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Lysosomes are important cellular structures for human health as centers for recycling, signaling, metabolism and stress adaptation. However, the potential role of lysosomes in stress‐related emotions has long been overlooked. Here, it is found that lysosomal morphology in astrocytes is altered in the medial prefrontal cortex (mPFC) of susceptible mice after chronic social defeat stress. A screen of lysosome‐related genes revealed that the expression of the mucolipin 1 gene (Mcoln1; protein: mucolipin TRP channel 1) is decreased in susceptible mice and depressed patients. Astrocyte‐specific knockout of mucolipin TRP channel 1 (TRPML1) induced depressive‐like behaviors by inhibiting lysosomal exocytosis‐mediated adenosine 5′‐triphosphate (ATP) release. Furthermore, this stress response of astrocytic lysosomes is mediated by the transcription factor EB (TFEB), and overexpression of TRPML1 rescued depressive‐like behaviors induced by astrocyte‐specific knockout of TFEB. Collectively, these findings reveal a lysosomal stress‐sensing signaling pathway contributing to the development of depression and identify the lysosome as a potential target organelle for antidepressants. [ABSTRACT FROM AUTHOR]

As computer graphics technology continues to advance, Collision Detection (CD) has emerged as a critical element in fields such as virtual reality, computer graphics, and interactive simulations. CD is indispensable for ensuring the fidelity of physical interactions and the realism of virtual environments, particularly within complex scenarios like virtual assembly, where both high precision and real-time responsiveness are imperative. Despite ongoing developments, current CD techniques often fall short in meeting these stringent requirements, resulting in inefficiencies and inaccuracies that impede the overall performance of virtual assembly systems. To address these limitations, this study introduces a novel algorithm that leverages the capabilities of a Backpropagation Neural Network (BPNN) to optimize the structural composition of the Hybrid Bounding Volume Tree (HBVT). Through this optimization, the research proposes a refined Hybrid Hierarchical Bounding Box (HHBB) framework, which is specifically designed to enhance the computational efficiency and precision of CD processes. The HHBB framework strategically reduces the complexity of collision detection computations, thereby enabling more rapid and accurate responses to collision events. Extensive experimental validation within virtual assembly environments reveals that the proposed algorithm markedly improves the performance of CD, particularly in handling complex models. The optimized HBVT architecture not only accelerates the speed of collision detection but also significantly diminishes error rates, presenting a robust and scalable solution for real-time applications in intricate virtual systems. These findings suggest that the proposed approach offers a substantial advancement in CD technology, with broad implications for its application in virtual reality, computer graphics, and related fields. [ABSTRACT FROM AUTHOR]

Background: Cognitive function (CF) deterioration is a pressing concern in geriatric research. This study aimed to explore the relationship between physical activity (PA) and CF in older adults. Methods: This study adopted a dual approach, employing both observational and genetic approaches through data from the National Health and Nutrition Examination Survey (NHANES) 2011-2014 and Mendelian Randomization (MR) analysis. For the NHANES component, PA levels were evaluated using the Global Physical Activity Questionnaire, and CF was assessed via standardized tests. Multivariate regression, threshold effect analysis, smoothing curve fitting, and subgroup analyses were conducted to examine the association between PA and CF. In parallel, MR methods, using genetic variants as instrumental variables, assessed the causal impact of PA on CF and related conditions such as Alzheimer's disease and dementia. Results: Observational findings from NHANES demonstrated a positive correlation between PA and CF, notably among female participants. The detailed analysis identified specific thresholds of PA that correlate with cognitive enhancements. However, MR results did not support a significant causal relationship between PA and CF or dementia-related outcomes, indicating an absence of a direct genetic basis for the observational associations. Conclusion: Although observational data from NHANES suggest that PA is positively associated with CF in older adults, particularly among women, MR analysis did not confirm these findings as causally related. The discrepancy highlights the complexity of the PA-CF relationship and underscores the need for further research. These results emphasize the potential of PA as a modifiable risk factor for CF, though causal effects remain to be definitively established. [ABSTRACT FROM AUTHOR]

Introduction: Deep learning (DL) models predicting biomarker expression in images of hematoxylin and eosin (H&E)-stained tissues can improve access to multi-marker immunophenotyping, crucial for therapeutic monitoring, biomarker discovery, and personalized treatment development. Conventionally, these models are trained on ground truth cell labels derived from IHC-stained tissue sections adjacent to H&Estained ones, which might be less accurate than labels from the same section. Although many such DL models have been developed, the impact of ground truth cell label derivation methods on their performance has not been studied. Methodology: In this study, we assess the impact of cell label derivation on H&E model performance, with CD3+ T-cells in lung cancer tissues as a proof-ofconcept. We compare two Pix2Pix generative adversarial network (P2P-GAN)- based virtual staining models: one trained with cell labels obtained from the same tissue section as the H&E-stained section (the 'same-section' model) and one trained on cell labels from an adjacent tissue section (the 'serial-section' model). Results: We show that the same-section model exhibited significantly improved prediction performance compared to the 'serial-section' model. Furthermore, the same-section model outperformed the serial-section model in stratifying lung cancer patients within a public lung cancer cohort based on survival outcomes, demonstrating its potential clinical utility. Discussion: Collectively, our findings suggest that employing ground truth cell labels obtained through the same-section approach boosts immunophenotyping DL solutions. [ABSTRACT FROM AUTHOR]

Epigenetic mechanisms bridge genetic and environmental factors that contribute to the pathogenesis of major depression disorder (MDD). However, the cellular specificity and sensitivity of environmental stress on brain epitranscriptomics and its impact on depression remain unclear. Here, we found that ALKBH5, an RNA demethylase of N6-methyladenosine (m6A), was increased in MDD patients' blood and depression models. ALKBH5 in astrocytes was more sensitive to stress than that in neurons and endothelial cells. Selective deletion of ALKBH5 in astrocytes, but not in neurons and endothelial cells, produced antidepressant-like behaviors. Astrocytic ALKBH5 in the mPFC regulated depression-related behaviors bidirectionally. Meanwhile, ALKBH5 modulated glutamate transporter-1 (GLT-1) m6A modification and increased the expression of GLT-1 in astrocytes. ALKBH5 astrocyte-specific knockout preserved stress-induced disruption of glutamatergic synaptic transmission, neuronal atrophy and defective Ca2+ activity. Moreover, enhanced m6A modification with S-adenosylmethionine (SAMe) produced antidepressant-like effects. Our findings indicate that astrocytic epitranscriptomics contribute to depressive-like behaviors and that astrocytic ALKBH5 may be a therapeutic target for depression. The regulatory mechanism and function of astrocytic epigenetic effects on depression remain to be explored. Here, the authors show astrocytic ALKBH5 contributes to depressive-like behaviors via the m6A RNA methylation of GLT-1. [ABSTRACT FROM AUTHOR]

Laminate substrates in advanced IC packages serve as not only the principal heat dissipation pathway but also the critical component governing the thermomechanical performance of advanced packaging technologies. A solid and profound grasp of their thermomechanical properties is of crucial importance to better understand IC packages' thermomechanical behavior. This study attempts to introduce a subregion homogenization modeling framework for effectively and efficiently modeling and characterizing the equivalent thermomechanical behavior of large-scale and high-density laminate substrates comprising the non-uniform distribution and non-unidirectional orientation of tiny metal traces. This framework incorporates subregion modeling, trace mapping and modeling, and finite element analysis (FEA)-based effective modeling. In addition, the laminates are macroscopically described as elastic orthotropic or elastic anisotropic material. This framework is first validated with simple uniaxial tensile and thermomechanical test simulations, and the calculation results associated with these two effective material models are compared with each other, as well as with those of two existing mixture models, and direct the detailed FEA. This framework is further tested on the prediction of the process-induced warpage of a flip chip chip-scale package, and the results are compared against the measurement data and the results of the whole-domain modeling-based effective approach and two existing mixture models. [ABSTRACT FROM AUTHOR]

Posttranslational modification dramatically enhances protein complexity, but the function and precise mechanism of novel lysine acylation modifications remain unknown. Chemoresistance remains a daunting challenge to successful treatment. We found that lysine butyrylation (Kbu) is specifically upregulated in chemoresistant tumor cells and tissues. By integrating butyrylome profiling and gain/loss-of-function experiments, lysine 754 in HSP90 (HSP90 K754) was identified as a substrate for Kbu. Kbu modification leads to overexpression of HSP90 in esophageal squamous cell carcinoma (ESCC) and its further increase in relapse samples. Upregulation of HSP90 contributes to 5-FU resistance and can predict poor prognosis in cancer patients. Mechanistically, HSP90 K754 is regulated by the cooperation of KAT8 and HDAC11 as the writer and eraser, respectively; SDCBP increases the Kbu level and stability of HSP90 by binding competitively to HDAC11. Furthermore, SDCBP blockade with the lead compound V020-9974 can target HSP90 K754 to overcome 5-FU resistance, constituting a potential therapeutic strategy. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor-T (CAR-T) cell therapy based on functional immune cell transfer is showing a booming situation. However, complex manufacturing processes, high costs, and disappointing results in the treatment of solid tumors have limited its use. Encouragingly, it has facilitated the development of new strategies that fuse immunology, cell biology, and biomaterials to overcome these obstacles. In recent years, CAR-T engineering assisted by properly designed biomaterials has improved therapeutic efficacy and reduced side effects, providing a sustainable strategy for improving cancer immunotherapy. At the same time, the low cost and diversity of biomaterials also offer the possibility of industrial production and commercialization. Here, we summarize the role of biomaterials as gene delivery vehicles in the generation of CAR-T cells and highlight the advantages of in-situ construction in vivo. Then, we focused on how biomaterials can be combined with CAR-T cells to better enable synergistic immunotherapy in the treatment of solid tumors. Finally, we describe biomaterials' potential challenges and prospects in CAR-T therapy. This review aims to provide a detailed overview of biomaterial-based CAR-T tumor immunotherapy to help investigators reference and customize biomaterials for CAR-T therapy to improve the efficacy of immunotherapy. [ABSTRACT FROM AUTHOR]

Objective Few studies have reported the cost and cost-effectiveness of workplace interventions to reduce sedentary time. The purpose of this study was to complete an economic evaluation of a multilevel intervention to reduce sitting time and increase light-intensity physical activity (LPA) among employees. Methods We conducted a retrospective within-trial cost and cost-effectiveness analysis (CEA) to compare a 12-month multilevel intervention with (STAND+) and without (MOVE+) a sit-stand workstation, across 24 worksites (N=630 employee participants) enrolled in a cluster randomized clinical trial. We estimated the intervention costs using activity-based costing strategy. The intervention costs were further expressed as per person and per worksite. CEA was conducted using an incremental cost-effectiveness ratio (ICER) metric, expressed as costs for additional unit of sitting time (minute/day), LPA (minutes/day), cardiometabolic risk score, and qualityadjusted life years (QALY) increased/decreased at 12 months. We assessed the cost analysis and CEA from the organizational (ie, employer) perspective with a one-year time horizon. Results Total intervention costs were $134 and $72 per person, and $3939 and $1650 per worksite for the STAND+ (N worksites = 12; N employees = 354) and MOVE+ (N worksites = 12; N employees = 276) interventions, respectively. The ICER was $1 (95% CI $0.8–1.4) for each additional minute reduction of workplace sitting time (standardized to 8-hour workday); and $4656 per QALY gained at 12 months. There was a modest and non-significant change of loss of work productivity improvement (-0.03 hours, 95% CI -4.16–4.09 hours), which was associated with a $0.34 return for every $1 invested. Conclusions The multi-level intervention with sit-stand workstations has the potential to be widely implemented to reduce workplace sitting time. Future research into work productivity outcomes in terms of cost-benefits for employers is warranted. [ABSTRACT FROM AUTHOR]

Objectives The purpose of this paper is to ascertain the effect and mechanism of Radix Isatidis polysaccharide (RIP) on obesity. Methods High fat diet (HFD)-induced obese rats and the MDI-induced 3T3-L1 adipocyte cells were established to evaluate the ameliorated obesity effect and mechanism from RIP. Key findings Experiments in vivo show that oral administration of RIP has significant preventive effects on HFD-induced obesity and metabolic disorders in rats. With treatment of RIP (20, 40 and 80 mg/kg BW), the body weight, fat accumulation, adipocyte cell size, serum lipid levels and antioxidant enzyme activity were progressively improved. On the other hand, the treatment of 3T3-L1 cells with RIP (25, 50 and 100 mg/L) led to a decrease in lipid accumulation and glucose consumption. In addition, during adipogenesis in 3T3-L1 cells, RIP remarkably down-regulated mRNA levels of peroxisome proliferator-activated receptor-γ (PPARγ), CCAAT/enhancer binding protein-α (C/EBPα), sterol regulatory element-binding protein-1c (SREBP-1c), fatty acid synthase (FAS), acetyl-CoA carboxylase and glycerol-3-phosphate dehydrogenase. Furthermore, after RIP treatment, the protein expression of PPARγ, C/EBPα, FAS, HMG-CoA reductase and acetyl-CoA synthetase-1 (AceCS1) were significantly decreased and the expression of p-AMPK was increased. Conclusion These results highlight the potential of RIP for obesity interventions and suggest that RIP inhibited adipocyte differentiation and lipid synthesis by activating adenosine 5ʹ-monophosphate (AMP)-activated protein kinase (AMPK) signalling pathway and down-regulating the expression of major adipogenic transcription factors, PPARγ, C/EBPα, etc. [ABSTRACT FROM AUTHOR]

After its discovery in the 1950 s, the autophagy research field has seen its annual number of publications climb from tens to thousands. The ever-growing number of autophagy publications is a wealth of information but presents a challenge to researchers, especially those new to the field, who are looking for a general overview of the field to, for example, determine current topics of the field or formulate new hypotheses. Here, we employed text mining tools to extract research trends in the autophagy field, including those of genes, terms, and topics. The publication trend of the field can be separated into three phases. The exponential rise in publication number began in the last phase and is most likely spurred by a series of highly cited research papers published in previous phases. The exponential increase in papers has resulted in a larger variety of research topics, with the majority involving those that are directly physiologically relevant, such as disease and modulating autophagy. Our findings provide researchers a summary of the history of the autophagy research field and perhaps hints of what is to come. Abbreviations: 5Y-IF: 5-year impact factor; AIS: article influence score; EM: electron microscopy; HGNC: HUGO gene nomenclature committee; LDA: latent Dirichlet allocation; MeSH: medical subject headings; ncRNA: non-coding RNA [ABSTRACT FROM AUTHOR]

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To investigate the contaminant characteristics of heavy metals in soils and vegetables surrounding a lead-zinc mine in Huize County, Yunnan Province, thirty surface soil samples and vegetable samples were collected to measure the contents of heavy metals, including lead (Pb), zinc (Zn), copper (Cu), and cadmium (Cd). The potential risk was evaluated by using the single factor pollution index, Nemerow comprehensive pollution index, and target hazard index. The results showed that the contents of Pb, Zn, Cu, and Cd in the soil were 954.1, 2236.5, 151.1, and 4.83 mg·kg−1, respectively. Compared with the soil background values in Yunnan Province, the soil surrounding the lead-zinc mine was polluted by Pb, Zn and Cd. The Nemerow comprehensive pollution index evaluation indicated that the soil was heavily polluted. The contents of Pb, Zn, Cu, and Cd in vegetables were 117.5–778.6, 430.3–2212.4, 16.8–89, and 1.28–34.3 mg·kg−1, respectively. Among them, the contents of Pb and Cd in vegetables exceeded the pollutant limit in food products of China's National Standard for Food Safety (GB 2762–2017). The contents of Pb, Zn and Cd in the soil were extremely significantly or significantly correlated with the contents of Pb, Zn and Cd in the edible parts of vegetables. The results indicated that there was serious heavy metal pollution and significant health risk for the soil and vegetables surrounding the lead-zinc mine. The research results not only reveal the contaminant characteristics of heavy metals in soils and vegetables surrounding a lead-zinc mine in Huize County, Yunnan Province, but also could provide a scientific evidence for reasonable utilization and ecological remediation. [ABSTRACT FROM AUTHOR]

Damaged lysosomes can be repaired by calcium release-dependent recruitment of the ESCRT machinery. However, the involvement of annexins, another group of calcium-responding membrane repair proteins, has not been fully addressed. Here, we show that although all ubiquitously expressed annexins (ANXA1, A2, A4, A5, A6, A7, and A11) localize to damaged lysosomes, only ANXA1 and ANXA2 are important for repair. Their recruitment is calcium-dependent, ESCRT-independent, and selective towards lysosomes with large injuries. Lysosomal leakage was more severe when ANXA1 or ANXA2 was depleted compared to that of ESCRT components. These findings suggest that ANXA1 and ANXA2 constitute an additional repair mechanism that serves to minimize leakage from damaged lysosomes. [ABSTRACT FROM AUTHOR]

Structural alloys applied at high temperatures rely on an external dense layer of oxide scale for protection. As some reactive alloy components are selectively oxidized internally, understanding how these dispersed metal oxide particles reach the surface to form a protective scale—the so-called internal to external oxidation transition—is crucial for designing these alloys. While the literature is replete with experimental studies on oxidation of alloys, there is a lack of computational studies in this realm due to the complex nature of coupled reaction and diffusion processes in multicomponent multi-phase alloy systems. In this work, we apply a recently developed phase-field model to simulate the oxidation processes under different compositions and nucleation scenarios to gain insights into how a continuous oxide scale can be established. The results show that while alloy composition is critical for internal to external oxidation transition, the oxide nuclei size, shape and distribution also have significant impact on the transition kinetics. [ABSTRACT FROM AUTHOR]

Gout with etiological hyperuricemia deteriorates patient's quality of life, making an urgent need for effective uric acid-lowering drugs. Uric acid-lowering peptides derived from naturally-occurring proteins have great potential therapeutic applications and are found to be rich in aromatic amino acids (AAAs) and branched-chain amino acids (BCAAs). This study proposed a new method to rationally synthesize uric-acid lowering peptides from amino acids mainly composed of AAAs and BCAAs by papain in non-aqueous medium. Firstly, L-tryptophan and L-phenylalanine were screened out for the synthesis of uric acid-lowering peptides from all the 49 possible pairwise combinations of 7 amino acids dominating in reported natural uric-acid lowering peptides, which are 3 AAAs (L-tryptophan, L-phenylalanine, L-tyrosine), 2 BCAAs (L-leucine and L-alanine), 1 L-proline and 1 L-histidine. Secondly, the optimal reaction conditions of 90 mmol/L triethylamine, reaction at pH 6.0 for 1.5 h for the synthesis of uric-acid lowering peptides were determined using single factor method and response surface experiments (RSE). By means of preparative HPLC and LC–MS/MS identification, a newly synthesized tripeptide (FWF) was obtained, which inhibited xanthine oxidase activity by 18.47%. The tripeptide FWF was further confirmed by the chemical synthesis and its underlying XOD inhibition was supported by the computational molecular docking experiments. The newly identified uric acid-lowering tripeptide FWF and its protease-catalyzed rational synthesis in non-aqueous medium method provide alternative choices to developing uric acid-lowering peptides for anti-gout or anti-hyperuricemia treatments. [ABSTRACT FROM AUTHOR]

Functionalized water-soluble silicon nanoparticles were fabricated and applied in biomedical imaging. Firstly, hydrophobic hydride-capped silicon nanoparticles (H-SiNPs) were synthesized by hydrogen silsesquioxane, subsequently modified by allylthiourea and further chelated with gadopentetate dimeglumine (Gd-DTPA) to fabricate water-soluble functionalized SiNPs. Fourier transform infrared technology and X-ray photoelectron spectroscopy evidenced the successful function. The properties of functionalized SiNPs were significantly improved including fluorescence intensity, photoluminescence quantum yield (from 0.87 to 14.04%), fluorescence lifetimes (from 29.9 to 63.8 μs), photo-stability, biocompatibility, etc. Hematoxylin and eosin (H&E) staining assay further demonstrated the low toxicity and the satisfactory biocompatibility of Gd-SiNPs. The longitudinal relaxation (r1) of Gd-SiNPs was measured to be 11.59 mM−1 s−1 and much higher than that of the commercial contrast agent Gd-DTPA (4.29 mM−1 s−1). Finally, the charming Gd-SiNPs were successfully applied as a biologic probe in fluorescence and magnetic resonance dual-mode imaging in vivo and in vitro. Fabrication of the water-soluble functionalized silicon nanoparticles and their application in fluorescence and magnetic resonance dual-mode bioimaging [ABSTRACT FROM AUTHOR]

Objective: To classify the fabellae and discuss the relationship between the classification of fabellae and the severity of knee osteoarthritis (KOA) in Chinese. Methods: From February 2019 to February 2020, 136 patients were measured and classified using three‐dimensional computed tomography (CT) reconstruction. According to the CT imaging characteristics, the fabellae were divided into five types: type I, a fabella on the lateral femoral condyle; type II, a fabella on the medial femoral condyle; type III, a fabella on the lateral femoral condyle and a fabella on the medial femoral condyle; type IV, two fabellae on the medial femoral condyle; and type V, two fabellae on the lateral femoral condyle. The severity of KOA was assessed on the Recht grade by magnetic resonance imaging (MRI). The data were analyzed with SPSS 24.0. Results: The classification of fabellae were correlated with KOA grades (χ2 = 35.026, P < 0.05). In terms of KOA grades, grade I and grade II were occupied most by fabellar type II (32, 72.8%); type II and other types showed significant statistical difference (P < 0.05). Grade I and grade II were also mainly fabellar type IV (four, 100%). Fabellar type V's biggest component was grade III and grade IV (six, 75%). Type IV and type V showed significant statistical difference (P < 0.05). Conclusion: The classification of fabellae were correlated with KOA grades. The type II may mean the lower KOA grades while type V may mean the higher KOA grades. [ABSTRACT FROM AUTHOR]

Modeling of ductile fracture in polycrystalline structures is challenging, since it requires integrated modeling of cracks, crystal plasticity, and grains. Here we extend the typical phase-field framework to the situations with constraints on the order parameters, and formulate two types of phase-field models on ductile fracture. The Type-I model incorporates three sets of order parameters, which describe the distributions of cracks, plastic strain, and grains, respectively. Crystal plasticity is employed within grain interiors accommodated by J2 plasticity at grain boundaries. The applications of the Type-I model to single crystals and bicrystals demonstrate the influences of grain orientations and grain boundaries on crack growth. In the Type-II model, J2 plasticity is assumed for the whole system and grain structures are neglected. Taking advantage of the efficiency of the fast Fourier transform, our Type-II model is employed to study low cycle fatigue. Crack closure and striation-like patterning of plastic strain are observed in the simulations. Crack growth rate is analyzed as a function of the J-integral, and the simulated fatigue life as a function of plastic strain agrees with the Coffin–Manson relation without a priori assumption. [ABSTRACT FROM AUTHOR]

Background: Family caregivers are more likely to experience insomnia relative to noncaregivers but have significant barriers to accessing gold standard cognitive behavioral therapy for insomnia treatment. Delivering interventions to caregivers through the internet may help increase access to care, particularly among higher-intensity caregivers who provide assistance with multiple care tasks over many hours per week. Although there are existing internet interventions that have been thoroughly studied and demonstrated as effective in the general population, the extent to which these interventions may be effective for caregivers without tailoring to address this population's unique psychosocial needs has not been studied. Objective: The goal of this trial is to determine what tailoring may be necessary for which caregivers to ensure they receive optimal benefit from an existing evidence-based, internet-delivered cognitive behavioral therapy for insomnia program named Sleep Healthy Using the Internet (SHUTi). Specifically, we will test the association between caregivers' engagement with SHUTi and their caregiving context characteristics (ie, caregiving strain, self-efficacy, and guilt) and environment (ie, proximity to care recipient; functional status, cognitive status, and problem behavior of care recipient; and type of care provided). Among caregivers using the program, we will also test the associations between change in known treatment mechanisms (sleep beliefs and sleep locus of control) and caregiving context factors. Methods: A total of 100 higher-intensity caregivers with significant insomnia symptoms will be recruited from across the United States to receive access to SHUTi in an open-label trial with mixed methods preassessments and postassessments. At postassessment (9 weeks following preassessment completion), participants will be categorized according to their engagement with the program (nonusers, incomplete users, or complete users). Study analyses will address 3 specific aims: to examine the association between caregivers' engagement with SHUTi and their caregiving context (aim 1a); to describe caregivers' barriers to and motivations for SHUTi engagement from open-ended survey responses (aim 1b); and among caregivers using SHUTi, to determine whether cognitive mechanisms of change targeted by SHUTi are associated with differences in caregiving context (aim 2). Results: Institutional review board approvals have been received. Data collection is anticipated to begin in December 2021 and is expected to be completed in 2023. Conclusions: Findings will inform the next research steps for tailoring and testing SHUTi for optimal impact and reach among caregivers. Beyond implication to the SHUTi program, the findings will be translatable across intervention programs and will hold significant promise to reduce inefficiencies in developing digital health interventions for caregivers while also increasing their impact and reach for this underserved population. [ABSTRACT FROM AUTHOR]

Arabidopsis CHLOROPLAST IMPORT APPARATUS 2 (CIA2) and its paralogous protein CIA2‐LIKE (CIL) are nuclear transcription factors containing a C‐terminal CCT motif. CIA2 promotes the expression of nuclear genes encoding chloroplast‐localized translocons and ribosomal proteins, thereby increasing the efficiency of protein import and synthesis in chloroplasts. We have previously reported that CIA2 and CIL form a homodimer or heterodimer through their C‐terminal sequences and interact with other nuclear proteins, such as CONSTANS (CO), via their N‐terminal sequences, but the function of CIL had remained unclear. In this study, we verified through transgenic cia2 mutant plants expressing the CIL coding sequence that CIL is partially functionally redundant to CIA2 during vegetative growth. We also compared phenotypes and gene expression profiles of wildtype Col‐0, cia2, cil, and cia2/cil mutants. Our results indicate that CIA2 and CIL coordinate chloroplast biogenesis and function mainly by upregulating the expression of the nuclear factor GOLDEN2‐LIKE 1 (GLK1) and chloroplast transcription‐, translation‐, protein import‐, and photosynthesis‐related genes, with CIA2 playing a more crucial role. Furthermore, we compared flowering phenotypes in single, double, and triple mutant plants of co, cia2, and cil. We found that CIA2 and CIL participate in modulating long‐day floral development. Notably, CIA2 increases flower number and height of the inflorescence main axis, whereas CIL promotes flowering. [ABSTRACT FROM AUTHOR]

The medial prefrontal cortex (mPFC), a key part of the brain networks that are closely related to the regulation of behavior, acts as a key regulator in emotion, social cognition, and decision making. Astrocytes are the majority cell type of glial cells, which play a significant role in a number of processes and establish a suitable environment for the functioning of neurons, including the brain energy metabolism. Astrocyte's dysfunction in the mPFC has been implicated in various neuropsychiatric disorders. Glucose is a major energy source in the brain. In glucose metabolism, part of glucose is used to convert UDP-GlcNAc as a donor molecule for O-GlcNAcylation, which is controlled by a group of enzymes, O-GlcNAc transferase enzyme (OGT), and O-GlcNAcase (OGA). However, the role of O-GlcNAcylation in astrocytes is almost completely unknown. Our research showed that astrocytic OGT could influence the expression of proteins in the mPFC. Most of these altered proteins participate in metabolic processes, transferase activity, and biosynthetic processes. GFAP, an astrocyte maker, was increased after OGT deletion. These results provide a framework for further study on the role of astrocytic OGT/O-GlcNAcylation in the mPFC. [ABSTRACT FROM AUTHOR]

Pentatomic heterobiaryl performs as a key structural motif in various natural products and bioactive compounds. With the rapid growth of asymmetric catalysis, five‐membered heterobiaryl‐based catalysts and ligands have emerged as an efficient complementary toolbox for asymmetric catalysis. Therefore, the development of enantioselective construction of such pentatomic atropisomers has received significant attention in recent decade. Various catalytic asymmetric strategies have been established, including central to axial chirality conversion, direct generation of heteroaryl, direct assembly of aryl‐heteroaryls, functionalization of racemic or prochiral biaryls, and chirality transfer from atropisomeric alkenes. Hundreds of unprecedented pentatomic atropisomers have proliferated. Importantly, a few promising axially chiral catalysts and ligands have been obtained from the prepared heterobiaryls after simple transformations. Hence, recent advances of catalytic asymmetric construction of axially chiral pentatomic heterobiaryls through asymmetric catalysis are summarized in this review, involving their scope, mechanism, transformations, and applications. [ABSTRACT FROM AUTHOR]

Purpose: Plant-derived exogenous microRNAs (miRNAs) regulate human physiological functions by blocking the translation of target mRNAs. Although several computational approaches have been developed to elucidate the interactions of cross-species miRNAs and their targets in mammals, the number of verified plant miRNAs is still limited, and the biological roles of most exogenous plant miRNAs remain unknown. Methods: A miRNA mimic library-based phenotypic screening, which contained 8394 plant mature miRNAs published in the official database miRbase, was performed to identify more novel bioactive plant miRNAs for the prevention of hepatic fibrosis. Inhibition of candidates for the activation of hepatic stellate cells (HSCs) and the underlying mechanisms were evaluated in TGF-β 1- and PDGF-exposed HSC models. The protective effects of the candidates against CCl4-induced liver fibrosis were evaluated in a mouse model. Results: Among the 8394 plant mature miRNAs reported in the official database miRBase, five candidates were found to effectively inhibit the differentiation of HSCs. gma-miR-159a (miR159a) exerted the strongest inhibitory activities on both TGF-β 1- and PDGF-induced HSC activation and proliferation by inhibiting the GSK-3β-mediated NF-κB and TGF-β 1 pathways. Moreover, miR159a was mainly accumulated in the liver after intravenous injection, and it reduced CCl4-induced hepatic fibrosis and inflammation in mice. Conclusion: Results indicated that miR159a has the therapeutic potential for preventing hepatic fibrosis. This study provides a novel strategy for achieving natural nucleic acid drugs. [ABSTRACT FROM AUTHOR]

A phase-field model is proposed to simulate coherency loss coupled with microstructure evolution. A special field variable is employed to describe the degree of coherency loss of each particle and its evolution is governed by a Ginzburg-Landau type kinetic equation. For the sake of computational efficiency, a flood-fill algorithm is introduced that can drastically reduce the required number of field variables, which allows the model to efficiently simulate a large number of particles sufficient for characterizing their statistical features during Ostwald ripening. The model can incorporate size dependence of coherency loss, metastability of coherent particles, and effectively incorporate the underlying mechanisms of coherency loss by introducing a so-called differential energy criterion. The model is applied to simulate coarsening of Al3Sc precipitates in aluminum alloy and comprehensively compared with experiments. Our results clearly show how the particle size distribution is changed during coherency loss and affects the coarsening rate. [ABSTRACT FROM AUTHOR]

Objective: Changes in gut microbiota have been linked to systemic lupus erythematosus (SLE), but knowledge is limited. Our study aimed to provide an in‐depth understanding of the contribution of gut microbiota to the immunopathogenesis of SLE. Methods: Fecal metagenomes from 117 patients with untreated SLE and 52 SLE patients posttreatment were aligned with 115 matched healthy controls and analyzed by whole‐genome profiling. For comparison, we assessed the fecal metagenome of MRL/lpr mice. The oral microbiota origin of the gut species that existed in SLE patients was documented by single‐nucleotide polymorphism–based strain‐level analyses. Functional validation assays were performed to demonstrate the molecular mimicry of newly found microbial peptides. Results: Gut microbiota from individuals with SLE displayed significant differences in microbial composition and function compared to healthy controls. Certain species, including the Clostridium species ATCC BAA‐442 as well as Atopobium rimae, Shuttleworthia satelles, Actinomyces massiliensis, Bacteroides fragilis, and Clostridium leptum, were enriched in SLE gut microbiota and reduced after treatment. Enhanced lipopolysaccharide biosynthesis aligned with reduced branched chain amino acid biosynthesis was observed in the gut of SLE patients. The findings in mice were consistent with our findings in human subjects. Interestingly, some species with an oral microbiota origin were enriched in the gut of SLE patients. Functional validation assays demonstrated the proinflammatory capacities of some microbial peptides derived from SLE‐enriched species. Conclusion: This study provides detailed information on the microbiota of untreated patients with SLE, including their functional signatures, similarities with murine counterparts, oral origin, and the definition of autoantigen‐mimicking peptides. Our data demonstrate that microbiome‐altering approaches may offer valuable adjuvant therapies in SLE. [ABSTRACT FROM AUTHOR]

It is difficult for drug delivery systems to release drugs as expected, often leading to undesired side effects. To solve this problem, a CuS@MSN/DOX@MnO2@membrane (CMDMm) was reasonably designed. It was introduced to release the drug by a double response, similar to using two keys to open two locks at the same time for one door. CuS@MSN was used as a photothermal therapy (PTT) material and carrier, and then the surface of CuS@MSN/DOX was sealed by MnO2 to prevent drug release in advance. MnO2 could be reduced and degraded in a tumor microenvironment. It was applied in MR imaging due to the T1 magnetism of Mn2+ following the reduction of MnO2. Finally, the 4T1 cell membrane was extracted and coated onto the surface of CuS@MSN/DOX@MnO2, which served as a target for 4T1 tumor cells. A noteworthy phenomenon was that the fluorescence of DOX was quenched by the coordination between DOX and CuS, and this greatly improved the interaction between DOX and CuS@MSN. However, the coordination was weakened when DOX was protonated in a tumor microenvironment (∼pH 5.0), leading to the release of DOX and fluorescence recovery. The drug release experiments showed that the release efficiency was higher at pH 5.0 with 10 mmol L−1 GSH. Through in vitro laser confocal imaging, it was successfully observed that DOX was reliably released in specific tumor cells according to the fluorescence recovery, and that there was no leakage in other cells. In short, effective double response drug release was successfully confirmed. [ABSTRACT FROM AUTHOR]

The single particle reconstruction (SPR) in cryogenic electron microscopy is considered in this paper. This is an emerging technique for determining the three-dimensional (3D) structure of biological specimens from a limited number of the micrographs. Because the micrographs are modulated by contrast transfer functions and corrupted by heavy noise, the number of micrographs might be limited, in general it is a serious ill-posed problem to reconstruct the original particle. In this paper, we propose a constrained total variation (TV) model for single particle reconstruction. The TV norm is represented by the dual formulation that changes the SPR problem into a minimax one. The primal-dual method is applied to find the saddle point of the minimax problem, and the convergence condition is given. Numerical results show that the proposed model is very effective in reconstructing the particle. [ABSTRACT FROM AUTHOR]

Metastasis accounts for 90% of cancer death worldwide, and effective therapeutic strategies are lacking. The aim of this work is to identify the key drivers in tumor metastasis and screen therapeutics for treatment of esophageal squamous cell carcinoma (ESCC). Gene Ontology analysis of The Cancer Genome Atlas (TCGA) gene expression datasets of ESCC patients with or without lympy metastasis identifies that TGFβ2 is highly enriched in the pathways essential for tumor metastasis and upregulates in the metastatic ESCC tumors. High TGFβ2 expression in ESCC correlates with metastasis and patient survival, and functionally contributes to tumor metastasis via activating extracellular signal‐regulated kinases (ERK) signaling. By screening of a library consisting of 429 bioactive compounds, imperatorin is verified as a novel TGFβ2 inhibitor, with robustly suppressive effect on tumor metastasis in multiple mice models. Mechanistically, direct binding of imperatorin and CREB1 inhibits phosphorylation, nuclear translocation of CREB1, and its interaction with TGFβ2 promoter, represses TGFβ2 expression and fibroblasts‐secreted CCL2, and then inactivates ERK signaling to block cancer invasion and abrogates the paracrine effects of fibroblasts on tumor angiogenesis and metastasis. Overall, the findings suggest the use of TGFβ2 as a diagnostic and prognostic biomarker and therapeutic target in ESCC, and supports the potential of imperatorin as a novel therapeutic strategy for cancer metastasis. [ABSTRACT FROM AUTHOR]

Stresses in the steam-side oxide of boiler tubes are evaluated based on analytical derivations and numerical simulations. With only thermal strain considered, analytical solutions of stress distribution are obtained for a cylindrical geometry representative of boiler tubes and a flat-plate geometry—a typical simplification assumed in the literature to represent boiler tubes with extremely thin oxide scale. In these analytical derivations, the substrate metal has finite dimensions or is assumed to be very thick. The solutions under the approximations of flat-plate geometry and very thick substrate are employed to examine the accuracy of various approximations adopted in the literature to analyze the stress distribution in boiler tubes. For more complicated situations where the contributions from thermal strain, interface roughness, creep of the oxide and metal, and oxide growth are considered, numerical simulations are performed for a cylindrical geometry to evaluate the stress distribution in boiler tubes. The simulation results reveal that: (1) the local radial stress at curved oxide–metal interfaces is enhanced by interface roughness with implications about interfacial crack growth; (2) contrary to the general belief that creep relieves the oxide stresses, creep may actually increase the stresses in the oxide due to different creep rates of the oxide and substrate metal; and (3) the geometrically induced oxide growth strain substantially increases the magnitudes of the hoop and axial stresses in the oxide. Based on the assumption that the failure of the oxide scales is caused by crack growth which is dominated by the stress intensity factor, damage maps are plotted directly using the hoop, axial, and radial stresses as the critical variables. Our work provides a quantitative understanding of the interactions between different thermomechanochemical processes and oxide scale failure in boiler tubes. [ABSTRACT FROM AUTHOR]

The fault diagnosis and fault-tolerant control of electric heating distributed control system are improved by the thermal performance analysis of rooms. The given values are tracked to meet the heating requirements, and the reliability of heating is increased without increasing hardware resources, which improves the reliability and economy of electric heating. From the perspective of energy conservation of electric heating for buildings and rooms, a predictive control model based on loadside three-phase power self-balance is proposed. A fault tolerance method for the electric heating distributed control system control system heating is designed. The load-side three-phase power self-balancing method of the electric heating control system is implemented by using the advantages of the Internet of Things and the heat storage performance of a room, which is its characteristics. Simulation results show that the performance of predictive control for non-minimum phase process is significantly better than that of conventional proportion integral differential control. For complex control problems, predictive control technology can provide better control performance than proportion integral differential control technology. Without increasing any hardware resources, reliable and economical heating is achieved through software. [ABSTRACT FROM AUTHOR]

A carbon dots-embedded epitope imprinted polymer (C-MIP) was fabricated for targeted fluorescence imaging of cervical cancer by specifically recognizing the epidermal growth factor receptor (EGFR). The core-shell C-MIP was prepared by a reverse microemulsion polymerization method. This method used silica nanoparticles embedded with carbon dots as carriers, acrylamide as the main functional monomer, and N-terminal nonapeptides of EGFR modified by palmitic acid as templates. A series of characterizations (transmission electron microscope, dynamic light scattering, X-ray photoelectron spectroscopy, Fourier transform infrared spectroscopy, zeta potential, and energy dispersive X-ray spectroscopy) prove the successful synthesis of C-MIP. The fluorescence of C-MIP is quenched by the epitopes of EGFR due to the specific recognition of epitopes of EGFR through their imprinted cavities (analytical excitation/emission wavelengths, 540 nm/610 nm). The linear range of fluorescence quenching is 2.0 to 15.0 μg mL−1 and the determination limit is 0.73 μg mL−1. The targeted imaging capabilities of C-MIP are demonstrated through in vitro and in vivo experiments. The laser confocal imaging results indicate that HeLa cells (over-expression EGFR) incubated with C-MIP show stronger fluorescence than that of MCF-7 cells (low-expression EGFR), revealing that C-MIP can target tumor cells overexpressing EGFR. The results of imaging experiments in tumor-bearing mice exhibit that C-MIP has a better imaging effect than C-NIP, which further proves the targeted imaging ability of C-MIP in vivo. [ABSTRACT FROM AUTHOR]

This study aims to examine the frictional behavior of staple carbon fiber composites (sCFCs). The staple carbon fiber reinforced polycarbonate (PC) composites were prepared by film stacking for two different impregnation levels. Mechanical properties such as tensile and flexural strengths and moduli and static/dynamic friction coefficient (COF) were determined. The COF and temperature as a function of wearing cycles for sCFCs subjected to different applied pressures were also determined by a disk-on-disk sliding wear test machine. The less impregnated sample exhibited superior tribological performance owing to its rough surface and low frictional heat generation. [ABSTRACT FROM AUTHOR]

Autophagy is a major intracellular degradation system that derives its degradative abilities from the lysosome. The most well-studied form of autophagy is macroautophagy, which delivers cytoplasmic material to lysosomes via the double-membraned autophagosome. Other forms of autophagy, namely chaperone-mediated autophagy and microautophagy, occur directly on the lysosome. Besides providing the means for degradation, lysosomes are also involved in autophagy regulation and can become substrates of autophagy when damaged. During autophagy, they exhibit notable changes, including increased acidification, enhanced enzymatic activity, and perinuclear localization. Despite their importance to autophagy, details on autophagy-specific regulation of lysosomes remain relatively scarce. This review aims to provide a summary of current understanding on the behaviour of lysosomes during autophagy and outline unexplored areas of autophagy-specific lysosome research. [ABSTRACT FROM AUTHOR]

Monitoring mammalian macroautophagic/autophagic flux is necessary in most autophagy studies but has generally been difficult to do. Here, we discuss our recent report of a HaloTag-based processing method that offers a straightforward readout for autophagic flux. We found that the self-labeling protein HaloTag becomes resistant to proteolysis when labeled with its ligand. Fusing HaloTag to an autophagy protein such as LC3 results in a reporter that is completely degraded when delivered into lysosomes but, when pulse-labeled with HaloTag ligand, releases free HaloTagligand when processed by lysosomal enzymes. The quantifiable amount of free HaloTagligand, observed by immunoblotting or in-gel fluorescence detection, reflects autophagic flux. Besides being compatible with fluorescence microscopy and flow cytometry applications, this quantitative assay can be readily adapted to monitor most autophagy pathways or the autophagic degradation of a protein of interest. [ABSTRACT FROM AUTHOR]

Background: Augmented renal clearance (ARC) is common in critically ill patients and could result in subtherapeutic antibiotic concentration. However, data in the Asian population are still lacking. The aim of this study was to explore the incidence and risk factors of ARC and its effect on β-lactam pharmacokinetics/pharmacodynamics (PK/PD) in Asian populations admitted to a medical ICU. In addition, we evaluated the appropriateness of using three estimated glomerular filtration (eGFR) formulas [Cockcroft–Gault (CG), Modification of Diet in Renal Disease (MDRD), and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)] as screening tools. Methods: We measured 2-, 8-, and 24-hr creatinine clearance (CLCr) and calculated eGFR by using three formulas for each. ARC was defined as CLCr24hr >130 mL/min/1.73 m2. Concentrations at the mid-dosing interval and prior to the next dose were collected if patients received the β-lactam antibiotic of piperacillin/tazobactam, cefepime, and meropenem, to determine the PK/PD index of fT > MIC. Multiple logistic regression analysis was conducted to identify the risk factors for ARC. Pearson correlation coefficient and the Bland and Altman method were applied to assess the accuracy of CLCr2hr, CLCr8hr, and eGFR for predicting ARC. Results: Of 100 patients, 46 (46%) manifested ARC. Younger age (<50 years) and lower Sequential Organ Failure Assessment score increased the likelihood of ARC. ARC resulted in a low chance of achieving 50% fT >4MIC (33% vs 75%, p<0.01), 100% fT > MIC (23% vs 69%, p<0.01), and 100% fT >4MIC (3% vs 25%, p<0.02). CLCr8hr wielded the best correlation and agreement with CLCr24hr. eGFRCG was the most appropriate screening tool, and the optimal cutoff value for detecting ARC was 130.5 mL/min/1.73 m2. Conclusion: ARC is associated with inadequate β-lactam PK/PD target in Asian ICU. [ABSTRACT FROM AUTHOR]

For the hypersonic inlet and fore-body integrated design, the non-uniform incoming flow generated by the fore-body will bring a relatively big challenge to the inward-turning inlet design. To make the inlet match the non-uniform incoming flow, this paper, based on previous studies, develops a cross-stream marching plus (CSMP) method, by which an aerodynamic surface used to generate a given shock shape can be acquired. The method can correct such solution points as may give rise to grid distortions or flow-field abnormity and overcome the shortcoming of the insufficient stability of previous methods. Numerical simulation results of the conical supersonic flowfield show that the error obtained from the proposed CSMP method drops with the reduction of the grid dimension and the marching step, being less than 0.05% for reducing the marching step to 10%; that with this method the maximum relative error of the pressure on the profile is less than 0.23%. In the design process of the inward-turning inlets that match the fuselage fore-body, it's found that in comparison with the results of the inviscid CFD results, the aerodynamic surface designed with the CSMP method can fully generate the given shock wave shape. Thus, the CSMP method provides a new direction for the inlet/fore-body integrated design. [ABSTRACT FROM AUTHOR]

Objectives: The objective of this paper was to explore the effects of Radix isatidis polysaccharide (RIP) extracted from Radix isatis on alleviating insulin resistance. Methods: The insulin resistance models of 3T3‐L1 preadipocytes and type 2 diabetic rats were established to evaluate the insulin resistance activity of RIP. Key findings: Radix isatidis polysaccharide within the concentration range of 25–100 μg/ml could reduce cell supernatant glucose and TNF‐α levels (P < 0.01) and increase the expression of PI‐3K P85, Glut4, IRS‐1 and Akt protein in symptoms of IR 3T3‐L1 preadipocytes. In the meantime, RIP contributed to relieve the weight loss of diabetic rats whose liver weight and liver index were decreased due to the effects of RIP. Experiments in rats also showed that RIP had capacity in reduced serum TC, TG, LDL‐C, FFA, FBG, FINS, MDA, ALT, AST activities and increased serum HDL‐C, SOD, ISI (P < 0.05 or 0.01). In addition, the oral glucose tolerance in rats was improved (P < 0.05) and liver damage was restored due to RIP. Conclusions: Radix isatidis polysaccharide significantly alleviates insulin resistance in 3T3‐L1 preadipocytes and type 2 diabetic rats. These beneficial effects of RIP may associate with their roles in improving the glucose metabolism, lipid metabolism and oxidative stress. [ABSTRACT FROM AUTHOR]

At present, multimodal probes for fluorescence and magnetic resonance imaging based on gadolinium-silicon hybrid nanoparticles have been reported. However, the existing preparations for these nanoparticles usually involve multi-step complicated processes and harsh conditions. Herein, to avoid complex procedures, we conveniently adopted a one-pot hydrothermal method to synthesize gadolinium (Gd)-doped silicon nanoparticles (D-SiGdNPs) using gadolinium chloride and diethylenetriaminepentaacetic acid (DTPA) as dopants. This is the first report on the synthesis of Gd-doped silicon nanoparticles. The D-SiGdNPs presented bright fluorescence (QY: 38%), good stability, and low biotoxicity. In particular, due to the dopants, the nanoparticles exhibited higher longitudinal relaxivity than the commercial contrast agent (Gd–DTPA) and obvious excitation-dependent photoluminescence whose emission wavelength ranged from 467 nm to 557 nm under serial excitation from 400 to 510 nm; thus, these NPs could be used for magnetic resonance imaging (MRI) and anti-counterfeiting stain applications. Moreover, the successful application of D-SiGdNPs, such as in the T1-weight MRI of mice and cellular fluorescence imaging, proves that the D-SiGdNPs have the potential to become an efficient dual-modal nanoprobe for multicolor fluorescence and magnetic resonance imaging in the future. [ABSTRACT FROM AUTHOR]

In this paper we study inverse problems where observations are corrupted by uniform noise. By using maximum a posteriori approach, an L∞-norm constrained minimization problem can be formulated for uniform noise removal. The main difficulty of solving such minimization problem is how to deal with non-differentiability of the L∞-norm constraint and how to estimate the level of uniform noise. The main contribution of this paper is to develop an efficient semi-smooth Newton method for solving this minimization problem. Here the L∞-norm constraint can be handled by active set constraints arising from the optimality conditions. In the proposed method, linear systems based on active set constraints are required to solve in each Newton step. We also employ the method of moments (MoM) to estimate the level of uniform noise for the minimization problem. The combination of the proposed method and MoM is quite effective for solving inverse problems with uniform noise. Numerical examples are given to demonstrate that our proposed method outperforms the other testing methods. [ABSTRACT FROM AUTHOR]

Aldosterone plays a pivotal role in the pathogenesis of metabolic syndrome and cardiovascular disease; however, the underlying mechanisms have not been clarified. Chemerin has been characterized as an adipokine with crucial roles in obesity-associated disorders and cardiovascular homeostasis. The aim of the present study was to investigate the direct effects of aldosterone on chemerin expression and secretion in 3T3-L1 adipocytes and to identify the potential signalling pathways involved. Chemerin mRNA levels were measured using realtime PCR, whereas the levels of secreted chemerin in the culture media were determined using ELISA. Treatment with aldosterone induced time- and dose-dependent increases of chemerin gene expression and protein secretion, and effect that was mediated through the mineralocorticoid receptor. Signalling studies suggested that the NF-κB pathway is involved in aldosterone-induced chemerin expression. Taken together, our data demonstrate a direct interaction between aldosterone and chemerin in adipocytes, which may be an underlying mechanism linking aldosterone-associated metabolic abnormalities and cardiovascular disease. [ABSTRACT FROM AUTHOR]

The platelet-derived growth factor (PDFG) signaling pathway exerts persistent activation in response to a variety of stimuli and facilitates the progression of hepatic fibrosis. Since this pathway modulates a broad spectrum of cellular processes, including cell growth, differentiation, inflammation and carcinogenesis, it has emerged as a therapeutic target for hepatic fibrosis and liver-associated disorders. The present review exhibits the current knowledge of the role of the PDGF signaling pathway and its pathological profiles in hepatic fibrosis, and assesses the potential of inhibitors which have been investigated in the experimental hepatic fibrosis model, in addition to the clinical challenges associated with these inhibitors. [ABSTRACT FROM AUTHOR]