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LSD1, a lysine-specific histone demethylase, is overexpressed in several types of cancers and linked to poor outcomes. In breast cancer, the significance of LSD1 overexpression is not clear. We have performed an in silico analysis to assess the relationship of LSD1 expression to clinical outcome. We demonstrate that LSD1 overexpression is a poor prognostic factor in breast cancer, especially in basal-like breast cancer, a subtype of breast cancer with aggressive clinical features. This link is also observed in samples of triple negative breast cancer. Interestingly, we note that overexpression of LSD1 correlates with down-regulation of BRCA1 in triple negative breast cancer. This phenomenon is also observed in in vitro models of basal-like breast cancer, and is associated with an increased sensitivity to PARP inhibitors. We propose therefore that high expression levels of the demethylase LSD1 is a potential prognostic factor of poor outcome in basal-like breast cancer, and that PARP inhibition may be a therapeutic strategy of interest in this poor prognostic subtype with overexpression of LSD1.

Type I interferons (IFNs) are secreted by many cell types upon stimulation via pattern recognition receptors and bind to IFN-α/β receptor (IFNAR), which is composed of IFNAR1 and IFNAR2. Although type I IFNs are well known as anti-viral cytokines, limited information is available on their role during fungal infection. In the present study, we addressed this issue by examining the effect of IFNAR1 defects on the host defense response to Cryptococcus neoformans. In IFNAR1KO mice, the number of live colonies was lower and the host immune response mediated not only by Th1 but also by Th2 and Th17-related cytokines was more accelerated in the infected lungs than in WT mice. In addition, mucin production by bronchoepithelial cells and expression of MUC5AC, a major core protein of mucin in the lungs, were significantly higher in IFNAR1KO mice than in WT mice. This increase in mucin and MUC5AC production was significantly inhibited by treatment with neutralizing anti-IL-4 mAb. In contrast, administration of recombinant IFN-αA/D significantly suppressed the production of IL-4, but not of IFN-γ and IL-17A, in the lungs of WT mice after cryptococcal infection. These results indicate that defects of IFNAR1 led to improved clearance of infection with C. neoformans and enhanced synthesis of IFN-γ and the IL-4-dependent production of mucin. They also suggest that type I IFNs may be involved in the negative regulation of early host defense to this infection.

Directing attention to the spatial location or the distinguishing feature of a visual object modulates neuronal responses in the visual cortex and the stimulus discriminability of subjects. However, the spatial and feature-based modes of attention differently influence visual processing by changing the tuning properties of neurons. Intriguingly, neurons' tuning curves are modulated similarly across different visual areas under both these modes of attention. Here, we explored the mechanism underlying the effects of these two modes of visual attention on the orientation selectivity of visual cortical neurons. To do this, we developed a layered microcircuit model. This model describes multiple orientation-specific microcircuits sharing their receptive fields and consisting of layers 2/3, 4, 5, and 6. These microcircuits represent a functional grouping of cortical neurons and mutually interact via lateral inhibition and excitatory connections between groups with similar selectivity. The individual microcircuits receive bottom-up visual stimuli and top-down attention in different layers. A crucial assumption of the model is that feature-based attention activates orientation-specific microcircuits for the relevant feature selectively, whereas spatial attention activates all microcircuits homogeneously, irrespective of their orientation selectivity. Consequently, our model simultaneously accounts for the multiplicative scaling of neuronal responses in spatial attention and the additive modulations of orientation tuning curves in feature-based attention, which have been observed widely in various visual cortical areas. Simulations of the model predict contrasting differences between excitatory and inhibitory neurons in the two modes of attentional modulations. Furthermore, the model replicates the modulation of the psychophysical discriminability of visual stimuli in the presence of external noise. Our layered model with a biologically suggested laminar structure describes the basic circuit mechanism underlying the attention-mode specific modulations of neuronal responses and visual perception.

Representation of shape is a fundamental problem in vision science. Neurophysiological studies of macaque have reported that neurons in the primary visual cortex (V1) respond to Medial Axis (MA) of 2D surface, and that those in higher cortex (IT) respond to surfaces of 3D shape. However, how the cortex translates a pair of 2D retinal images into 3D shape has not been clarified. In the present study, we investigated the problem of 3D shape representation in the cortices with the specific focus on the translation of 2D to 3D shape representation. Based on the neurophysiological evidence, we propose that a pair of 2D-MA that encodes 2D surfaces in V1 is fused to generate a 3D-MA that represents 3D shape in higher cortex. In order to investigate this hypothesis, we developed a computational model and analyzed its behavior. The model computes 2D-MAs from a pair of stereo images, detects the disparities of the 2D-MAs using an energy model that mimics V1 complex cells, and computes 3D-MA from the disparities between the 2D-MAs. Our model reconstructed successfully 3D shape from a number of objects including natural objects and those with complex structures. The results support our hypothesis that a pair of 2D-MA is computed independently in V1, and then 3D-MA that represent 3D shape is computed from the fusion of the 2D-MAs.

Gestalt factors such as convexity, closure, and size promote the perception of the direction of figure. Although recent studies have investigated the effects of the individual factors, it has not been clarified how these factors interact with each other, when the features coexist in a local contour. In the present study, we examined psychophysically the interaction of convexity and closure that coexist in a local contour of natural image. First, we established the quantification of convexity and closure (indices to represent the factors) for contours of natural images. By using these quantities, we selected a set of local contours that includes a uniform and wide variation of convexity and closure. Second, we performed a psychophysical experiment to measure the apparent direction of figure for the set of local contours. The result showed that the perceived direction of figure tends to agree with the direction of closure when both convexity and closure coexist in a local contour. The result also showed that while the direction of closure dominates the perception of the direction of figure, the index of closure does not correlate linearly with the perceptual judgment. These results suggest that the perceptual judgment of the direction of figure depends mostly on closure when it coexists with convexity, and that the dependence is dichotomic; two contours with different degrees of closure do not evoke distinct perception. Closure appears to be a dominant and strong cue for the direction of figure.

A quantum field theory in its algebraic description may admit many irregular states. So far, selection criteria to distinguish physically reasonable states have been restricted to free fields (Hadamard condition) or to flat spacetimes (e.g., Buchholz-Wichmann nuclearity). We propose instead to use a modular ℓp -condition, which is an extension of a strengthened modular nuclearity condition to generally covariant theories. The modular nuclearity condition was previously introduced in Minkowski space, where it played an important role in constructive two dimensional algebraic QFT’s. We show that our generally covariant extension of this condition makes sense for a vast range of theories, and that it behaves well under causal propagation and taking mixtures. In addition we show that our modular ℓp -condition holds for every quasi-free Hadamard state of a free scalar quantum field (regardless of mass or scalar curvature coupling). However, our condition is not equivalent to the Hadamard condition.

Abstract Introduction Budd-Chiari syndrome is a very rare pathological entity that ultimately leads to liver failure. Several therapeutic modalities, including percutaneous transluminal angioplasty, have been attempted to save the life of patients with Budd-Chiari syndrome. Few reports have described a salvage living donor liver transplantation performed after percutaneous transluminal angioplasty in a patient with acute Budd-Chiari syndrome. Case presentation A 26-year-old Japanese man developed severe progressive manifestations, such as massive ascites and hematemesis due to rupture of esophageal varices. After making several investigations, we diagnosed the case as Budd-Chiari syndrome. We first performed percutaneous transluminal angioplasty to dilate a short-segment stenosis of his inferior vena cava. The first percutaneous transluminal angioplasty greatly improved the clinical manifestations. However, after a year, re-stenosis was detected, and a second percutaneous transluminal angioplasty failed to open the severe stricture of his inferior vena cava. Since our patient had manifestations of acute liver failure, we decided to perform salvage living donor liver transplantation from his brother. The transplantation was successfully performed and all clinical manifestations were remarkably alleviated. Conclusion In cases of recurrent Budd-Chiari syndrome, the blocked hepatic venous outflow is not always relieved, even with invasive therapies. We have to take into account the possibility of adopting alternative salvage therapies if the first therapeutic modalities fail. When invasive therapy such as percutaneous transluminal angioplasty fails, liver transplantation should be considered as an alternative option.

Background: Although depression is one of the most common mental health disorders outpacing other diseases and conditions, poor access to care and limited resources leave many untreated. Secure messaging (SM) offers patients an online means to bridge this gap by communicating nonurgent medical questions. We focused on self-care health management behaviors and delved into SM initiation as the initial act of engagement and SM exchanges as continuous engagement patterns. This study examined whether those with depression might be using SM more than those without depression. Methods: Patient portal data were obtained from a large academic medical center's electronic health records spanning 5 years, from January 2018 to December 2022. We organized and analyzed SM initiations and exchanges using the linear mixed-effects modeling technique. Results: Our predictors correlated with SM initiations, accounting for 25.1% of variance explained. In parallel, 24.9% of SM exchanges were attributable to these predictors. Overall, our predictors demonstrate stronger associations with SM exchanges. Discussion: We examined patients with and without depression across 2,629 zip codes over five years. Our findings reveal that the predictors affecting SM initiations and exchanges are multifaceted, with certain predictors enhancing its utilization and others impeding it. Conclusions: SM telehealth service provided support to patients with mental health needs to a greater extent than those without. By increasing access, fostering better communication, and efficiently allocating resources, telehealth services not only encourage patients to begin using SM but also promote sustained interaction through ongoing SM exchanges.

This study aimed to investigate the effect of age in patients with chronic rhinosinusitis with nasal polyp (CRSwNP). 269 patients were divided into eosinophilic and non-eosinophilic groups based on tissue eosinophilia, defined by eosinophils accounting for more than 20% of the total inflammatory cells. Patients were then further divided into younger and older groups based on the age of 35 years. Clinical characteristics including blood eosinophil, Lund Mackay score, and modified Lund-Kennedy (mLK) scores were compared. Levels of 14 cytokines from nasal tissues of an additional 78 patients were analyzed. Tissue eosinophilia was significantly associated with age and the proportion of non-eosinophilic CRSwNP was significantly higher in younger patients as compared to older patients (79.2% vs 56.6%). There was no difference in clinical characteristics and cytokine levels between the younger and older patients with eosinophilic CRSwNP. In contrast, in patients with non-eosinophilic CRSwNP, younger patients had significantly lower preoperative blood eosinophils and higher mLK scores at three and six months, postoperatively, compared to older patients. Alpha-1 antitrypsin and IL-5 levels were significantly lower in younger patients than in older patients in non-eosinophilic CRSwNP. This study suggests a potential association between age, non-type 2 inflammation and treatment outcome in CRSwNP., (© 2022. The Author(s).)

Precise estimation of electrical conductivity of the eyes is important for the accurate analysis of electric field distributions in the eyes during ocular iontophoresis. In this study, we estimated the tissue electrical conductivities of a rabbit eye, which has been widely employed for neuro-ophthalmological experiments, through an in vivo experiment for the first time. Electrical potentials were measured at multiple locations on the skin, while weak currents were transmitted into the skin via two surface electrodes attached to the skin around the eye. A finite element model was constructed to calculate the electric potentials at the measurement locations. The conductivity values of different tissues were then estimated using an optimization procedure to minimize the difference between the measured and calculated electric potentials. The accuracy of the estimated tissue conductivity values of the rabbit eye was validated by comparing the measured and calculated electric potential values for different electrode montages. Further multi-physical analyses of iontophoretic drug delivery to the rabbit eye showed a significant influence of the conductivity profile on the resultant particle distribution. Overall, our results provide an important reference for the tissue electrical conductivity values of the rabbit eye, which could be further utilized for designing new medical devices for delivering electric fields to the eyes, such as transorbital and transscleral electrical stimulations., (© 2021 John Wiley & Sons Ltd.)

The effect of cell cycle synchronisation on glucose metabolism in cancer cells is not known. We assessed how cell cycle synchronisation by thiazolidinediones (TZDs) can affect glucose uptake by cancer cells and investigated the anti-cancer effect of combination therapy with TZDs and 2-deoxy-glucose (2-DG) in colon cancer cells and in mouse xenograft models. Troglitazone (58.1 ± 2.0 vs 48.6 ± 1.3%, p = 0.002) or pioglitazone (82.9 ± 1.9 vs 61.6 ± 3.4%, p < 0.001) induced cell cycle arrest in SW480 cells at G1 phase. Western blot analysis showed the degradation of cyclin D1 and CDK4, and an increase in the expression levels of p21 and p27 after TZDs treatment. Withdrawal of troglitazone treatment induced significant increase in cellular 3 H-DG uptake (141.5% ± 12.9% of controls) and membrane GLUT1 expression levels (146.3% of controls) by 24 h; 1 mM 2-DG treatment alone decreased cell survival by 5.8% as compared with the controls.; however, combination therapy enhanced the anti-tumour effects to 34.6% or 20.3% as compared with control cells. In vivo, each combination treatment group showed significant anti-tumour effects unlike the 2-DG alone group. Cell cycle synchronisation using TZDs induced cellular glucose uptake, which significantly enhanced the therapeutic effect of 2-DG in colon cancer.

In this study, we synthesized a Zr-89-labeled anti-adenosine triphosphate synthase monoclonal antibody (ATPS mAb) for applications in immuno-positron emission tomography (PET) and evaluated its feasibility for angiogenesis imaging. The cellular uptake of Zr-89 ATPS mAb was measured after treatment of cancer cell lines in vitro, and its biodistribution was evaluated at 4, 24 and 48 h in vivo in mice bearing xenografts. PET images were acquired at 4, 24, 48, and 96 h after Zr-89 ATPS mAb administration. Tumor angiogenesis was analyzed using anti-CD31 immunofluorescence staining. The cellular uptake of Zr-89 ATPS mAb increased over time in MDA-MB-231 breast cancer cells but did not increase in PC3 prostate cancer cells. The tumor uptake of Zr-89 ATPS mAb at 24 h was 9.4 ± 0.9% ID/g for MDA-Mb-231 cells and was 3.8 ± 0.6% ID/g for PC3 cells ( p = 0.004). Zr-89 ATPS mAb uptake in MDA-MB-231 xenografts was inhibited by the administration of cold ATPS mAb (4.4 ± 0.5% ID/g, p = 0.011). Zr-89 ATPS mAb uptake could be visualized by PET for up to 96 h in MDA-MB-231 tumors. In contrast, there was no distinct tumor uptake detected by PET in the PC3 xenograft model. CD31-positive tumor vessels were abundant in MDA-MB-231 tumors, whereas they were scarcely detected in PC3 tumors. In conclusion, ATPS mAb was successfully labeled with Zr-89, which could be used for immuno-PET imaging targeting tumor angiogenesis.

To treat glaucoma, conventional eye drops are often prescribed. However, the eye drops have limited effectiveness as a result of low drug bioavailability due to their rapid clearance from the preocular space. To resolve this, we proposed amino-functionalized mesoporous silica (AMS) particles as delivery carriers of the glaucoma drug, brimonidine. Because of the presence of mesopores, brimonidine (BMD) could be encapsulated in the AMS with a loading amount of 41.73 μg/mg (i.e., drug loading capacity of about 4.17%) to give the BMD-AMS, which could release the drug in a sustained manner over 8 h. BMD-AMS was also shown to be mucoadhesive due to the presence of both hydroxyl and amino groups in the surface, allowing for formation of hydrogen bonds and an ionic complex with the mucin, respectively. Therefore, when topically administered to rabbit eyes in vivo, BMD-AMS could reside in the preocular space for up to 12 h because of its adherence to the mucous layer. To assess in vivo efficacy, we examined the variance in intraocular pressure (IOP) and brimonidine concentration in the aqueous humor (AH) after applying BMD-AMS to the eye, which was compared with that induced by Alphagan P, the marketed brimonidine eye drops. For BMD-AMS, the duration in the decrease in IOP and the area under the drug concentration in the AH-time curve (AUC) were 12 h and 2.68 μg·h/mL, respectively, which were about twice as large as those obtained with Alphagan P; this finding indicated enhanced ocular bioavailability of brimonidine with BMD-AMS.