Search

BackgroundThe emergence and spread of multidrug-resistant Staphylococcus aureus strains demonstrates the urgent need for new antimicrobials. Xanthorrhizol, a plant-derived sesquiterpenoid compound, has a rapid killing effect on methicillin-susceptible strains and methicillin-resistant strains of S. aureus achieving the complete killing of staphylococcal cells within 2 min using 64 μg/mL xanthorrhizol. However, the mechanism of its action is not yet fully understood.MethodsThe S. aureus cells treated with xanthorrhizol were studied using optical diffraction tomography. Activity of xanthorrhizol against the wild-type and mscL null mutant of S. aureus ATCC 29213 strain was evaluated in the time-kill assay. Molecular docking was conducted to predict the binding of xanthorrhizol to the SaMscL protein.ResultsXanthorrhizol treatment of S. aureus cells revealed a decrease in cell volume, dry weight, and refractive index (RI), indicating efflux of the cell cytoplasm, which is consistent with the spontaneous activation of the mechanosensitive MscL channel. S. aureus ATCC 29213ΔmscL was significantly more resistant to xanthorrhizol than was the wild-type strain. Xanthorrhizol had an enhanced inhibitory effect on the growth and viability of exponentially growing S. aureus ATCC 29213ΔmscL cells overexpressing the SaMscL protein and led to a noticeable decrease in their viability in the stationary growth phase. The amino acid residues F5, V14, M23, A79, and V84 were predicted to be the residues of the binding pocket for xanthorrhizol. We also showed that xanthorrhizol increased the efflux of solutes such as K+ and glutamate from S. aureus ATCC 29213ΔmscL cells overexpressing SaMscL. Xanthorrhizol enhanced the antibacterial activity of the antibiotic dihydrostreptomycin, which targets the MscL protein.ConclusionOur findings indicate that xanthorrhizol targets the SaMscL protein in S. aureus cells and may have important implications for the development of a safe antimicrobial agent.

Objectives 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 (GSEA-GO), and regulated the ribosome, spliceosome, and primary immune deficiency in the GSEA-Kyoto 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.

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.

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] β1/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-β to confirm the TGF-β 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-β1–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.

Abstract 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.

Background and objectives: Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide and is caused by multiple factors. To explore novel targets for HCC treatment, we comprehensively analyzed the expression of HomeoboxB13 (HOXB13) and its role in HCC. Materials and Methods: The clinical significance of HCC was investigated using open gene expression databases, such as TIMER, UALCAN, KM, OSlihc, and LinkedOmics, and immunohistochemistry analysis. We also analyzed cell invasion and migration in HCC cell lines transfected with HOXB13-siRNA and their association with MMP9, E2F1, and MEIS1. Results: HOXB13 expression was higher in fibrolamellar carcinoma than in other histological subtypes. Its expression was associated with lymph node metastasis, histological stage, and tumor grade. It was positively correlated with immune cell infiltration of B cells (R = 0.246), macrophages (R = 0.182), myeloid dendritic cells (R = 0.247), neutrophils (R = 0.117), and CD4+ T cells (R = 0.258) and negatively correlated with immune cell infiltration of CD8+ T cells (R = −0.107). A positive correlation was observed between HOXB13, MMP9 (R = 0.176), E2F1 (R = 0.241), and MEIS1 (R = 0.189) expression (p < 0.001). The expression level of HOXB13 was significantly downregulated in both HepG2 and PLC/PFR/5 cell lines transfected with HOXB13-siRNA compared to that in cells transfected with NC siRNA (p < 0.05). Additionally, HOXB13 significantly affected cell viability and wound healing. Conclusions: HOXB13 overexpression may lead to poor prognosis in patients with HCC. Additional in vivo studies are required to improve our understanding of the biological role and the exact mechanism of action of HOXB13 in HCC.

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)-β, 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-β/SMAD3 pathway, proinflammatory cytokine/chemokines (interleukin [IL]-1β, 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.

Abstract 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.

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.

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.

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.

Abstract 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.

Objectives The aims of this study were to investigate the expression of Yes-associated protein 1 (YAP1), its prognostic significance, and the correlation between YAP1 and telomerase in various cancers. Methods The Gene Expression Profiling Interactive Analysis database was used to analyze RNA sequencing data and the survival rate of patients with various cancers in The Cancer Genome Atlas (TCGA) database. PrognoScan was used to analyze the prognostic value of YAP1 expression in various cancers. Tumor Immune Estimation Resource was used to determine the correlation between YAP1 expression and telomerase in various cancer types based on TCGA data. Results The analysis suggested that YAP1 was differentially expressed between tissues of various cancers and non-tumor tissues. High YAP1 expression was also related to a poor prognosis in adrenocortical carcinoma, bladder urothelial carcinoma, and pancreatic adenocarcinoma. Moreover, YAP1 expression was correlated with the expression of telomerase reverse transcriptase and telomerase RNA component in various cancer types. Conclusion These results suggest that YAP1 is a potential biomarker with prognostic significance and relevance for oncogene research in various cancer types. The correlation between the expression of YAP1 and telomere-associated genes will help to understand their cancer-promoting mechanisms and interactions.

Despite recent developments in deep learning and their success in computer vision, model efficiency is increasingly becoming a vital factor for their deployment in various real-world applications. To provide a more effective form of computational capabilities, bio-inspired spiking neural networks (SNNs) have attracted considerable interest in recent years. SNNs are known as the third-generation of neural networks, which mimic how information is transmitted and processed in the human brain. SNNs enable sparse yet efficient information transmission through spike trains, leading to exceptional computational and energy efficiency. Nevertheless, critical challenges in SNNs to date are two-fold: (a) latency: the number of time steps required to achieve competitive results and (b) synaptic operations: the total number of spikes generated during inference. Many researchers have attempted to address these challenges, but their applications have been mainly limited to image classification. In this work, we present a threshold voltage balancing method for object detection in SNNs, which utilizes Bayesian optimization to find optimal threshold voltages in SNNs. We specifically design Bayesian optimization to consider important characteristics of SNNs such as latency and number of synaptic operations. Furthermore, we introduce two-phase threshold voltages to provide faster and more accurate object detection while providing high energy efficiency. According to experimental results, the proposed methods achieve the state-of-the-art object detection accuracy in SNNs, and converge 2x and 1.85x faster than conventional methods on PASCAL VOC and MS COCO, respectively. Moreover, the total number of synaptic operations is reduced by 40.33% and 45.31% on PASCAL VOC and MS COCO, respectively.

The artificial neural network (ANN) has been applied to the various fields due to its capability to process complicated nonlinear functions involving a large amount of data. A pseudorandom binary sequence (PRBS) is commonly used to train the ANN since the PRBS is easily generated by using a linear feedback shift register and has a correlation function which is peaked at zero delay but is almost zero at other delays. However, when the PRBS length is not sufficiently long (compared to the input size of the ANN), the ANN trained by the PRBS could suffer from the overfitting where the ANN describes the behavior of the training sequence very well, but does poorly on new data inputs. In this paper, we provide a minimum length of the PRBS required by the ANN to avoid the overfitting for a given input size of the ANN. For this purpose, we analyze the minimum length of the input sequence required to estimate the PRBS pattern through theoretical study. These analyses are confirmed by numerical simulation. The findings of this paper would be used to select the PRBS length for training the ANN.

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.

Summary: Hemophilia A (HA) is caused by genetic mutations in the blood coagulation factor VIII (FVIII) gene. Genome-editing approaches can be used to target the mutated site itself in patient-derived induced pluripotent stem cells (iPSCs). However, these approaches can be hampered by difficulty in preparing thousands of editing platforms for each corresponding variant found in HA patients. Here, we report a universal approach to correct the various mutations in HA patient iPSCs by the targeted insertion of the FVIII gene into the human H11 site via CRISPR/Cas9. We derived corrected clones from two types of patient iPSCs with frequencies of up to 64% and 66%, respectively, without detectable unwanted off-target mutations. Moreover, we demonstrated that endothelial cells differentiated from the corrected iPSCs successfully secreted functional protein. This strategy may provide a universal therapeutic method for correcting all genetic variants found in HA patients. : Hemophilia A (HA) is caused by various genetic mutations within the blood coagulation factor VIII (FVIII) gene. In this article, Kim and colleagues attempt the targeted insertion of the FVIII gene into the human H11 site in two types of HA patient iPSCs. This approach may offer a universal therapeutic method for correcting all genetic variants found in HA patients. Keywords: genome editing, H11 locus, CRISPR/Cas9, hemophilia, iPSCs

X-linked inhibitor of apoptosis protein (XIAP) is an important regulator of cancer cell survival whose BIR3 domain (XIAP-BIR3) recognizes the Smac N-terminal tetrapeptide sequence (AVPI), making it an attractive protein-protein interaction (PPI) target for cancer therapies. We used the fragment molecular orbital (FMO) method to study the binding modes and affinities between XIAP-BIR3 and a series of its inhibitors (1–8) that mimic the AVPI binding motif; the inhibitors had common interactions with key residues in a hot spot region of XIAP-BIR3 (P1–P4 subpockets) with increased binding affinity mainly attributed to specific interactions with the P1 and P4 subpockets. Based on the structural information from FMO results, we proposed a novel XIAP natural product inhibitor, neoeriocitrin 10, which was derived from our preciously reported XIAP-BIR3 inhibitor 9, can be used as a highly potent candidate for XIAP-BIR3 inhibition. We also performed pair interaction energy decomposition analysis to investigate the binding energies between specific binding residues and individual ligands, showing that the novel natural product neoeriocitrin 10 had a higher binding affinity than epicatechin gallate 9. Molecular docking and dynamics simulations were performed to explore the mode of binding between 10 and XIAP-BIR3, demonstrating that 10 binds more strongly to the P1 and P4 pockets than 9. Overall, we present a novel natural product, neoeriocitrin 10, and demonstrate that the FMO method can be used to identify hot spots in PPIs and design new compounds for XIAP inhibition. Keywords: Protein-protein interaction, Natural product, X-linked inhibitor of apoptosis protein, XIAP-BIR3 inhibitor, Molecular docking, MD simulation, Fragment molecular orbital method, Drug discovery

Hemophilia A is an ideal target for cell or gene therapy because a mild increase in coagulation factor VIII (FVIII) improves symptoms in patients with severe hemophilia A. In this study, we used CRISPR/Cas9 to insert FVIII cDNA into exon 1 of the mutant FVIII locus in induced pluripotent stem cells (iPSCs) from a hemophilia A patient. This gene-modified YCMi001-B-1 line maintained its pluripotency, formed all three germ layers, and had a normal karyotype. In addition, FVIII expression was confirmed in YCMi001-B-1-derived endothelial cells.

A growing literature supports the existence of interactions between emotion and action in the brain, and the central participation of the anterior midcingulate cortex (aMCC) in this regard. In the present functional magnetic resonance imaging study, we sought to investigate the role of self-relevance during such interactions by varying the context in which threating pictures were presented (with guns pointed towards or away from the observer). Participants performed a simple visual detection task following exposure to such stimuli. Except for voxelwise tests, we adopted a Bayesian analysis framework which evaluated evidence for the hypotheses of interest, given the data, in a continuous fashion. Behaviorally, our results demonstrated a valence by context interaction such that there was a tendency of speeding up responses to targets after viewing threat pictures directed towards the participant. In the brain, interaction patterns that paralleled those observed behaviorally were observed most notably in the middle temporal gyrus, supplementary motor area, precentral gyrus, and anterior insula. In these regions, activity was overall greater during threat conditions relative to neutral ones, and this effect was enhanced in the directed towards context. A valence by context interaction was observed in the aMCC too, where we also observed a correlation (across participants) of evoked responses and reaction time data. Taken together, our study revealed the context-sensitive engagement of motor-related areas during emotional perception, thus supporting the idea that emotion and action interact in important ways in the brain.

Increased endoplasmic reticulum (ER) stress is known to be one of the causes of hypothalamic neuronal damage, as well as a cause of metabolic disorders such as obesity and diabetes. Recent evidence has suggested that Undaria pinnatifida (UP), an edible brown algae, has antioxidant activity. However, the neuroprotective effect of UP has yet to be examined. In this study, to investigate the neuroprotective effect of UP on ER stress-induced neuronal damage in mouse hypothalamic neurons, mice immortal hypothalamic neurons (GT1-7) were incubated with extract of UP. ER stress was induced by treating with tunicamycin. Tunicamycin induced apoptotic cell death was compared with the vehicle treatment through excessive ER stress. However UP protected GT1-7 cells from cell death, occurring after treatment with tunicamycin by reducing ER stress. Treatment with UP resulted in reduced increment of ATF6 and CHOP, and recovered the decrease of phosphorylation of Akt/mTOR by tunicamycin and the increment of autophagy. These results show that UP protects GT1-7 cells from ER stress induced cell death through the Akt/mTOR pathway. The current study suggests that UP may have a beneficial effect on cerebral neuronal degeneration in metabolic diseases with elevated ER stress.

Recent research has demonstrated that affective states elicited by viewing pictures varying in valence and arousal are identifiable from whole brain activation patterns observed with functional magnetic resonance imaging (fMRI). Identification of affective states from more naturalistic stimuli has clinical relevance, but the feasibility of identifying these states on an individual trial basis from fMRI data elicited by dynamic multimodal stimuli is unclear. The goal of this study was to determine whether affective states can be similarly identified when participants view dynamic naturalistic audiovisual stimuli. Eleven participants viewed 5s audiovisual clips in a passive viewing task in the scanner. Valence and arousal for individual trials were identified both within and across participants based on distributed patterns of activity in areas selectively responsive to audiovisual naturalistic stimuli while controlling for lower level features of the stimuli. In addition, the brain regions identified by searchlight analyses to represent valence and arousal were consistent with previously identified regions associated with emotion processing. These findings extend previous results on the distributed representation of affect to multimodal dynamic stimuli.

Background: The emergence and spread of multidrug-resistant Staphylococcus aureus strains demonstrates the urgent need for new antimicrobials. Xanthorrhizol, a plant-derived sesquiterpenoid compound, has a rapid killing effect on methicillin-susceptible strains and methicillin-resistant strains of S. aureus achieving the complete killing of staphylococcal cells within 2 min using 64 µg/mL xanthorrhizol. However, the mechanism of its action is not yet fully understood. Methods: The S. aureus cells treated with xanthorrhizol were studied using optical diffraction tomography. Activity of xanthorrhizol against the wild-type and mscL null mutant of S. aureus ATCC 29213 strain was evaluated in the time-kill assay. Molecular docking was conducted to predict the binding of xanthorrhizol to the SaMscL protein. Results: Xanthorrhizol treatment of S. aureus cells revealed a decrease in cell volume, dry weight, and refractive index (RI), indicating efflux of the cell cytoplasm, which is consistent with the spontaneous activation of the mechanosensitive MscL channel. S. aureus ATCC 29213mscL was significantly more resistant to xanthorrhizol than was the wild-type strain. Xanthorrhizol had an enhanced inhibitory effect on the growth and viability of exponentially growing S. aureus ATCC 29213mscL cells overexpressing the SaMscL protein and led to a noticeable decrease in their viability in the stationary growth phase. The amino acid residues F5, V14, M23, A79, and V84 were predicted to be the residues of the binding pocket for xanthorrhizol. We also showed that xanthorrhizol increased the efflux of solutes such as K+ and glutamate from S. aureus ATCC 29213mscL cells overexpressing SaMscL. Xanthorrhizol enhanced the antibacterial activity of the antibiotic dihydrostreptomycin, which targets the MscL protein. Conclusion: Our findings indicate that xanthorrhizol targets the SaMscL protein in S. aureus cells and may have important implications for the development of a safe antimicrobial agent. [ABSTRACT FROM AUTHOR]

Physiological responses have been regarded as better measures of arousal than valence of core affect dimensions. Recently, valence was explained by two valence hypotheses (bipolarity and bivalent), represented as signed and unsigned valence. In this paper, with reference to two valence models and an arousal dimension, we explored whether affective representations can be identified based on physiological responses across participants. By re-analyzing a shared dataset that includes physiological responses and behavioral ratings of affect, we performed a regression-based decoding to predict affective representations of participants based on their physiological responses. Additionally, a one-way repeated measures ANOVA with a trend analysis was conducted to compare the accuracies of two valence models and the arousal dimension. The results revealed that all predictions were significant, indicating that physiological responses can identify valence and arousal. A trend analysis showed that arousal was predicted more accurately than two valence models, suggesting that physiological responses capture arousal better than valence. [ABSTRACT FROM AUTHOR]