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Over 4% of the global population is estimated to live with autoimmune disease, necessitating immunosuppressive treatment that is often chronic, not curative, and carries associated risks. B cells have emerged as key players in disease pathogenesis, as evidenced by partial responsiveness to B cell depletion by antibody-based therapies. However, these treatments often have transient effects due to incomplete depletion of tissue-resident B cells. Chimeric antigen receptor (CAR) T cells targeting B cells have demonstrated efficacy in refractory systemic lupus erythematosus. To this end, we developed an anti-CD19 CAR T cell product candidate, CABA-201, containing a clinically evaluated fully human CD19 binder (IC78) with a 4-1BB costimulatory domain and CD3 zeta stimulation domain for treatment refractory autoimmune disease. Here, we demonstrate specific cytotoxic activity of CABA-201 against CD19+ Nalm6 cells with no off-target effects on primary human cells. Novel examination of CABA-201 generated from primary T cells from multiple patients with autoimmune disease displayed robust CAR surface expression and effective elimination of the intended target autologous CD19+ B cells in vitro. Together, these findings support the tolerability and activity of CABA-201 for clinical development in patients with autoimmune disease.

The open reduction of mandibular condyle neck fractures is difficult due to the limited surgical field and complex facial nerve structures. The most effective fixation method for narrow fractured segments is debated as standard double four-hole plate fixation is often not feasible. This research compared bone stability and force resistance between single-long-plate and double-short-plate fixations using clinical outcomes, a Sawbones mandible model, and finite element analysis. In patients with condyle neck fractures, nine were fixed with single-long-plate and twelve with double-short-plate fixations, with no significant differences in malocclusion and facial palsy rates. In compression tests with a Sawbones model, displacements in the posterior part were similar in both fixation groups. In contrast, the anterior part had significantly higher displacements in the single-long-plate group. Finite element analysis showed higher displacements in both anterior and posterior parts in the single-plate group compared to the double-short-plate group. Maximum stresses were at the second screw hole in single-long-plate fixation and the turning point of the upper plate at the condyle neck in double-short-plate fixation. Double-short-plate fixations demonstrated better stability and force resistance than single-long-plate fixations.

Abstract Effects of type 2 diabetes on achromatic and chromatic contrast sensitivity (CS) are still controversial. In this study, we aimed to investigate CS in patients without diabetic retinopathy (no-DR) and in those with non-proliferative DR (NPDR) and proliferative DR (PDR) using psychophysical methods with transient and sustained achromatic stimuli and color patches. Achromatic CS was measured with the pulsed pedestal (PP) paradigm (7, 12, and 19 cd/m2) and pedestal-△-pedestal (P-△-P) paradigm (11.4, 18, and 28.5 cd/m2). A chromatic discrimination paradigm that assesses protan, deutan, and tritan color vision was adopted. Forty-two patients (no-DR n = 24, NPDR n = 12, PDR = 6; male n = 22, mean age = 58.1 y/o) and 38 controls (male n = 18, mean age = 53.4 y/o) participated. In patients, mean thresholds were higher than in controls and linear trends were significant in most conditions. For the PP paradigm, differences were significant in the PDR and NPDR groups in the 7 and 12 cd/m2 condition. For the P-△-P paradigm, differences were only significant in the PDR group in the 11 cd/m2 condition. Chromatic contrast loss was significant in the PDR group along the protan, deutan and tritan axes. The results suggest independent involvements of achromatic and chromatic CS in diabetic patients.

Abstract We investigated lateral modulation effects with functional magnetic resonance imaging. We presented radial sinusoidal gratings in random sequence: a scotoma grating with two arc-shaped blank regions (scotomata) in the periphery, one in the left and one in the right visual field, a center grating containing pattern only in the scotoma regions, and a full-field grating where the pattern occupied the whole screen. On each trial, one of the three gratings flickered in counterphase for 10 s, followed by a blank period. Observers were instructed to perform a fixation task and report whether filling-in was experienced during the scotoma condition. The results showed that the blood-oxygen-level-dependent signal was reduced in areas corresponding to the scotoma regions in the full-field compared to the center condition in V1 to V3 areas, indicating a lateral inhibition effect when the surround was added to the center pattern. The univariate analysis results showed no difference between the filling-in and no-filling-in trials. However, multivariate pattern analysis results showed that classifiers trained on activation pattern in V1 to V3 could differentiate between filling-in and no-filling-in trials, suggesting that the neural activation pattern in visual cortex correlated with the subjective percept.

Abstract Background Precision is crucial in determining the appropriate procedure for implementing further trials. We conducted a study to explore the reliability of a novel measuring system for human skin color. Methods The novel skin color measuring system was used to capture the skin color of four volunteers (2 males and 2 females) from the same location on each subject by the same operator. The measurement was repeated for different poses and instrument factors (camera and shooting protocol) in the red, green, and blue (RGB) system. The average color depth in each image was calculated and converted from 0 to 255. The spread of measures and the Bland‐Altman plot was displayed to determine each variance source's random error, with the interclass correlation coefficients applied to reflect the reliability. Result The RGB color depth in the experiment ranged from 190, 152, and 122 to 208, 170, and 142. The 95% confidential interval of the differences from the means in RGB colors for the different protocols were ±2.8, ±2.6, and ±2.1, respectively. The largest variation in the replicate trials was observed when subjects were in a supine position (standard deviation: 2). The interclass correlation coefficients were greater than 90%, suggesting that the developed system is highly precise. Conclusion This study demonstrated that the developed device could stably and reliably detect human skin color across different common sources of variation, and thus could be applied clinically to explore relationships between health/disease and skin color changes.

Abstract Collinear search impairment (CSI) is a phenomenon where a task-irrelevant collinear structure impairs a target search in a visual display. It has been suggested that CSI is monocular, occurs without the participants’ access to consciousness and is possibly processed at an early visual site (e.g. V1). This effect has frequently been compared with a well-documented opposite effect called attentional capture (AC), in which salient and task-irrelevant basic features (e.g. color, orientation) enhance target detection. However, whether this phenomenon can be attributed to non-attentional factors such as collinear facilitation (CF) has not yet been formally tested. Here we used one well-established property of CF, i.e. that target contrast modulates its effect direction (facilitation vs suppression), to examine whether CSI shared similar signature profiles along different contrast levels. In other words, we tested whether CSI previously observed at the supra-threshold level was reduced or reversed at near-threshold contrast levels. Our results showed that, regardless of the luminance contrast levels, participants spent a longer time searching for targets displayed on the salient singleton collinear structure than those displayed off the structure. Contrast invariance suggests that it is unlikely that CSI is exclusively sub-served by an early vision mechanism (e.g. CF).

Background:. Management of comminuted facial fractures with maxillary-mandibular arch interruption is difficult, resulting in inadequate bone reduction and malocclusion. Traditionally, a good quality dental splint is helpful, but difficult to obtain in acute trauma. We apply a computer-assisted design and three-dimensional printing technology to improve splint fabrication and utilization, thus facilitating restoration of dental occlusion and facial fracture. Methods:. We retrospectively reviewed patients who suffered from facial fractures with interruption of the maxillary-mandibular arches. We developed the “computer-assisted reverse planning and three-dimensional printing model surgery” algorithm and applied it in selected patients. An occlusal splint was created as a surgical guide to enhance the maxilla-mandibular unit repair by taking care of the bone reduction and occlusion. All included patients were followed up to assess the functional outcome and patients suitable for this method. Results:. From Jan 2015 to Aug 2020, 10 patients (eight men and two women) with comminuted facial fractures were included. The average time of surgery was 9.2 days. The average follow-up time was 8.6 months. There was no patient who needed major revision to correct malocclusion or facial asymmetry. Conclusions:. A computer-assisted design splint decreases intraoperative inaccuracies and difficulty in comminuted maxillo-mandibular fractures. It is a useful and reliable alternative. Collaboration with an experienced engineer and patient selection are indispensable in delivering successful outcomes. Patients who have more than three bone fragments in a single dental arch or more than four bone fragments in the entire maxillary-mandibular unit appear to be excellent candidates for this method.

Objective: Lower serum low-density lipoprotein cholesterol (LDL-C) levels are associated with increased intracerebral hemorrhage (ICH) risk. However, reverse causality and residual confounding has not attracted public attention. Therefore, we assessed whether people with LDL-C have increased risk of mortality adjusting for potential confounders using two large Taiwan cohorts.Methods: The Mei-Jhao (MJ) cohort has 414,372 adults participating in a medical screening program with 378 ICH deaths within 15 years of follow-up (1994–2008). Cox proportional hazards regressions estimated hazard death ratios according to LDL-C levels. We identified 4,606 ICH patients from the Taiwan Stroke Registry (TSR) and analyzed the impact of LDL-C on 3-month mortality.Results: Low cholesterol (LDL-C

Photonic crystals possess metastructures with a unique dispersion relation. An integrated optical circuit plays a crucial role in quantum computing, for which miniaturized optical components can be designed according to the characteristics of photonic crystals. Because the stable light transmission mode for a square waveguide is transverse electric or transverse magnetic polarization, we designed a half-waveplate element with a photonic crystal that can rotate the polarization direction of the light incident on a waveguide by 90°. Using the dispersion relation of photonic crystals, the polarization rotation length and the optical axis’s angle of deviation from the electric field in the eigenmode can be effectively calculated. Polarization rotators designed on the basis of photonic crystal structures can effectively reduce the insertion loss of components and exhibit favorable polarization rotation performance.

In a stimulus with multiple moving elements, an observer may perceive that the whole stimulus moves in unison if (a) one can associate an element in one frame with one in the next (correspondence) and (b) a sufficient proportion of correspondences signal a similar motion direction (coherence). We tested the necessity of these two conditions by asking the participants to rate the perceived intensity of linear, concentric, and radial motions for three types of stimuli: (a) random walk motion , in which the direction of each dot was randomly determined for each frame, (b) random image sequence , which was a set of uncorrelated random dot images presented in sequence, and (c) global motion , in which 35% of dots moved coherently. The participants perceived global motion not only in the global motion conditions but also in the random image sequences, though not in random walk motion. The type of perceived motion in the random image sequences depends on the spatial context of the stimuli. Thus, although there is neither a fixed correspondence across different frames nor a coherent motion direction, observers can still perceive global motion in the random image sequence. This result cannot be explained by motion energy or local aperture border effects.

Immunotherapy is one of the most promising forms of cancer treatment. In particular, immune checkpoint blockers (ICBs) represent some of the leading candidates which many drug developers have heavily invested in. During pre-clinical development and prior to human clinical trials, animal tests are a critical component for determining the safety and efficacy of newly developed ICBs for cancer treatment. In this study, we strive to demonstrate the feasibility of using hollow fiber assay microtube array membrane (MTAM-HFA) in the screening of anti-cancer ICBs. The MTAM-HFA process was carried out by encapsulating peripheral blood mononuclear cells (PBMCs) and the target cancer cells (cell lines or primary cells) and subcutaneously implanting them into Balb/C mice. At predetermined time points combination regimens of PD-1/PD-L1+ were administered accordingly and at a predetermined time point, the MTAMs were retrieved, and cell viability assays were carried out. The outcomes of the MTAM-HFA were compared against the clinical outcome of patients. Clinical comparison demonstrated excellent correlation between the screening outcome of MTAM-HFA of PD-1/PD-L1+ combination therapy and the clinical outcome of the lung cancer patients. Basic cell studies revealed that the utilization of MTAM-HFA in PD-1/PD-L1+ combination therapy revealed enhanced T-cell activity upon the administration of the PD-1/PD-L1 drug; thereby resulting in the reduction of tumor cell viability by up to 70%, and the cytotoxic effects by 82%. The outcome was echoed in the in vivo cell studies. This suggested that the MTAM-HFA system is suitable for use in PD-1/PD-L1+ screening and the accuracy, rapidity and cost effectiveness made it extremely suitable for application as a companion diagnostic system in both personalized medicine for cancer treatment and could potentially be applied to screen for candidate compounds in the development of next generation PD-1/PD-L1+ combination therapies.

Coronary artery disease is one of the major diseases that plagues today’s modern society. Conventional treatments utilize synthetic vascular grafts such as Dacron® and Teflon® in bypass graft surgery. Despite the wide adaptation, these synthetic grafts are often plagued with weaknesses such as low hemocompatibility, thrombosis, intimal hyperplasia, and risks of graft infection. More importantly, these synthetic grafts are not available at diameters of less than 6 mm. In view of these challenges, we strived to develop and adapt the electrospun Poly Lactic-co-Glycolic Acid (PLGA) Microtube Array Membrane (MTAM) vascular graft for applications smaller than 6 mm in diameter. Homogenously porous PLGA MTAMs were successfully electrospun at 5.5–8.5 kV under ambient conditions. Mechanically, the PLGA MTAMs registered a maximum tensile strength of 5.57 ± 0.85 MPa and Young’s modulus value of 1.134 ± 0.01 MPa; while MTT assay revealed that seven-day Smooth Muscle Cells (SMCs) and Human Umbilical Vein Endothelial Cells (HUVECs) registered a 6 times and 2.4 times higher cell viability when cultured in a co-culture setting in medium containing α-1 haptaglobulin. When rolled into a vascular graft, the PLGA MTAMs registered an overall degradation of 82% after 60 days of cell co-culture. After eight weeks of culturing, immunohistochemistry staining revealed the formation of a monolayer of HUVECs with tight junctions on the surface of the PLGA MTAM, and as for the SMCs housed within the lumens of the PLGA MTAMs, a monolayer with high degree of orientation was observed. The PLGA MTAM registered a burst pressure of 1092.2 ± 175.3 mmHg, which was sufficient for applications such as small diameter blood vessels. Potentially, the PLGA MTAM could be used as a suitable substrate for vascular engineering.

Oxytocin (OXT) has been implicated in adult neurogenesis. Here the authors show that CA3 pyramidal cells in the adult mouse hippocampus express OXT receptors and receive inputs from hypothalamic OXT neurons; activation of OXT signaling in CA3 pyramidal cells promotes the survival and maturation of newborn neurons in the dentate gyrus in a non-cell autonomous manner.

Previously, we successfully developed an extracorporeal endotoxin removal device (EERD) that is based on the novel next generation alternating microtube array membrane (MTAM-A) that was superior to the commercial equivalent. In this article, we demonstrated multiple different parameter modifications that led to multiple different types of novel new MTAM structures, which ultimately led to the formation of the MTAM-A. Contrary to the single layered MTAM, the MTAM-A series consisted of a superior packing density fiber connected in a double layered, alternating position which allowed for the greater fiber count to be packed per unit area. The respective MTAM variants were electrospun by utilizing our internally developed tri-axial electrospinning set up to produce the novel microstructures as seen in the respective MTAM variants. A key uniqueness of this study is the ability to produce self-arranged fibers into the respective MTAM variants by utilizing a single spinneret, which has not been demonstrated before. Of the MTAM variants, we observed a change in the microstructure from a single layered MTAM to the MTAM-A series when the ratio of surfactant to shell flow rate approaches 1:1.92. MTAM-A registered the greatest surface area of 2.2 times compared to the traditional single layered MTAM, with the greatest tensile strength at 1.02 ± 0.13 MPa and a maximum elongation of 57.70 ± 9.42%. The MTAM-A was selected for downstream immobilization of polymyxin B (PMB) and assembly into our own internally developed and fabricated dialyzer housing. Subsequently, the entire setup was tested with whole blood spiked with endotoxin; and benchmarked against commercial Toraymyxin fibers of the same size. The results demonstrated that the EERD based on the MTAM-A performed superior to that of the commercial equivalent, registering a rapid reduction of 73.18% of endotoxin (vs. Toraymyxin at 38.78%) at time point 15 min and a final total endotoxin removal of 89.43% (vs. Toraymyxin at 65.03%).

Within the spectrum of a natural image, the amplitude of modulation decreases with spatial frequency. The speed of such an amplitude decrease, or the amplitude spectrum slope, of an image affects the perceived aesthetic value. Additionally, a human observer would consider a symmetric image more appealing than they would an asymmetric one. We investigated how these two factors jointly affect aesthetic preferences by manipulating both the amplitude spectrum slope and the symmetric level of images to assess their effects on aesthetic preference on a 6-point Likert scale. Our results showed that the preference ratings increased with the symmetry level but had an inverted U-shaped relation to amplitude spectrum slope. In addition, a strong interaction existed between symmetry level and amplitude spectrum slope on preference rating, in that symmetry can amplify the amplitude spectrum slope’s effects. A quadratic function of the spectrum slope can describe such effects. That is, preference is an inverted U-shaped function of spectrum slope whose intercept is determined by the number of symmetry axes. The modulation depth of the quadratic function manifests the interaction between the two factors.

The treatment of cancer has evolved significantly in recent years with a strong focus on immunotherapy. Encapsulated Cell Therapy (ECT) for immunotherapy-based anti-cancer treatment is a unique niche within this landscape, where molecules such as signaling factors and antibodies produced from cells are encapsulated within a vehicle, with a host amount of benefits in terms of treatment efficacy and reduced side effects. However, traditional ECTs generally lie in two extremes; either a macro scale vehicle is utilized, resulting in a retrievable system but with limited diffusion and surface area, or a micro scale vehicle is utilized, resulting in a system that has excellent diffusion and surface area but is unretrievable in the event of side effects occurring, which greatly compromises the biosafety of patients. In this study we adapted our patented and novel electrospun Polysulfone (PSF) Microtube Array Membranes (MTAMs) as a ‘middle’ approach to the above dilemma, which possess excellent diffusion and surface area while being retrievable. Hybridoma cells were encapsulated within the PSF MTAMs, where they produced CEACAM6 antibodies to be used in the suppression of cancer cell line A549, MDA-MB-468 and PC 3 (control). In vitro and in vivo studies revealed excellent cell viability of hybridoma cells with continuous secretion of CEACAM6 antibodies which suppressed the MDA-MB-468 throughout the entire 21 days of experiment. Such outcome suggested that the PSF MTAMs were not only an excellent three-dimensional (3D) cell culture substrate but potentially also an excellent vehicle for the application in ECT systems. Future research needs to include a long term in vivo >6 months study before it can be used in clinical applications.

Basic color terms used in Mandarin Chinese have been controversial since first discussed by Berlin and Kay in 1969. Previous studies showed much inconsistency on what should be considered as basic color terms in Mandarin Chinese. In the present study, we investigated categories of color rather than merely the color terms used by Taiwanese native Mandarin speakers. Using samples conforming to the Berlin and Kay survey, various colors were chosen from a collection of Natural Color System (NCS) colored papers and mounted on a piece of neutral gray card. The card was then mounted on a touch-screen, under D65 illumination. Thirty-two single-character color related Mandarin terms were selected from a Chinese character database according to frequency of use. Participants were required to select the color sample that matched the term by pressing a virtual button on the touch screen. The results show that certain terms can be directly correlated to basic color terms in English, comparable with the results of Berlin and Kay's original study and those that followed. However, some terms, such as Mo ( ink), Tie ( iron), and Cai (vegetable), show a wide spread of term maps and inconsistent use among subjects. Principle component analysis (PCA) procedures were used to analysis the commodity of data among subjects. The findings suggest that the basic color categories among Mandarin Chinese speakers are similar to those found in the World Color Survey (WCS), but are represented by wide-spread and inconsistent color terms among speakers.

High matrix metalloproteinase 1 (MMP1) expression is associated with enhanced breast cancer growth and metastasis and also might predict poor prognosis. In this study, we further investigated the functional role of MMP1 and how it is upregulated in multi-drug resistant (MDR) breast cancer cells. By retrieving microarray data in GEO datasets and the survival data in the Kaplan Meier plotter, we observed that MMP1 is significantly upregulated in MCF-7/ADR cells compared to the parental MCF-7 cells, while high MMP1 expression is associated with worse overall survival (OS) and recurrence free survival (RFS) in breast cancer patients after systematic therapy. Functional studies showed that MMP1 overexpression significantly reduced the drug sensitivity in MCF-7 cells, while MMP1 knockdown substantially enhanced the sensitivity in MCF-7/ADR cells. By performing western blotting and immunofluorescent staining, we confirmed that MCF-7/ADR cells had enhanced mesenchymal properties than MCF-7 cells. In MCF-7 cells, enforced Slug expression resulted in significant MMP1 upregulation, while in MCF-7/ADR cells, Slug knockdown led to reduced MMP1 expression. By performing bioinformatic analysis, we observed that the promoter of MMP1 has three putative Slug binding sites. The following dual luciferase assay and ChIP-qPCR verified these three binding sites. Therefore, we infer that Slug enhances MMP1 transcription via directly binding to the promoter region in breast cancer cells, which is a previously unrecognized mechanism in the development of MDR.

The guided tissue regeneration (GTR) membrane is a barrier intended to maintain a space for alveolar bone and periodontal ligament tissue regeneration but prevent the migration of fast-growing soft tissue into the defect sites. This study evaluated the physical properties, in vivo animal study, and clinical efficacy of hydrophilic PLA95/β-TCP GTR membranes prepared by electrospinning (ES). The morphology and cytotoxicity of ES PLA95/β-TCP membranes were evaluated by SEM and 3-(4,5-cimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) respectively. The cementum and bone height were measured by an animal study at 8 and 16 weeks after surgery. Fifteen periodontal patients were selected for the clinical trial by using a commercial product and the ES PLA95/β-TCP membrane. Radiographs and various indexes were measured six months before and after surgery. The average fiber diameter for this ES PLA95/β-TCP membrane was 2.37 ± 0.86 µm. The MTT result for the ES PLA95/β-TCP membrane showed negative for cytotoxicity. The significant differences in the cementum and bone height were observed between empty control and the ES PLA95/β-TCP membrane in the animal model (p < 0.05). Clinical trial results showed clinical attachment level (CAL) of both control and ES PLA95/β-TCP groups, with a significant difference from the pre-surgery results after six months. This study demonstrated that the ES PLA95/β-TCP membrane can be used as an alternative GTR membrane for clinical applications.

A plaid is a combination of two gratings whose orientations are orthogonal to each other with the same or similar contrasts. We used plaid patterns as stimuli to investigate the mechanisms underlying the detection of a plaid to understand how the visual system combines information from orientation-selective channels. We used a masking paradigm in which an observer was required to detect a target (either a spiral or a plaid) superimposed on a pedestal. We measured the target threshold versus pedestal contrast (TvC) functions at 7 pedestal contrasts for various target-pedestal combinations with a temporal 2AFC paradigm and a staircase procedure. All TvC functions, except the one with an orthogonal spiral pedestal, showed a dipper shape, although the position of the dip and the slope varied across conditions. The result can be explained by a multiple-mechanism divisive inhibition model, which contains several orientation-selective mechanisms. The response of each mechanism is the excitation of a linear filter divided by a broadband inhibitory input. The threshold is determined by a nonlinear combination of the responses of those mechanisms. Alternative models with mechanism(s) specific for plaid did not provide a better description of the data. Thus, a plaid pattern is mediated by a combination of orientation-selective mechanisms. An early plaid-specific mechanism is not necessary for plaid detection.

Perceived depth is conveyed by multiple cues, including binocular disparity and luminance shading. Depth perception from luminance shading information depends on the perceptual assumption for the incident light, which has been shown to default to a diffuse illumination assumption. We focus on the case of sinusoidally corrugated surfaces to ask how shading and disparity cues combine defined by the joint luminance gradients and intrinsic disparity modulation that would occur in viewing the physical corrugation of a uniform surface under diffuse illumination. Such surfaces were simulated with a sinusoidal luminance modulation (0.26 or 1.8 cy/deg, contrast 20%-80%) modulated either in-phase or in opposite phase with a sinusoidal disparity of the same corrugation frequency, with disparity amplitudes ranging from 0'-20'. The observers' task was to adjust the binocular disparity of a comparison random-dot stereogram surface to match the perceived depth of the joint luminance/disparity-modulated corrugation target. Regardless of target spatial frequency, the perceived target depth increased with the luminance contrast and depended on luminance phase but was largely unaffected by the luminance disparity modulation. These results validate the idea that human observers can use the diffuse illumination assumption to perceive depth from luminance gradients alone without making an assumption of light direction. For depth judgments with combined cues, the observers gave much greater weighting to the luminance shading than to the disparity modulation of the targets. The results were not well-fit by a Bayesian cue-combination model weighted in proportion to the variance of the measurements for each cue in isolation. Instead, they suggest that the visual system uses disjunctive mechanisms to process these two types of information rather than combining them according to their likelihood ratios.