVID-19 (Model II: HR: 3.28, 95% CI: 1.6~6.72; Model III: HR: 3.39, 95% CI: 1.45~7.95), compared with lung cancer patients without COVID-19. Targeted therapy patients recovered from SARS-CoV-2 infection more quickly (Model I: ß: -0.58, 95% CI: -0.75~-0.41; Model II: ß: -0.59, 95% CI: -0.76~-0.41; Model III: ß: -0.57; 95% CI: -0.75~-0.40). Conclusions: PFS in lung cancer patients is shortened by COVID-19. The outcome of COVID-19 in lung cancer patients was not significantly different from that of the healthy population. In lung cancer patients, targeted therapy patients had a better outcome of COVID-19, while chemotherapy patients had the worst.

An Automated Grading System Based on Topological Features for the Evaluation of Corneal Fluorescein Staining in Dry Eye Disease.

BACKGROUND: Corneal fluorescein staining is a key biomarker in evaluating dry eye disease. However, subjective scales of corneal fluorescein staining are lacking in consistency and increase the difficulties of an accurate diagnosis for clinicians. This study aimed to propose an automatic machine learning-based method for corneal fluorescein staining evaluation by utilizing prior information about the spatial connection and distribution of the staining region. METHODS: We proposed an end-to-end automatic machine learning-based classification model that consists of staining region identification, feature signature construction, and machine learning-based classification, which fully scrutinizes the multiscale topological features together with conventional texture and morphological features. The proposed model was evaluated using retrospective data from Beijing Tongren Hospital. Two masked ophthalmologists scored images independently using the Sjögren's International Collaborative Clinical Alliance Ocular Staining Score scale. RESULTS: A total of 382 images were enrolled in the study. A signature with six topological features, two textural features, and two morphological features was constructed after feature extraction and selection. Support vector machines showed the best classification performance (accuracy: 82.67%, area under the curve: 96.59%) with the designed signature. Meanwhile, topological features contributed more to the classification, compared with other features. According to the distribution and correlation with features and scores, topological features performed better than others. CONCLUSIONS: An automatic machine learning-based method was advanced for corneal fluorescein staining evaluation. The topological features in presenting the spatial connectivity and distribution of staining regions are essential for an efficient corneal fluorescein staining evaluation. This result implies the clinical application of topological features in dry-eye diagnosis and therapeutic effect evaluation.

Asymmetric Substitution by Alkynyl Copper Driven Dearomatization and Rearomatization.

Catalytic asymmetric transformations by dearomatization have developed into a widely applicable synthetic strategy, but heavily relied on the use of arenes bearing a heteroatom. In this case, the dearomatization is facilitated by the involvement of a p-orbital electron of the heteroatom. Different from the conventional substrate-dependent model, here we demonstrate that the activation by a d-orbital electron of the transition-metal center can serve as a driving force for dearomatization, and is applied to the development of a novel asymmetric alkynyl copper facilitated remote substitution reaction. A newly modified PyBox chiral ligand enables the construction of valuable diarylmethyl and triarylmethyl skeletons in high enantioselectivities. An unexpected tandem process involving sequential remote substitution/cyclization/1,5-H shift leads to the formation of the enantioenriched C-N axis. A gram-scale reaction and various downstream transformations highlight the robustness of this method and the potential transformations of the products. Preliminary mechanistic studies reveal a mononuclear Cu-catalyzed remote substitution process.

BaLa5V2O3N7: a novel anti-perovskite oxynitride for electrode applications.

The exploration of transition metal oxynitrides has garnered significant interest due to their intriguing property diversity. Herein, we present a promising new transition metal oxynitride BaLa5V2O3N7, which features an anti-perovskite structure type. This unique structural configuration endows the material with remarkable conductivity, particularly at low temperatures, paving the way for the material to be used in a wide range of technological applications.

The African swine fever virus I10L protein inhibits the NF-κB signaling pathway by targeting IKKß.

Proinflammatory factors play important roles in the pathogenesis of African swine fever virus (ASFV), which is the causative agent of African swine fever (ASF), a highly contagious and severe hemorrhagic disease. Efforts in the prevention and treatment of ASF have been severely hindered by knowledge gaps in viral proteins responsible for modulating host antiviral responses. In this study, we identified the I10L protein (pI10L) of ASFV as a potential inhibitor of the TNF-α- and IL-1ß-triggered NF-κB signaling pathway, the most canonical and important part of host inflammatory responses. The ectopically expressed pI10L remarkably suppressed the activation of NF-κB signaling in HEK293T and PK-15 cells. The ASFV mutant lacking the I10L gene (ASFVΔI10L) induced higher levels of proinflammatory cytokines production in primary porcine alveolar macrophages (PAMs) compared with its parental ASFV HLJ/2018 strain (ASFVWT). Mechanistic studies suggest that pI10L inhibits IKKß phosphorylation by reducing the K63-linked ubiquitination of NEMO, which is necessary for the activation of IKKß. Morever, pI10L interacts with the kinase domain of IKKß through its N-terminus, and consequently blocks the association of IKKß with its substrates IκBα and p65, leading to reduced phosphorylation. In addition, the nuclear translocation efficiency of p65 was also altered by pI10L. Further biochemical evidence supported that the amino acids 1-102 on pI10L were essential for the pI10L-mediated suppression of the NF-κB signaling pathway. The present study clarifies the immunosuppressive activity of pI10L, and provides novel insights into the understanding of ASFV pathobiology and the development of vaccines against ASF. IMPORTANCE African swine fever (ASF), caused by the African swine fever virus (ASFV), is now widespread in many countries and severely affects the commercial rearing of swine. To date, few safe and effective vaccines or antiviral strategies have been marketed due to large gaps in knowledge regarding ASFV pathobiology and immune evasion mechanisms. In this study, we deciphered the important role of the ASFV-encoded I10L protein in the TNF-α-/IL-1ß-triggered NF-κB signaling pathway. This study provides novel insights into the pathogenesis of ASFV and thus contributes to the development of vaccines against ASF.

Polyhydroxyalkanoates: the natural biopolyester for future medical innovations.

Polyhydroxyalkanoates (PHAs) are a family of natural microbial biopolyesters with the same basic chemical structure and diverse side chain groups. Based on their excellent biodegradability, biocompatibility, thermoplastic properties and diversity, PHAs are highly promising medical biomaterials and elements of medical devices for applications in tissue engineering and drug delivery. However, due to the high cost of biotechnological production, most PHAs have yet to be applied in the clinic and have only been studied at laboratory scale. This review focuses on the biosynthesis, diversity, physical properties, biodegradability and biosafety of PHAs. We also discuss optimization strategies for improved microbial production of commercial PHAs via novel synthetic biology tools. Moreover, we also systematically summarize various medical devices based on PHAs and related design approaches for medical applications, including tissue repair and drug delivery. The main degradation product of PHAs, 3-hydroxybutyrate (3HB), is recognized as a new functional molecule for cancer therapy and immune regulation. Although PHAs still account for only a small percentage of medical polymers, up-and-coming novel medical PHA devices will enter the clinical translation stage in the next few years.

Serum metabolomics analysis revealed metabolic disorders in Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is by now the second of the most prevalent neurodegenerative diseases in the world, and its incidence is increasing rapidly as the global population ages, with 14.2 million PD patients expected worldwide by 2040. METHODS: We gathered a completion of 45 serum samples, including 15 of healthy controls and 30 from the PD group. We used non-targeted metabolomics analysis based on liquid chromatography-mass spectrometry to identify the molecular changes in PD patients, and conducted bioinformatics analysis on this basis to explore the possible pathogenesis of PD. RESULTS: We found significant metabolomics changes in the levels of 30 metabolites in PD patients compared with healthy controls. CONCLUSION: Lipids and lipid-like molecules accounted for the majority of the 30 differentially expressed metabolites. Also, pathway enrichment analysis showed significant enrichment in sphingolipid metabolic pathway. These assessments can improve our perception on the underlying mechanism of PD as well as facilitate a better targeting on therapeutic interventions.

Effects of 18 Months of Growth Hormone Replacement Therapy on Bone Mineral Density in Patients with Adult Growth Hormone Deficiency: A Retrospective Study.

Objective: The effect of physiological dose growth hormone (GH) replacement therapy on bone mineral density (BMD) in adults with growth hormone deficiency (GHD) is not well defined. We aimed to investigate the effects of 18 months of treatment with recombinant human growth hormone (rhGH) at physiological doses on BMD, body composition (BC), and quality of life (QoL). Methods: Sixty-eight patients diagnosed with adult growth hormone deficiency (AGHD) in our hospital were included in this retrospective study. All patients received individualized rhGH replacement to maintain normal serum insulin-like growth factor-1 (IGF-1) levels. BMD and BC measurements were performed by dual energy X-ray absorptiometry (DXA). Excluding those with incomplete follow-up data, we analyzed BMD in 68 patients, as well as BC and QoL in 36 of them. Results: Compared with the baseline, lumbar spine BMD decreased by 0.008 g/cm2 (P=0.006) and increased by 0.011 g/cm2 (P=0.045) at month 18, and total hip BMD decreased by 0.005 g/cm2 (P=0.008) and did not change significantly from the baseline at month 18. The changes in BMD did not differ by sex, and the increase in BMD was more pronounced in patients with low Z-scores at the baseline (lumbar spine: P=0.005 and total hip: P=0.018). The percentage change from the baseline in BMD was greater for the lumbar spine than for the total hip (P=0.003). Lean body mass (LBM) increased significantly (P=0.012), total body fat ratio (TBF%) decreased significantly (P=0.011), visceral adipose tissue (VAT) decreased significantly (P=0.016), and QoL improved significantly (P < 0.001). Conclusions: Within 18 months of treatment, bone resorption manifested first, BMD decreased to a nadir at month 6, and then it increased. The increase in BMD was greater in the lumbar spine than in the hip, and the increase was more pronounced in patients with low BMD. Eighteen months of rhGH replacement therapy significantly improved lumbar spine BMD and improved BC and QoL.

Emerging effects of non-coding RNA in vascular endothelial cells during strokes.

Vascular and neurological damage are the typical outcomes of ischemic strokes. Vascular endothelial cells (VECs), a substantial component of the blood-brain barrier (BBB), are necessary for normal cerebrovascular physiology. During an ischemic stroke (IS), changes in the brain endothelium can lead to a BBB rupture, inflammation, and vasogenic brain edema, and VECs are essential for neurotrophic effects and angiogenesis. Non-coding RNAs (nc-RNAs) are endogenous molecules, and brain ischemia quickly changes the expression patterns of several non-coding RNA types, such as microRNA (miRNA/miR), long non-coding RNA (lncRNA), and circular RNA (circRNA). Furthermore, vascular endothelium-associated nc-RNAs are important mediators in the maintenance of healthy cerebrovascular function. In order to better understand how VECs are regulated epigenetically during an IS, in this review, we attempted to assemble the molecular functions of nc-RNAs that are linked with VECs during an IS.

Fast X-ray fluorescence microscopy provides high-throughput phenotyping of element distribution in seeds.

The concentration, chemical speciation, and spatial distribution of essential and toxic mineral elements in cereal seeds have important implications for human health. To identify genes responsible for element uptake, translocation, and storage, high-throughput phenotyping methods are needed to visualize element distribution and concentration in seeds. Here, we used X-ray fluorescence microscopy (µ-XRF) as a method for rapid and high-throughput phenotyping of seed libraries and developed an ImageJ-based pipeline to analyze the spatial distribution of elements. Using this method, we nondestructively scanned 4,190 ethyl methanesulfonate (EMS)-mutagenized M1 rice (Oryza sativa) seeds and 533 diverse rice accessions in a genome-wide association study (GWAS) panel to simultaneously measure concentrations and spatial distribution of elements in the embryo, endosperm, and aleurone layer. A total of 692 putative mutants and 65 loci associated with the spatial distribution of elements in rice seed were identified. This powerful method provides a basis for investigating the genetics and molecular mechanisms controlling the accumulation and spatial variations of mineral elements in plant seeds.

Nutrient accumulation and transcriptome patterns during grain development in rice.

Rice is an important source of calories and mineral nutrients for more than half of the world's population. The accumulation of essential and toxic mineral elements in rice grain affects its nutritional quality and safety. However, the patterns and processes by which different elements progressively accumulate during grain filling remain largely unknown. In the present study, we investigated temporal changes in dry matter, elemental concentrations, and the transcriptome in the grain of field-grown rice. We also investigated the effects of seed setting rate and the position of the grain within the rice panicle on element accumulation. Three different patterns of accumulation were observed: (i) elements including K, Mn, B, and Ca showed an early accumulation pattern; (ii) dry matter and elements including N, P, S, Mg, Cu, Zn, Mo, As, and Cd showed a mid accumulation pattern; and (iii) elements such as Fe showed a gradual increase pattern. These different accumulation patterns can be explained by the differences in the biogeochemical behavior of the various elements in the soil, as well as differences in plant nutrient redistribution, gene expression, and the sink-source relationship. These results improve our knowledge of the dynamics of elemental accumulation in rice grain and are helpful for identification of functional genes mediating the translocation of elements to grain.

Presence of novel and legacy flame retardants and other pollutants in an e-waste site in China and associated risks.

Electrical and Electronic Equipment (EEE) residues and their management have been widely identified as potential sources of plasticizers and flame retardants to the environment, especially in non-formal e-waste facilities. This study evaluates the distribution, partitioning and environmental and human impact of organophosphate esters (OPEs), legacy polychlorinated biphenyls (PCBs), polybromodiphenyl ethers (PBDEs) and organochlorine pesticides (OCPs) in the e-waste recycling area of Baihe Tang village, in the Qingyuan county, Guangdong province, China. A plastic debris lump accumulated in a small pond during years was identified as the main source of pollution with ∑pollutants of 8400 µg/g dw, being OPEs the main contaminants detected, followed by PBDEs. This lump produced the contamination of water, sediments, soils and hen eggs in the surrounding area at high concentrations. Plastic-water and water-sediment partitioning coefficients explained the migration of OPEs to the water body and accumulation in sediments, with a strong dependence according to the KOW. Triphenyl phosphate (TPhP), tricresyl phosphate (TCPs) and high chlorination degree PCBs produced a risk in soils and sediments, considering the lowest predicted no effect concentration, while the presence of PCBs and PBDEs in free range hen eggs exceeded the acceptable daily intake. OCPs were detected at low concentrations in all samples. The presence of organic contaminants in e-waste facilities worldwide is discussed to highlight the need for a strict control of EEE management to minimize environmental and human risks.

PCET-Mediated Ring-Opening Alkenylation of Cycloalkanols via Dual Photoredox and Cobalt Catalysis.

The construction of molecular skeletons and modification of molecules using widely available and easily prepared alcohols as radical precursors for coupling reactions are significant and challenging subjects. We herein report a straightforward strategy for the dehydrogenative ring-opening alkenylation of cycloalkanols with alkenes by combining a proton-coupled electron transfer strategy and a dual photoredox and cobalt catalysis system. With this approach, a series of distally unsaturated ketones were obtained in 17-83% yields with high E selectivity.

Low Dimensional Nanostructure-Assisted Long-Range Surface Plasmon Resonance Sensors With High Figure of Merit.

Long-range surface plasmon resonance (LRSPR) sensors have been extensively studied by virtue of their extremely narrow full width at half maxima (FWHM) characteristics, but their low sensitivity remains an important factor limiting the figure of merit (FOM), making the sensors have difficulties in detecting small refractive index changes accurately. To address this problem, this paper proposes and demonstrates a low dimensional nanostructure (Au nanospheres, WS2) assisted LRSPR sensor to achieve an effective enhancement of the sensor interfaced electric field and thus improve the sensitivity. The performance parameters of the two sensors are compared with the LRSPR sensor by finite element method analysis, and the results showed that the assistance of the low dimensional nanostructure has a positive effect on the sensor. The first refractive index sensing experiment of the WS2-assisted LRSPR sensor was realized with a 25.47% increase in sensitivity and a 7.13% increase in FOM simultaneously, and the Au nanospheres-assisted LRSPR sensor with a 29.23% increase in sensitivity and a 15.95% increase in FOM simultaneously. The introduction of low dimensional nanostructures provides a flexible and effective means of sensitization for LRSPR sensors, making the plasmon resonance sensors combine high sensitivity, narrow FWHM and high FOM, which have promising applications in biochemical sensing.

One-pot synthesis and enzyme-responsiveness of amphiphilic doxorubicin prodrug nanomicelles for cancer therapeutics.

In this study, we report a one-pot synthesis and enzyme-responsiveness of polyethylene glycol (PEG) and glutamic acid (Glu)-based amphiphilic doxorubicin (DOX) prodrug nanomicelles for cancer therapeutics. The nanomicelles were accomplished by esterification and amidation reactions. The nuclear magnetic resonance (NMR) and Fourier transform infrared (FTIR) data confirmed the structure of nanomicelles. The DOX-loaded nanomicelles showed a DLS-measured average size of 107 nm and excellent stability in phosphate-buffered saline (PBS) for 7 days. The drug loading and cumulative release rates were measured by ultraviolet-visible (UV-vis) spectrophotometry at 481 nm. The cumulative release rate could reach 100% in an enzyme-rich environment. Further, the therapeutic efficiency of nanomicelles to cancer cells was determined by cell viability and cellular uptake and distribution using HeLa cells. The cell viability study showed that the DOX-loaded nanomicelles could effectively inhibit the HeLa cell proliferation. The cellular uptake study confirmed that the nanomicelles could be effectively ingested by HeLa cells and distributed into cell nuclei. Based on the collective experimental data, this study demonstrated that the synthesized nanomicellar prodrug of DOX is a potential candidate for cancer therapeutics.

Linking Nonalcoholic Fatty Liver Disease and Brain Disease: Focusing on Bile Acid Signaling.

A metabolic illness known as non-alcoholic fatty liver disease (NAFLD), affects more than one-quarter of the world's population. Bile acids (BAs), as detergents involved in lipid digestion, show an abnormal metabolism in patients with NAFLD. However, BAs can affect other organs as well, such as the brain, where it has a neuroprotective effect. According to a series of studies, brain disorders may be extrahepatic manifestations of NAFLD, such as depression, changes to the cerebrovascular system, and worsening cognitive ability. Consequently, we propose that NAFLD affects the development of brain disease, through the bile acid signaling pathway. Through direct or indirect channels, BAs can send messages to the brain. Some BAs may operate directly on the central Farnesoid X receptor (FXR) and the G protein bile acid-activated receptor 1 (GPBAR1) by overcoming the blood-brain barrier (BBB). Furthermore, glucagon-like peptide-1 (GLP-1) and the fibroblast growth factor (FGF) 19 are released from the intestine FXR and GPBAR1 receptors, upon activation, both of which send signals to the brain. Inflammatory, systemic metabolic disorders in the liver and brain are regulated by the bile acid-activated receptors FXR and GPBAR1, which are potential therapeutic targets. From a bile acid viewpoint, we examine the bile acid signaling changes in NAFLD and brain disease. We also recommend the development of dual GPBAR1/FXR ligands to reduce side effects and manage NAFLD and brain disease efficiently.