Prolactin receptor potentiates chemotherapy through miRNAs-induced G6PD/TKT inhibition in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies, with a notoriously dismal prognosis. As a competitive inhibitor of DNA synthesis, gemcitabine is the cornerstone drug for treating PDAC at all stages. The therapeutic effect of gemcitabine, however, is often hindered by drug resistance, and the underlying mechanisms remain largely unknown. It is unclear whether their response to chemotherapeutics is regulated by endocrine regulators, despite the association between PDAC risk and endocrine deregulation. Here, we show that prolactin receptor (PRLR) synergizes with gemcitabine in both in vitro and in vivo treatment of PDAC. Interestingly, PRLR promotes the expression of miR-4763-3p and miR-3663-5p, two novel miRNAs whose functions are unknown. Furthermore, the analysis of transcriptome sequencing data of tumors from lactating mouse models enriches the PPP pathway, a multifunctional metabolic pathway. In addition to providing energy, the PPP pathway mainly provides a variety of raw materials for anabolism. We demonstrate that two key enzymes of the pentose phosphate pathway (PPP), G6PD and TKT, are directly targeted by miR-4763-3p and miR-3663-5p. Notably, miR-4763-3p and miR-3663-5p diminish the nucleotide synthesis of the PPP pathway, thereby increasing gemcitabine sensitivity. As a result, PRLR harnesses these two miRNAs to suppress PPP and nucleotide synthesis, subsequently elevating the gemcitabine sensitivity of PDAC cells. Also, PDAC tissues and tumors from LSL-KrasG12D/+, LSL-Trp53R172H/+, and PDX1-cre (KPC) mice exhibit downregulation of PRLR. Bisulfite sequencing of PDAC tissues revealed that PRLR downregulation is due to epigenetic methylation. In this study, we show for the first time that the endocrine receptor PRLR improves the effects of gemcitabine by boosting two new miRNAs that block the PPP pathway and nucleotide synthesis by inhibiting two essential enzymes concurrently. The PRLR-miRNAs-PPP axis may serve as a possible therapeutic target to supplement chemotherapy advantages in PDAC.

Anti-Inflammatory Effects of Fargesin on Chemically Induced Inflammatory Bowel Disease in Mice.

Fargesin is a bioactive lignan from Flos Magnoliae, an herb widely used in the treatment of allergic rhinitis, sinusitis, and headache in Asia. We sought to investigate whether fargesin ameliorates experimental inflammatory bowel disease (IBD) in mice. Oral administration of fargesin significantly attenuated the symptoms of dextran sulfate sodium (DSS)-induced colitis in mice by decreasing the inflammatory infiltration and myeloperoxidase (MPO) activity, reducing tumor necrosis factor (TNF)-α secretion, and inhibiting nitric oxide (NO) production in colitis mice. The degradation of inhibitory κBα (IκBα), phosphorylation of p65, and mRNA expression of nuclear factor κB (NF-κB) target genes were inhibited by fargesin treatment in the colon of the colitis mice. In vitro, fargesin blocked the nuclear translocation of p-p65, downregulated the protein levels of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2), and dose-dependently inhibited the activity of NF-κB-luciferase in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. Taken together, for the first time, the current study demonstrated the anti-inflammatory effects of fargesin on chemically induced IBD might be associated with NF-κB signaling suppression. The findings may contribute to the development of therapies for human IBD by using fargesin or its derivatives.

ON and OFF inhibition as mechanisms for forward masking in the inferior colliculus: a modeling study.

Masking effects of a preceding stimulus on the detection or perception of a signal have been found in several sensory systems in mammals, including humans and rodents. In the auditory system, it has been hypothesized that a central "OFF-inhibitory" mechanism, which is generated by neurons that respond after a sound is terminated, may contribute to the observed psychophysics. The present study constructed a systems model for the inferior colliculus that includes major ascending monaural and binaural auditory pathways. The fundamental characteristics of several neuron types along the pathways were captured by Hodgkin-Huxley models with specific membrane and synaptic properties. OFF responses were reproduced with a model of the superior paraolivary nucleus containing a hyperpolarization-activated h current and a T-type calcium current. When the gap between the end of the masker and the onset of the signal was large, e.g., >5 ms, OFF inhibition generated strong suppressive effects on the signal response. For smaller gaps, an additional inhibitory source, which was modeled as ON inhibition from the contralateral dorsal nucleus of the lateral lemniscus, showed the potential of explaining the psychophysics. Meanwhile, the effect of a forward masker on the binaural sensitivity to a low-frequency signal was examined, which was consistent with previous psychophysical findings related to sound localization.

Behavior and modeling of two-dimensional precedence effect in head-unrestrained cats.

The precedence effect (PE) is an auditory illusion that occurs when listeners localize nearly coincident and similar sounds from different spatial locations, such as a direct sound and its echo. It has mostly been studied in humans and animals with immobile heads in the horizontal plane; speaker pairs were often symmetrically located in the frontal hemifield. The present study examined the PE in head-unrestrained cats for a variety of paired-sound conditions along the horizontal, vertical, and diagonal axes. Cats were trained with operant conditioning to direct their gaze to the perceived sound location. Stereotypical PE-like behaviors were observed for speaker pairs placed in azimuth or diagonally in the frontal hemifield as the interstimulus delay was varied. For speaker pairs in the median sagittal plane, no clear PE-like behavior occurred. Interestingly, when speakers were placed diagonally in front of the cat, certain PE-like behavior emerged along the vertical dimension. However, PE-like behavior was not observed when both speakers were located in the left hemifield. A Hodgkin-Huxley model was used to simulate responses of neurons in the medial superior olive (MSO) to sound pairs in azimuth. The novel simulation incorporated a low-threshold potassium current and frequency mismatches to generate internal delays. The model exhibited distinct PE-like behavior, such as summing localization and localization dominance. The simulation indicated that certain encoding of the PE could have occurred before information reaches the inferior colliculus, and MSO neurons with binaural inputs having mismatched characteristic frequencies may play an important role.

On the localization of complex sounds: temporal encoding based on input-slope coincidence detection of envelopes.

Behavioral and neural findings demonstrate that animals can locate low-frequency sounds along the azimuth by detecting microsecond interaural time differences (ITDs). Information about ITDs is also available in the amplitude modulations (i.e., envelope) of high-frequency sounds. Since medial superior olivary (MSO) neurons encode low-frequency ITDs, we asked whether they employ a similar mechanism to process envelope ITDs with high-frequency carriers, and the effectiveness of this mechanism compared with the process of low-frequency sound. We developed a novel hybrid in vitro dynamic-clamp approach, which enabled us to mimic synaptic input to brain-slice neurons in response to virtual sound and to create conditions that cannot be achieved naturally but are useful for testing our hypotheses. For each simulated ear, a virtual sound, computer generated, was used as input to a computational auditory-nerve model. Model spike times were converted into synaptic input for MSO neurons, and ITD tuning curves were derived for several virtual-sound conditions: low-frequency pure tones, high-frequency tones modulated with two types of envelope, and speech sequences. Computational models were used to verify the physiological findings and explain the biophysical mechanism underlying the observed ITD coding. Both recordings and simulations indicate that MSO neurons are sensitive to ITDs carried by spectrotemporally complex virtual sounds, including speech tokens. Our findings strongly suggest that MSO neurons can encode ITDs across a broad-frequency spectrum using an input-slope-based coincidence-detection mechanism. Our data also provide an explanation at the cellular level for human localization performance involving high-frequency sound described by previous investigators.

Structural exploration of water, nitrate/water, and oxalate/water clusters with basin-hopping method using a compressed sampling technique.

Exploration of the low-lying structures of atomic or molecular clusters remains a fundamental problem in nanocluster science. Basin hopping is typically employed in conjunction with random motion, which is a perturbation of a local minimum structure. We have combined two different sampling technologies, "random sampling" and "compressed sampling", to explore the potential energy surface of molecular clusters. We used the method to study water, nitrate/water, and oxalate/water cluster systems at the MP2/aug-cc-pVDZ level of theory. An isomer of the NO3(-)(H2O)3 cluster molecule with a 3D structure was lower in energy than the planar structure, which had previously been reported by experimental study as the lowest-energy structure. The lowest-energy structures of the NO3(-)(H2O)5 and NO3(-)(H2O)7 clusters were found to have structures similar to pure (H2O)8 and (H2O)10 clusters, which contradicts previous experimental result by Wang et al.(J. Chem. Phys. 2002, 116, 561-570). The new minimum energy structures for C2O4(2-)(H2O)5 and C2O4(2-)(H2O)6 are found by our calculations.

Competing Visual Cues Revealed by Electroencephalography: Sensitivity to Motion Speed and Direction.

Motion speed and direction are two fundamental cues for the mammalian visual system. Neurons in various places of the neocortex show tuning properties in term of firing frequency to both speed and direction. The present study applied a 32-channel electroencephalograph (EEG) system to 13 human subjects while they were observing a single object moving with different speeds in various directions from the center of view to the periphery on a computer monitor. Depending on the experimental condition, the subjects were either required to fix their gaze at the center of the monitor while the object was moving or to track the movement with their gaze; eye-tracking glasses were used to ensure that they followed instructions. In each trial, motion speed and direction varied randomly and independently, forming two competing visual features. EEG signal classification was performed for each cue separately (e.g., 11 speed values or 11 directions), regardless of variations in the other cue. Under the eye-fixed condition, multiple subjects showed distinct preferences to motion direction over speed; however, two outliers showed superb sensitivity to speed. Under the eye-tracking condition, in which the EEG signals presumably contained ocular movement signals, all subjects showed predominantly better classification for motion direction. There was a trend that speed and direction were encoded by different electrode sites. Since EEG is a noninvasive and portable approach suitable for brain-computer interfaces (BCIs), this study provides insights on fundamental knowledge of the visual system as well as BCI applications based on visual stimulation.

Tactile Location Perception Encoded by Gamma-Band Power.

BACKGROUND: The perception of tactile-stimulation locations is an important function of the human somatosensory system during body movements and its interactions with the surroundings. Previous psychophysical and neurophysiological studies have focused on spatial location perception of the upper body. In this study, we recorded single-trial electroencephalography (EEG) responses evoked by four vibrotactile stimulators placed on the buttocks and thighs while the human subject was sitting in a chair with a cushion. METHODS: Briefly, 14 human subjects were instructed to sit in a chair for a duration of 1 h or 1 h and 45 min. Two types of cushions were tested with each subject: a foam cushion and an air-cell-based cushion dedicated for wheelchair users to alleviate tissue stress. Vibrotactile stimulations were applied to the sitting interface at the beginning and end of the sitting period. Somatosensory-evoked potentials were obtained using a 32-channel EEG. An artificial neural net was used to predict the tactile locations based on the evoked EEG power. RESULTS: We found that single-trial beta (13-30 Hz) and gamma (30-50 Hz) waves can best predict the tactor locations with an accuracy of up to 65%. Female subjects showed the highest performances, while males' sensitivity tended to degrade after the sitting period. A three-way ANOVA analysis indicated that the air-cell cushion maintained location sensitivity better than the foam cushion. CONCLUSION: Our finding shows that tactile location information is encoded in EEG responses and provides insights on the fundamental mechanisms of the tactile system, as well as applications in brain-computer interfaces that rely on tactile stimulation.

A Nutrient-Deficient Microenvironment Facilitates Ferroptosis Resistance via the FAM60A-PPAR Axis in Pancreatic Ductal Adenocarcinoma.

Ferroptosis, a nonapoptotic form of cell death, is an emerging potential therapeutic target for various diseases, including cancer. However, the role of ferroptosis in pancreatic cancer remains poorly understood. Pancreatic ductal adenocarcinoma (PDAC) is characterized by a poor prognosis and chemotherapy resistance, attributed to its high Kirsten rats arcomaviral oncogene homolog mutation rate and severe nutritional deficits resulting from a dense stroma. Several studies have linked rat sarcoma (RAS) mutations to ferroptosis, suggesting that inducing ferroptosis may be an effective strategy against oncogenic RAS-bearing tumors. We investigated the role of Family With Sequence Similarity 60 Member A (FAM60A) in this study, a protein closely associated with a poor prognosis and highly expressed in PDAC and tumor tissue from KrasG12D/+;Trp53R172H/+; Pdx1-Cre mice, in regulating ferroptosis, tumor growth, and gemcitabine sensitivity in vitro and in vivo. Our results demonstrate that FAM60A regulates 3 essential metabolic enzymes, ACSL1/4 and GPX4, to protect PDAC cells from ferroptosis. Furthermore, we found that YY1 transcriptionally regulates FAM60A expression by promoting its transcription, and the Hippo-YY1 pathway is restricted in the low-amino-acid milieu in the context of nutrient deprivation, leading to downstream suppression of peroxisome proliferator-activated receptor and ACSL1/4 and activation of GPX4 pathways. Importantly, FAM60A knockdown sensitized PDAC cells to gemcitabine treatment. A new understanding of FAM60A transcriptional regulation pattern in PDAC and its dual function in ferroptosis reliever and chemotherapy resistance is provided by our study. Targeting FAM60A may therefore offer a promising therapeutic approach for PDAC by simultaneously addressing 2 major features of the disease (high RAS mutation rate and tumor microenvironment nutrient deficiency) and preventing tumor cell metabolic adaptation.

Progesterone receptor potentiates macropinocytosis through CDC42 in pancreatic ductal adenocarcinoma.

Endocrine receptors play an essential role in tumor metabolic reprogramming and represent a promising therapeutic avenue in pancreatic ductal adenocarcinoma (PDAC). PDAC is characterized by a nutrient-deprived microenvironment. To meet their ascendant energy demands, cancer cells can internalize extracellular proteins via macropinocytosis. However, the roles of endocrine receptors in macropinocytosis are not clear. In this study, we found that progesterone receptor (PGR), a steroid-responsive nuclear receptor, is highly expressed in PDAC tissues obtained from both patients and transgenic LSL-KrasG12D/+; LSL-Trp53R172H/+; PDX1-cre (KPC) mice. Moreover, PGR knockdown restrained PDAC cell survival and tumor growth both in vitro and in vivo. Genetic and pharmacological PGR inhibition resulted in a marked attenuation of macropinocytosis in PDAC cells and subcutaneous tumor models, indicating the involvement of this receptor in macropinocytosis regulation. Mechanistically, PGR upregulated CDC42, a critical regulator in macropinocytosis, through PGR-mediated transcriptional activation. These data deepen the understanding of how the endocrine system influences tumor progression via a non-classical pathway and provide a novel therapeutic option for patients with PDAC.

Hematological and Neurological Expressed 1 Promotes Tumor Progression Through mTOR Signaling in Ovarian Cancer.

Ovarian cancer (OV) is a highly aggressive malignancy with poor prognosis due to recurrence and drug resistance. Therefore, it is imperative to investigate the key molecular mechanisms underlying OV progression in order to develop promising diagnostic and therapeutic interventions. Although the importance of hematological and neurological expressed 1 (HN1) protein in hemopoietic cell and neurological development has been well-established, its function in cancer, particularly in OV, remains uncertain. In this study, we compared the expression of HN1 in ovarian cancers and para-tumor tissues and predicted potential related signaling pathways through enrichment analysis. In order to confirm the role of HN1 in vitro and vivo, we carried out a variety of experiments including bioinformation analysis, colony formation, flow cytometry analysis, and subcutaneous tumor models. The results demonstrated that HN1 was upregulated in OV and was negatively associated with clinical prognosis. Moreover, we observed that HN1 enhances cell proliferation, migration, and drug resistance, while suppressing apoptosis in OV cells. Notably, we discovered that HN1 functions as a novel regulator of mTOR pathways. Our findings suggest that HN1-mediated mTOR regulation facilitates OV advancement and targeting HN1 could provide a promising therapeutic approach for clinical OV treatment.

Effects of forward masking on sound localization in cats: basic findings with broadband maskers.

Forward masking is traditionally measured with a detection task in which the addition of a preceding masking sound results in an increased signal-detection threshold. Little is known about the influence of forward masking on localization of free-field sound for human or animal subjects. Here we recorded gaze shifts of two head-unrestrained cats during localization using a search-coil technique. A broadband (BB) noise masker was presented straight ahead. A brief signal could come from 1 of the 17 speaker locations in the frontal hemifield. The signal was either a BB or a band-limited (BL) noise. For BB targets, the presence of the forward masker reduced localization accuracy at almost all target levels (20 to 80 dB SPL) along both horizontal and vertical dimensions. Temporal decay of masking was observed when a 15-ms interstimulus gap was added between the end of the masker and the beginning of the target. A large effect of forward masking was also observed for BL targets with low (0.2-2 kHz) and mid (2-7 kHz) frequencies, indicating that the interaural timing cue is susceptible to forward masking. Except at low sound levels, a small or little effect was observed for high-frequency (7-15 kHz) targets, indicating that the interaural level and the spectral cues in that frequency range remained relatively robust. Our findings suggest that different localization mechanisms can operate independently in a complex listening environment.

Behavioral and modeling studies of sound localization in cats: effects of stimulus level and duration.

Sound localization accuracy in elevation can be affected by sound spectrum alteration. Correspondingly, any stimulus manipulation that causes a change in the peripheral representation of the spectrum may degrade localization ability in elevation. The present study examined the influence of sound duration and level on localization performance in cats with the head unrestrained. Two cats were trained using operant conditioning to indicate the apparent location of a sound via gaze shift, which was measured with a search-coil technique. Overall, neither sound level nor duration had a notable effect on localization accuracy in azimuth, except at near-threshold levels. In contrast, localization accuracy in elevation improved as sound duration increased, and sound level also had a large effect on localization in elevation. For short-duration noise, the performance peaked at intermediate levels and deteriorated at low and high levels; for long-duration noise, this "negative level effect" at high levels was not observed. Simulations based on an auditory nerve model were used to explain the above observations and to test several hypotheses. Our results indicated that neither the flatness of sound spectrum (before the sound reaches the inner ear) nor the peripheral adaptation influences spectral coding at the periphery for localization in elevation, whereas neural computation that relies on "multiple looks" of the spectral analysis is critical in explaining the effect of sound duration, but not level. The release of negative level effect observed for long-duration sound could not be explained at the periphery and, therefore, is likely a result of processing at higher centers.

Photophysical studies of europium coordination polymers based on a tetracarboxylate ligand.

Reaction of europium sulfate octahydrate with p-terphenyl-3,3″,5,5″-tetracarboxylic acid (H4ptptc) in a mixed solvent system has afforded three new coordination polymers formulated as {[Eu(ptptc)0.75(H2O)2]·0.5DMF·1.5H2O}n (1), {[Me2H2N]2 [Eu2(ptptc)2(H2O)(DMF)]·1.5DMF·7H2O}n (2), and {[Eu(Hptptc)(H2O)4]·0.5DMF·H2O}n (3). Complex 1 exhibits a three-dimensional (3D) metal-organic framework based on {Eu2(µ2-COO)2(COO)4}n chains, complex 2 shows a 3D metal-organic framework constructed by [Eu2(µ2-COO)2(COO)6](2-) dimetallic subunits, and complex 3 features a 2D layer architecture assembling to 3D framework through π···π interactions. All complexes exhibit the characteristic red luminescence of Eu(III) ion. The triplet state of ligand H4ptptc matches well with the emission level of Eu(III) ion, which allows the preparation of new optical materials with enhanced luminescence properties. The luminescence properties of these complexes are further studied in terms of their emission quantum yields, emission lifetimes, and the radiative/nonradiative rates.

Structure, stability, and electronic property of carbon-doped gold clusters Au(n)C- (n = 1-10): a density functional theory study.

The equilibrium geometric structures, relative stabilities, and electronic properties of Au(n)C(-) and Au(n+1)(-) (n = 1-10) clusters are systematically investigated using density functional theory with hyper-generalized gradient approximation. The optimized geometries show that one Au atom capped on Au(n-1)C(-) clusters is a dominant growth pattern for Au(n)C(-) clusters. In contrast to Au(n+1)(-) clusters, Au(n)C(-) clusters are most stable in a quasi-planar or three-dimensional structure because C doping induces the local non-planarity while the rest of the structure continues to grow in a planar mode, resulting in an overall non-2D configuration. The relative stability calculations show that the impurity C atom can significantly enhance the thermodynamic stability of pure gold clusters. Moreover, the effect of C atom on the Au(n)(-) host decreases with the increase of cluster size. The HOMO-LUMO gap curves show that the interaction of the C atom with Au(n)(-) clusters improves the chemical stability of pure gold clusters, except for Au3(-) and Au4(-) clusters. In addition, a natural population analysis shows that the charges in corresponding Au(n)C(-) clusters transfer from the Au(n)(-) host to the C atom. Meanwhile, a natural electronic configuration analysis also shows that the charges mainly transfer between the 2s and 2p orbitals within the C atom.

Localizing concurrent sound sources with binaural microphones: A simulation study.

The human auditory system can localize multiple sound sources using time, intensity, and frequency cues in the sound received by the two ears. Being able to spatially segregate the sources helps perception in a challenging condition when multiple sounds coexist. This study used model simulations to explore an algorithm for localizing multiple sources in azimuth with binaural (i.e., two) microphones. The algorithm relies on the "sparseness" property of daily signals in the time-frequency domain, and sound coming from different locations carrying unique spatial features will form clusters. Based on an interaural normalization procedure, the model generated spiral patterns for sound sources in the frontal hemifield. The model itself was created using broadband noise for better accuracy, because speech typically has sporadic energy at high frequencies. The model at an arbitrary frequency can be used to predict locations of speech and music that occurred alone or concurrently, and a classification algorithm was applied to measure the localization error. Under anechoic conditions, averaged errors in azimuth increased from 4.5° to 19° with RMS errors ranging from 6.4° to 26.7° as model frequency increased from 300 to 3000 Hz. The low-frequency model performance using short speech sound was notably better than the generalized cross-correlation model. Two types of room reverberations were then introduced to simulate difficult listening conditions. Model performance under reverberation was more resilient at low frequencies than at high frequencies. Overall, our study presented a spiral model for rapidly predicting horizontal locations of concurrent sound that is suitable for real-world scenarios.

Chlorine-induced assembly of a cationic coordination cage with a µ5-carbonato-bridged Mn(II)24 core.

Chlorine caged in! The chlorine-induced assembly of six shuttlecock-like tetranuclear Mn(II) building blocks generated in situ based on p-tert-butylthiacalix[4]arene and facial anions gave rise to a novel truncated distorted octahedral cationic coordination cage with a µ(5)-carbonato-bridged Mn(II)(24) core.

Visible and NIR photoluminescence properties of a series of novel lanthanide-organic coordination polymers based on hydroxyquinoline-carboxylate ligands.

A series of novel two-dimensional (2D) lanthanide coordination polymers with 4-hydroxyquinoline-2-carboxylate (H(2)hqc) ligands, [Ln(Hhqc)(3)(H(2)O)](n)·3nH(2)O (Ln = Eu (1), Tb (2), Sm (3), Nd (4), and Gd (5)) and [Ln(Hhqc)(ox)(H(2)O)(2)](n) (Ln = Eu (6), Tb (7), Sm (8), Tm (9), Dy (10), Nd (11), Yb (12), and Gd (13); H(2)ox = oxalic acid), have been synthesized under hydrothermal conditions. Complexes 1-5 are isomorphous, which can be described as a two-dimensional (2D) hxl/Shubnikov network based on Ln(2)(CO(2))(4) paddle-wheel units, and the isomorphous complexes 6-13 feature a 2D decker layer architecture constructed by Ln-ox infinite chains cross-linked alternatively by bridging Hhqc(-) ligands. The room-temperature photoluminescence spectra of complexes Eu(III) (1 and 6), Tb(III) (2 and 7), and Sm(III) (3 and 8) exhibit strong characteristic emissions in the visible region, whereas Nd(III) (4 and 11) and Yb(III) (12) complexes display NIR luminescence upon irradiation at the ligand band. Moreover, the triplet state of H(2)hqc matches well with the emission level of Eu(III), Tb(III), and Sm(III) ions, which allows the preparation of new optical materials with enhanced luminescence properties.

3D finite-element modeling of air-cell-based cushions and buttock tissues during prolonged sitting.

INTRODUCTION: Prolonged sitting can lead to serious health issues. Patients with spinal cord injuries may even develop pressure ulcers as stress accumulates on the ischial tuberosity. Air-cell-based (ACB) cushions have been shown to reduce tissue stress and help mitigate the effects of chronic sitting. Meanwhile, finite-element simulations have been implemented for different patient conditions. However, existing models are mostly two-dimensional with unrealistic simplifications. METHODS: A realistic three-dimensional multi-physics model with fewer artificial assumptions is presented. A commercial ACB cushion and an emulational buttock consisting of an actual hip bone and soft tissue (muscle, fat, and skin layers) were considered. Computational Fluid Dynamics and Transient Structural Analysis using ANSYS were utilized to simulate the ACB cushion during expansion and buttock tissue during sitting. RESULTS: Profile of airflow and pressure distributions caused by the airflow within the ACB cushion were computed when the air was pumped into the cells. Expansion of the ACB cushion was simulated, and an optimal inner pressure range (100-500 Pa) was determined. The human buttock sitting on the cushion was then simulated and visualized. CONCLUSIONS: The realistic three-dimensional model can accurately capture deformation and stress profiles pertinent to sitting on an ACB cushion. The model allows us to optimize the ACB cushions and operating conditions missing in previous studies. The model has also resolved several weaknesses in former models, such as the artificial air layers between air cells and unrealistically imposed internal pressure.

Diet-Induced Obesity Promotes Liver Metastasis of Pancreatic Ductal Adenocarcinoma via CX3CL1/CX3CR1 Axis.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers, and the patients are generally diagnosed with distant metastasis. Liver is one of the preferred organs of distant metastasis, and liver metastasis is the leading cause of death in PDAC. Diet-induced obesity (DIO) is a risk factor for PDAC, and it remains unclear whether and how DIO contributes to liver metastasis of PDAC. In our study, we found that DIO significantly promoted PDAC liver metastasis compared with normal diet (ND) in intrasplenic injection mouse model. RNA-seq analysis for liver metastasis nodules showed that the various chemokines and several chemokine receptors were altered between ND and DIO samples. The expression levels of CX3CL1 and CX3CR1 were significantly upregulated in DIO-induced liver metastasis of PDAC compared to ND. Increased CX3CL1 promoted the recruitment of CX3CR1-expressing pancreatic tumor cells. Taken together, our data demonstrated that DIO promoted PDAC liver metastasis via CX3CL1/CX3CR1 axis.