A micro-fragmented collagen gel as a cell-assembling platform for critical limb ischemia repair.

Critical limb ischemia (CLI) is a devastating disease characterized by the progressive blockage of blood vessels. Although the paracrine effect of growth factors in stem cell therapy made it a promising angiogenic therapy for CLI, poor cell survival in the harsh ischemic microenvironment limited its efficacy. Thus, an imperative need exists for a stem-cell delivery method that enhances cell survival. Here, a collagen microgel (CMG) cell-delivery scaffold (40 × 20 µm) was fabricated via micro-fragmentation from collagen-hyaluronic acid polyionic complex to improve transplantation efficiency. Culturing human adipose-derived stem cells (hASCs) with CMG enabled integrin receptors to interact with CMG to form injectable 3-dimensional constructs (CMG-hASCs) with a microporous microarchitecture and enhanced mass transfer. CMG-hASCs exhibited higher cell survival (p < 0.0001) and angiogenic potential in tube formation and aortic ring angiogenesis assays than cell aggregates. Injection of CMG-hASCs intramuscularly into CLI mice increased blood perfusion and limb salvage ratios by 40 % and 60 %, respectively, compared to cell aggregate-treated mice. Further immunofluorescent analysis revealed that transplanted CMG-hASCs have greater muscle regenerative and angiogenic potential, with enhanced cell survival than cell aggregates (p < 0.05). Collectively, we propose CMG as a cell-assembling platform and CMG-hASCs as promising therapeutics to treat CLI.

Leveraging the Fragment Molecular Orbital Method to Explore the PLK1 Kinase Binding Site and Polo-Box Domain for Potent Small-Molecule Drug Design.

Polo-like kinase 1 (PLK1) plays a pivotal role in cell division regulation and emerges as a promising therapeutic target for cancer treatment. Consequently, the development of small-molecule inhibitors targeting PLK1 has become a focal point in contemporary research. The adenosine triphosphate (ATP)-binding site and the polo-box domain in PLK1 present crucial interaction sites for these inhibitors, aiming to disrupt the protein's function. However, designing potent and selective small-molecule inhibitors can be challenging, requiring a deep understanding of protein-ligand interaction mechanisms at these binding sites. In this context, our study leverages the fragment molecular orbital (FMO) method to explore these site-specific interactions in depth. Using the FMO approach, we used the FMO method to elucidate the molecular mechanisms of small-molecule drugs binding to these sites to design PLK1 inhibitors that are both potent and selective. Our investigation further entailed a comparative analysis of various PLK1 inhibitors, each characterized by distinct structural attributes, helping us gain a better understanding of the relationship between molecular structure and biological activity. The FMO method was particularly effective in identifying key binding features and predicting binding modes for small-molecule ligands. Our research also highlighted specific "hot spot" residues that played a critical role in the selective and robust binding of PLK1. These findings provide valuable insights that can be used to design new and effective PLK1 inhibitors, which can have significant implications for developing anticancer therapeutics.

Characterization of Spheno-occipital Synchondrosis Fusion From Preadolescents to Young Adults Using Age and Cervical Vertebrae Maturation Index.

The purpose of this study was to characterize the spheno-occipital synchondrosis fusion (SOSF) from preadolescents to young adults. A total of 630 Korean subjects (308 men, 322 women; age range, 6-18 y) were divided into 26 groups according to sex and age. After 3-dimensional computed tomography (CT) images were reoriented using the Frankfort horizontal (FH) plane, mid-sagittal plane, and frontal plane via ON3D software (3DONS), the cervical vertebrae maturation index (CVMI) and SOSF stages were identified using 6-stage and 5-stage scoring systems, respectively. The distributions of stage in each group were statistically investigated. Women showed early appearance and a short range of onset (CVMI stage 2, SOSF stage 2), middle (CVMI stage 4, SOSF stage 3 and stage 4), and completion (CVMI stage 6, SOSF stage 5), indicating rapid skeletal maturation compared with men. In both males and females, there were strong positive correlations between age and CVMI stage (rs=0.902, rs=0.890), between age and SOSF stage (rs=0.887, rs=0.885), and between CVMI and SOSF stages (rs=0.955, rs=0.964) (all P<0.001). The mean ages at SOSF stage 3 and stage 4 (12.7~13.9 y in males and 11.0~12.5 y in females) could be used as indicators of the pubertal growth peak. Regression equations for SOSF stage (y), age (a), and CVMI stage (b) were as follows: y=1.355-(0.133×a)+(0.29007×b)+(0.041×a×b) for males (r2=0.9496); y=1.305-(0.158×a)+(0.455×b)+(0.036×a×b) for females (r2=0.9606). Ordinal logistic regression analyses with the proportional odds model showed that females had more advanced SOSF stages than males (odds ratio: 1.972; 95% CI: 1.063-3.658, P<0.05). Our findings may provide basic references for CVMI and SOSF from preadolescents to young adults.

Comprehensive Analysis of NKX3.2 in Liver Hepatocellular Carcinoma by Bigdata.

Background and Objectives: The gene NKX3.2 plays a role in determining cell fate during development, and mutations of NKX3.2 have been studied in relation to human skeletal diseases. However, due to the lack of studies on the link between NKX3.2 and cancer, we aimed to provide insights into NKX3.2 as a new prognostic biomarker for liver hepatocellular carcinoma (LIHC). Materials and Methods: The clinical significance of LIHC was investigated using open gene expression databases. We comprehensively analyzed NKX3.2 expression in LIHC using Gene Expression Profiling Interactive Analysis 2, Tumor Immune Estimation Resource (TIMER), and Kaplan-Meier plotter databases. Then, we investigated the association between NKX3.2 expression and tumor-infiltrating immune cells (TIICs). Results: NKX3.2 expression was higher in the primary tumor group compared to the normal group, and expression was higher in fibrolamellar carcinoma (FLC) compared to other subtypes. When the prognostic value of NKX3.2 was evaluated, highly expressed NKX3.2 significantly improved the overall survival and had an unfavorable prognosis. In addition, NKX3.2 expression was associated with immune cell infiltration. Patients with low gene expression and high macrophage expression had a poorer survival rate than those with low NKX3.2 and low macrophage expression (p = 0.0309). Conclusions: High NKX3.2 expression may induce poorer prognosis in LIHC. In addition, these findings can be used as basic data due to the lack of available related research. However, further in vivo studies are essential to gain a deeper understanding of the biological role of NKX3.2 in LIHC and its potential implications for cancer development and progression.

Examining the consistency of continuous affect annotations and psychophysiological measures in response to emotional videos.

Despite the growing necessity of understanding the dynamics of emotion by naturalistic stimuli, averaging time-locked responses seems insufficient to capture emotional experiences that change over time. Intersubject correlation (ISC) has been implemented to examine dynamic emotional experiences by quantifying the consistency of responses across individuals. While previous research has shown that enhanced psychophysiological ISC can capture dynamic emotional experiences in response to long-lasting videos that evoke dimensional emotions, it is not yet fully understood how psychophysiological consistency varies during videos that elicit distinct emotions, such as fear. In this study, we re-analyzed publicly available data consisting of continuous affect annotations and psychophysiological signals, namely heart rate (HR), electrodermal activity (EDA), electromyographic signals from zygomaticus major (EMG-z), and corrugator supercilii (EMG-c), in response to categorical emotional videos, namely amusing, boring, relaxing, and fearful. Results showed an overall increase in ISC in multiple measures during fearful videos, indicating that emotional experiences during fearful videos were reliably consistent across participants. The effect of amusing and boring videos on ISC revealed varying results depending on the measurements. In particular, larger ISC in valence rating, EDA, and EMG-z was found for amusing than boring videos, whereas larger ISC in HR and EMG-c was observed for boring than amusing movies. Lastly, decreased ISC for relaxing videos was observed across multiple measurements, showing inconsistent emotional experiences during relaxing videos. This study builds on previous research on physiological consistency during emotional experiences by examining how the consistency of continuous affect annotations and psychophysiological measures differs in response to videos that elicit distinct emotions.

Transformer-Based Molecular Generative Model for Antiviral Drug Design.

Since the Simplified Molecular Input Line Entry System (SMILES) is oriented to the atomic-level representation of molecules and is not friendly in terms of human readability and editable, however, IUPAC is the closest to natural language and is very friendly in terms of human-oriented readability and performing molecular editing, we can manipulate IUPAC to generate corresponding new molecules and produce programming-friendly molecular forms of SMILES. In addition, antiviral drug design, especially analogue-based drug design, is also more appropriate to edit and design directly from the functional group level of IUPAC than from the atomic level of SMILES, since designing analogues involves altering the R group only, which is closer to the knowledge-based molecular design of a chemist. Herein, we present a novel data-driven self-supervised pretraining generative model called "TransAntivirus" to make select-and-replace edits and convert organic molecules into the desired properties for design of antiviral candidate analogues. The results indicated that TransAntivirus is significantly superior to the control models in terms of novelty, validity, uniqueness, and diversity. TransAntivirus showed excellent performance in the design and optimization of nucleoside and non-nucleoside analogues by chemical space analysis and property prediction analysis. Furthermore, to validate the applicability of TransAntivirus in the design of antiviral drugs, we conducted two case studies on the design of nucleoside analogues and non-nucleoside analogues and screened four candidate lead compounds against anticoronavirus disease (COVID-19). Finally, we recommend this framework for accelerating antiviral drug discovery.

Functionally enhanced cell spheroids for stem cell therapy: Role of TIMP1 in the survival and therapeutic effectiveness of stem cell spheroids.

Stem cell therapy has emerged as a promising regenerative medicine strategy but is limited by poor cell survival, leading to low therapeutic outcomes. We developed cell spheroid therapeutics to overcome this limitation. We utilized solid-phase FGF2 to form functionally enhanced cell spheroid-adipose derived (FECS-Ad), a type of cell spheroid that preconditions cells with intrinsic hypoxia to increase the survival of transplanted cells. We demonstrated an increase in hypoxia-inducible factor 1-alpha (HIF-1α) levels in FECS-Ad, which led to the upregulation of tissue inhibitor of metalloproteinase 1 (TIMP1). TIMP1 enhanced the survival of FECS-Ad, presumably through the CD63/FAK/Akt/Bcl2 anti-apoptotic signaling pathway. Cell viability of transplanted FECS-Ad was reduced by TIMP1 knockdown in an in vitro collagen gel block and a mouse model of critical limb ischemia (CLI). TIMP1 knockdown in FECS-Ad inhibited angiogenesis and muscle regeneration induced by FECS-Ad transplanted into ischemic mouse tissue. Genetic overexpression of TIMP1 in FECS-Ad further promoted the survival and therapeutic efficacy of transplanted FECS-Ad. Collectively, we suggest that TIMP1 acts as a key survival factor to improve the survival of transplanted stem cell spheroids, which provides scientific evidence for enhanced therapeutic efficacy of stem cell spheroids, and FECS-Ad as a potential therapeutic agent to treat CLI. STATEMENT OF SIGNIFICANCE: We used FGF2-tethered substrate platform to form adipose-derived stem cell spheroids, as we named as functionally enhanced cell spheroid-adipose derived (FECS-Ad). In this paper, we showed that intrinsic hypoxia of spheroids upregulated expression of HIF-1α, which in turn upregulated expression of TIMP1. Our paper highlights TIMP1 as a key survival factor to improve survival of transplanted stem cell spheroids. We believe that our study has a very strong scientific impact as extending transplantation efficiency is essential for successful stem cell therapy.

Diminazene aceturate exacerbates renal fibrosis after unilateral ureteral obstruction in female mice.

BACKGROUND: Diminazene aceturate (DIZE), an angiotensin-converting enzyme 2 (ACE2) activator, exerts anti-inflammatory and antifibrotic effects in a variety of human chronic diseases. However, the role of DIZE in kidney fibrosis and the underlying mechanism remain unclear. Therefore, we investigated the effects of DIZE on the progression of renal fibrosis after unilateral ureteral obstruction (UUO), a well-established model of chronic kidney disease. METHODS: C57BL/6 female or male mice were subjected to right UUO. Mice received 15 mg/kg DIZE or vehicle (saline) daily. On the 7th day after UUO, kidneys were collected for analysis of renal fibrosis (α-smooth muscle actin, phosphorylated SMAD3, transforming growth factor (TGF)-ß, Masson's trichrome, and Sirius red staining), inflammation (macrophage infiltration, proinflammatory cytokines/ chemokines), apoptosis/necrotic cell death (TUNEL and periodic acid-Schiff staining), and ACE2 activity and messenger RNA (mRNA) expression. RESULTS: Treatment with DIZE exacerbated renal fibrosis by upregulating the profibrotic TGF-ß/SMAD3 pathway, proinflammatory cytokine/chemokines (interleukin [IL]-1ß, monocyte chemoattractant protein-1, IL-6, and macrophage inflammatory protein-2) levels, M2 macrophage accumulation (CD206, IL-4, IL-10, and CX3CL1), and apoptotic/necrotic cell death in the obstructed kidneys of female mice but not male mice. However, DIZE treatment had no effect on ACE2 activity or mRNA expression. CONCLUSION: DIZE exacerbates UUO-induced renal fibrosis by aggravating tubular damage, apoptosis, and inflammation through independent of angiotensin (1-7), angiotensin II levels, and ACE2 expression/activity, rather than protecting against renal fibrosis after UUO. DIZE also has powerful effects on recruiting macrophages, including the M2-polarized subtype, in female UUO mice.

Statistical control of structural networks with limited interventions to minimize cellular phenotypic diversity represented by point attractors.

The underlying genetic networks of cells give rise to diverse behaviors known as phenotypes. Control of this cellular phenotypic diversity (CPD) may reveal key targets that govern differentiation during development or drug resistance in cancer. This work establishes an approach to control CPD that encompasses practical constraints, including model limitations, the number of simultaneous control targets, which targets are viable for control, and the granularity of control. Cellular networks are often limited to the structure of interactions, due to the practical difficulty of modeling interaction dynamics. However, these dynamics are essential to CPD. In response, our statistical control approach infers the CPD directly from the structure of a network, by considering an ensemble average function over all possible Boolean dynamics for each node in the network. These ensemble average functions are combined with an acyclic form of the network to infer the number of point attractors. Our approach is applied to several known biological models and shown to outperform existing approaches. Statistical control of CPD offers a new avenue to contend with systemic processes such as differentiation and cancer, despite practical limitations in the field.

The flavonoid fisetin ameliorates renal fibrosis by inhibiting SMAD3 phosphorylation, oxidative damage, and inflammation in ureteral obstructed kidney in mice.

BACKGROUND: Renal fibrosis is characterized by the accumulation of extracellular matrix and inflammatory cells and kidney dysfunction, which is a major pathway in the progression of chronic kidney disease (CKD). Accumulating evidence indicates that oxidative stress plays a critical role in the initiation and progression of CKD via proinflammatory and profibrotic signaling pathways. Fisetin (3,3',4',7-tetrahydroxyflavone) has biological activities including antioxidant, anti-inflammatory, and anti-aging effects. Therefore, we evaluated the antifibrotic effects of fisetin on unilateral ureteral obstruction (UUO)-induced kidneys. METHODS: C57BL/6 female mice were subjected to right UUO and intraperitoneally injected every other day with fisetin (25 mg/kg/ day) or vehicle from 1 hour before surgery to 7 days after surgery. Kidney samples were analyzed for renal fibrosis (α-smooth muscle actin [α-SMA] expression, collagen deposition, and transforming growth factor [TGF] ß1/SMAD3 signaling pathway), oxidative damage (4-HNE and 8-OHdG expression), inflammation (proinflammatory cytokine/chemokine, macrophage, and neutrophil infiltration), and apoptosis (TUNEL staining). Cultured human proximal tubule cells were treated with fisetin before TGF-ß to confirm the TGF-ß downstream pathway (SMAD2/3 phosphorylation). RESULTS: We found that fisetin treatment protected against renal fibrosis by inhibiting the phosphorylation of SMAD3, oxidative damage, inflammation, apoptotic cell death, and accumulation of profibrotic M2 macrophages in the obstructed kidneys. In cultured human proximal tubular cells, fisetin treatment inhibited TGF-ß1-induced phosphorylation of SMAD3 and SMAD2. CONCLUSION: Fisetin alleviates kidney fibrosis to protect against UUO-induced renal fibrosis, and could be a novel therapeutic drug for obstructive nephropathy.

Oxypurinol protects renal ischemia/reperfusion injury via heme oxygenase-1 induction.

Renal ischemia/reperfusion (I/R) injury is a major cause of acute kidney injury (AKI) by increasing oxidative stress, inflammatory responses, and tubular cell death. Oxypurinol, an active metabolite of allopurinol, is a potent anti-inflammatory and antioxidant agent. To investigate the therapeutic potential and underlying mechanism of oxypurinol in ischemic AKI, C57BL/6 male mice were intraperitoneally injected with oxypurinol and subjected to renal I/R or sham surgery. We found that oxypurinol-treated mice had lower plasma creatinine and blood urea nitrogen levels and tubular damage (hematoxylin-and-eosin staining) compared to vehicle-treated mice after renal I/R injury. Furthermore, oxypurinol treatment reduced kidney inflammation (i.e., neutrophil infiltration and MIP-2 mRNA induction), oxidative stress (i.e., 4-HNE, heme oxygenase-1 [HO-1], 8-OHdG expression, and Catalase mRNA induction), and apoptosis (i.e., TUNEL or cleaved caspase-3-positive renal tubular cells), compared to vehicle-treated mice. Mechanistically, oxypurinol induced protein expressions of HO-1, which is a critical cytoprotective enzyme during ischemic AKI, and oxypurinol-mediated protection against ischemic AKI was completely eliminated by pretreatment with tin protoporphyrin IX, an HO-1 inhibitor. In conclusion, oxypurinol protects against renal I/R injury by reducing oxidative stress, inflammation, and apoptosis via HO-1 induction, suggesting its preventive potential in ischemic AKI.

Audiovisual integration in the human brain: a coordinate-based meta-analysis.

People can seamlessly integrate a vast array of information from what they see and hear in the noisy and uncertain world. However, the neural underpinnings of audiovisual integration continue to be a topic of debate. Using strict inclusion criteria, we performed an activation likelihood estimation meta-analysis on 121 neuroimaging experiments with a total of 2,092 participants. We found that audiovisual integration is linked with the coexistence of multiple integration sites, including early cortical, subcortical, and higher association areas. Although activity was consistently found within the superior temporal cortex, different portions of this cortical region were identified depending on the analytical contrast used, complexity of the stimuli, and modality within which attention was directed. The context-dependent neural activity related to audiovisual integration suggests a flexible rather than fixed neural pathway for audiovisual integration. Together, our findings highlight a flexible multiple pathways model for audiovisual integration, with superior temporal cortex as the central node in these neural assemblies.

Testing the bipolar assumption of Singer-Loomis Type Deployment Inventory for Korean adults using classification and multidimensional scaling.

In this study, we explored whether the Korean version of Singer Loomis Type Deployment Inventory II (K-SLTDI) captures the opposing tendencies of Jung's theory of psychological type. The types are Extroverted Sensing, Extroverted Intuition, Extroverted Feeling, Extroverted Thinking, Introverted Sensing, Introverted Intuition, Introverted Feeling, and Introverted Thinking. A nationwide online survey was conducted in South Korea. We performed multidimensional scaling and classification analyses based on 521 Korean adult profiles with eight psychological types to test the bipolarity assumption. The results showed that the Procrustes-rotated four-dimensional space successfully represented four types of opposing tendencies. Moreover, the bipolarity assumption in the four dimensions of Jungian typology was tested and compared between lower and higher psychological distress populations via cluster analysis. Lastly, we explored patterns of responses in lower and higher psychological distress populations using intersubject correlation. Both similarity analyses and classification results consistently support the theoretical considerations on the conceptualization of Jung's type in independent order that the types could be derived without bipolar assumption as Singer and Loomis expected in their Type Development Inventory. Limitations in our study include the sample being randomly selected internet users during the COVID-19 pandemic, despite excellence in the use of the internet in the general Korean population.

The value of CDC42 effector protein 2 as a novel prognostic biomarker in liver hepatocellular carcinoma: a comprehensive data analysis.

BACKGROUND: The prognostic significance of CDC42 effector protein 2 (CDC42EP2) and its association with tumor-infiltrating immune cells (TIICs) have not been explored in liver hepatocellular carcinoma (LIHC). This study aims to assess the potential prognostic value of CDC42EP2 by conducting a comprehensive analysis of online databases pertaining to LIHC. METHODS: We evaluated the potential of CDC42EP2 as a prognostic biomarker by utilizing online databases such as TIMER, GEPIA2, KM, OSlihc, HPA, and LinkedOmics. RESULTS: In LIHC, we observed that the mRNA and protein expression of CDC42EP2 were upregulated compared to normal tissues. Upregulated CDC42EP2 expression was associated with a worse prognosis based on the clinicopathological characteristics of patients with LIHC. Furthermore, CDC42EP2 was positively associated with TIICs. In the co-expression and functional enrichment analyses of CDC42EP2, 11,416 genes showed positive associations with CDC42EP2 while 8,008 genes showed negative associations. CDC42EP2-related co-expression genes were involved in protein localization to the endoplasmic reticulum, translational initiation, and RNA catabolic processes in gene set enrichment analysis-Gene Ontology (GSEAGO), and regulated the ribosome, spliceosome, and primary immune deficiency in the GSEAKyoto Encyclopedia of Genes and Genomes (KEGG) pathway. In a survival map, 23 and 17 genes that exhibited positive associations with CDC42EP2 showed a significant hazard ratio (HR) for overall survival and disease-free survival, respectively. CONCLUSION: Our findings demonstrated that CDC42EP2 is a novel prognostic biomarker and a potential tumor immune therapeutic target in patients with LIHC.

Clinical Characteristics of TZAP (ZBTB48) in Hepatocellular Carcinomas from Tissue, Cell Line, and TCGA.

Background and Objectives: ZBTB48 is a telomere-related protein that has been renamed telomeric zinc finger-associated protein (TZAP). It favorably binds to elongated telomeres to regulate their appropriate length. However, TZAP expression has not been investigated in hepatocellular carcinomas (HCC). Materials and Methods: The clinical significance of TZAP expression in 72 HCC was investigated. Additionally, its findings were supported by open big data and cancer cell lines. Results: TZAP expression level was not associated with the clinical parameters of HCC. TZAP expression induced a poorer survival result (overall survival, p = 0.020; disease-free survival, p = 0.012). TCGA data showed TZAP expression was more frequently found in HCCs with hepatitis C infection (p = 0.023). However, TCGA data revealed that TZAP expression did not predict HCC prognosis. In a cell line study, TZAP inhibition via siRNA suppressed PLC/PRF/5 cell growth; however, cell viability was increased in HepG2 cells. Conclusions: We presented the clinical and prognostic values of TZAP expression in HCC tissues and cancer cell lines. Additionally, the TCGA results also revealed a significant role for TZAP expression. TZAP expression may involve HCC progression and its prognosis.

PRBS orders required to train ANN equalizer for PAM signal without overfitting.

Artificial neural network (ANN)-based nonlinear equalizers (NLEs) have been gaining popularity as powerful waveform equalizers for intensity-modulation (IM)/direct-detection (DD) systems. On the other hand, the M-ary pulse amplitude modulation (PAM-M) format is now widely used for high-speed IM/DD systems. For the training of ANN-NLE in PAM-M IM/DD systems, it is common to employ pseudorandom binary sequences (PRBSs) for the generation of PAM-M training sequences. However, when the PRBS orders used for training are not sufficiently high, the ANN-NLE might suffer from the overfitting problem, where the equalizer can estimate one or more of the constituent PRBSs from a part of PAM-M training sequence, and as a result, the trained ANN-NLE shows poor performance for new input sequences. In this paper, we provide a selection guideline of the PRBSs to train the ANN-NLE for PAM-M signals without experiencing the overfitting. For this purpose, we determine the minimum PRBS orders required to train the ANN-NLE for a given input size of the equalizer. Our theoretical analysis is confirmed through computer simulation. The selection guideline is applicable to training the ANN-NLE for the PAM-M signals, regardless of symbol coding.

Diminazene aceturate attenuates hepatic ischemia/reperfusion injury in mice.

Hepatic ischemia/reperfusion (I/R) injury is one of the leading causes of mortality following partial hepatectomy, liver transplantation, hypovolemic shock and trauma; however, effective therapeutic targets for the treatment of hepatic I/R injury are lacking. Recent studies have shown that diminazene aceturate (DIZE) has protective effects against inflammation, oxidative stress and cell death, which are the main pathogenetic mechanisms associated with hepatic I/R injury. However, the mechanistic effects DIZE exerts on hepatic I/R remain unknown. C57BL/6 male mice were pretreated with either 15 mg/kg DIZE or vehicle control (saline) and subjected to partial liver ischemia for 60 min. One day after induction of hepatic I/R, liver damage, inflammatory responses, oxidative stress and apoptosis were analyzed. By evaluating plasma alanine aminotransferase levels and histology, we found that DIZE treatment attenuated liver failure and was associated with a reduction in histologically-apparent liver damage. We also found that DIZE-treated mice had milder inflammatory responses, less reactive oxidative damage and less apoptosis following hepatic I/R compared to vehicle-treated mice. Taken together, our study demonstrates that DIZE protects against ischemic liver injury by attenuating inflammation and oxidative damage and may be a potential therapeutic agent for the prevention and treatment of ischemic liver failure.

Zinc Finger E-Box Binding Homeobox 2 as a Prognostic Biomarker in Various Cancers and Its Correlation with Infiltrating Immune Cells in Ovarian Cancer.

This study investigated the expression of zinc finger E-box binding homeobox 2 (ZEB2), its prognostic significance in various cancers, and the correlation between ZEB2 and infiltrating immune cells and ZEB2-related proteins in ovarian cancer (OV). The Gene Expression Profiling Interactive Analysis tool was used to analyze RNA sequencing data and cancer survival rates, based on normal and tumor tissue data available in The Cancer Genome Atlas (TCGA) database. The Kaplan-Meier plotter and PrognoScan databases were used to analyze the prognostic value of ZEB2 in OV (n = 1144). The Tumor Immune Estimation Resource was used to investigate the correlation between ZEB2 and infiltrating immune cells in various cancers, including OV. High ZEB2 expression was associated with a poorer prognosis in OV. In OV, ZEB2 is positively correlated with CD8+T cells, neutrophils, macrophages, and dendritic cell invasion; and ZEB2 is negatively correlated with tumor-infiltrating B cells. The STRING database was used to investigate the correlations with ZEB2-related proteins. The results reveal that ZEB2 was positively correlated with SMAD1 and SMAD2 in OV. Our findings may serve as a potential prognostic biomarker, and provide novel insights into the tumor immunology in OV. Thus, ZEB2 may be a potential diagnostic and therapeutic target in OV.

Distributed and Multifaceted Effects of Threat and Safety.

In the present fMRI study, we examined how anxious apprehension is processed in the human brain. A central goal of the study was to test the prediction that a subset of brain regions would exhibit sustained response profiles during threat periods, including the anterior insula, a region implicated in anxiety disorders. A second important goal was to evaluate the responses in the amygdala and the bed nucleus of the stria terminals, regions that have been suggested to be involved in more transient and sustained threat, respectively. A total of 109 participants performed an experiment in which they encountered "threat" or "safe" trials lasting approximately 16 sec. During the former, they experienced zero to three highly unpleasant electrical stimulations, whereas in the latter, they experienced zero to three benign electrical stimulations (not perceived as unpleasant). The timing of the stimulation during trials was randomized, and as some trials contained no stimulation, stimulation delivery was uncertain. We contrasted responses during threat and safe trials that did not contain electrical stimulation, but only the potential that unpleasant (threat) or benign (safe) stimulation could occur. We employed Bayesian multilevel analysis to contrast responses to threat and safe trials in 85 brain regions implicated in threat processing. Our results revealed that the effect of anxious apprehension is distributed across the brain and that the temporal evolution of the responses is quite varied, including more transient and more sustained profiles, as well as signal increases and decreases with threat.

Trophoblast glycoprotein is a new candidate gene for Parkinson's disease.

Parkinson's disease (PD) is a movement disorder caused by progressive degeneration of the midbrain dopaminergic (mDA) neurons in the substantia nigra pars compacta (SNc). Despite intense research efforts over the past decades, the etiology of PD remains largely unknown. Here, we discovered the involvement of trophoblast glycoprotein (Tpbg) in the development of PD-like phenotypes in mice. Tpbg expression was detected in the ventral midbrain during embryonic development and in mDA neurons in adulthood. Genetic ablation of Tpbg resulted in mild degeneration of mDA neurons in aged mice (12-14 months) with behavioral deficits reminiscent of PD symptoms. Through in silico analysis, we predicted potential TPBG-interacting partners whose functions were relevant to PD pathogenesis; this result was substantiated by transcriptomic analysis of the SNc of aged Tpbg knockout mice. These findings suggest that Tpbg is a new candidate gene associated with PD and provide a new insight into PD pathogenesis.