Kemprobles7792
As a cell-based cancer vaccine, dendritic cells (DC), derived from peripheral blood monocytes or bone marrow (BM) treated with GM-CSF (GMDC), were initially thought to induce antitumor immunity by presenting tumor antigens directly to host T cells. Subsequent work revealed that GMDCs do not directly prime tumor-specific T cells, but must transfer their antigens to host DCs. This reduces their advantage over strictly antigen-based strategies proposed as cancer vaccines. Type 1 conventional DCs (cDC1) have been reported to be superior to GMDCs as a cancer vaccine, but whether they act by transferring antigens to host DCs is unknown. To test this, we compared antitumor responses induced by GMDCs and cDC1 in Irf8 +32-/- mice, which lack endogenous cDC1 and cannot reject immunogenic fibrosarcomas. Both GMDCs and cDC1 could cross-present cell-associated antigens to CD8+ T cells in vitro. However, injection of GMDCs into tumors in Irf8 +32-/- mice did not induce antitumor immunity, consistent with their reported dependence on host cDC1. In contrast, injection of cDC1s into tumors in Irf8 +32-/- mice resulted in their migration to tumor-draining lymph nodes, activation of tumor-specific CD8+ T cells, and rejection of the tumors. Tumor rejection did not require the in vitro loading of cDC1 with antigens, indicating that acquisition of antigens in vivo is sufficient to induce antitumor responses. Finally, cDC1 vaccination showed abscopal effects, with rejection of untreated tumors growing concurrently on the opposite flank. These results suggest that cDC1 may be a useful future avenue to explore for antitumor therapy. See related Spotlight by Hubert et al., p. 918.
To investigate the expression of corneal epithelium-derived netrin-1 (NTN-1) and its immunoregulatory function in dry eye disease (DED) using a DED mouse model.
We generated DED mouse models with desiccating stress under scopolamine treatment. RNA sequencing was performed to identify differentially expressed genes (DEGs) in the corneal epithelium of DED mice. NTN-1 expression was analyzed via real-time PCR, immunofluorescence staining, and immunoblotting. The DED mice were then treated with recombinant NTN-1 or neutralizing antibodies to investigate the severity of the disease, dendritic cell (DC) activation, and inflammatory cytokine expression.
A total of 347 DEGs (292 upregulated and 55 downregulated) were identified in the corneal epithelium of DED mice corneal epithelium-derived NTN-1 expression was significantly decreased in DED mice compared to that in control mice. Topical recombinant NTN-1 application alleviated the severity of the disease, accompanied by restoration of tear secretion and goblet cell density. In addition, NTN-1 decreased the number of DCs, inhibited the activation of the DCs and Th17 cells, and reduced the expression of inflammatory factors in DED mice. In contrast, blocking endogenous NTN-1 activity with an anti-NTN-1 antibody aggravated the disease, enhanced DC activation, and upregulated the inflammatory factors in the conjunctivae of DED mice.
We identified decreased NTN-1 expression in the corneal epithelium of DED mice. Our findings elucidate the role of NTN-1 in alleviating DED and impeding DC activation, thereby indicating its therapeutic potential in suppressing ocular inflammation in DED.
We identified decreased NTN-1 expression in the corneal epithelium of DED mice. Our findings elucidate the role of NTN-1 in alleviating DED and impeding DC activation, thereby indicating its therapeutic potential in suppressing ocular inflammation in DED.
To characterize the distribution of pigment particles in aqueous drainage structures of DBA/2J mice with different intraocular pressure (IOP) levels.
DBA/2J mice were monitored from 9 to 44 weeks of age. IOP measurements were performed periodically. At 12, 20, 28, and 36 weeks, three mice were randomly selected for each time point and divided into three IOP groups. The morphology, size, and quantity of pigment particles in aqueous drainage structures were determined via transmission electron microscopy combined with ImageJ-based analysis. Between-group differences were evaluated with a one-way analysis of variance and Fisher's least significant difference test.
In the anterior chamber, 74.2% (187/252) of pigment particles were round (diameter range, 0.20-0.73µm), and 25.8% (65/252) were oval (length range, 0.35-1.20 µm). Selleckchem KRAS G12C inhibitor 19 In the high-IOP group (IOP≥15 mmHg), pigment particles in the trabecular meshwork (TM) were more abundant and larger in size than those in the normal-IOP group (P<0.001). All separate pigment particles in the TM of the high-IOP group were >0.4 µm in size. The diameters of round (IOP≤10 mmHg, 0.44±0.13 µm; IOP between 10 and 15 mmHg, 0.57±0.13 µm; IOP≥15 mmHg, 0.61±0.12 µm) and the lengths of oval (0.65±0.14 µm vs. 0.77±0.12 µm vs. 0.88±0.15 µm, respectively) pigment particles in the TM differed among groups (F=27.258 and F=27.295, respectively; both P<0.001). No such differences were discovered in the iris and around Schlemm's canal (P>0.05).
In DBA/2J mice, large and medium pigment particles (>0.4 µm) seem to play an important role in causing aqueous outflow obstruction and IOP elevation.
0.4 µm) seem to play an important role in causing aqueous outflow obstruction and IOP elevation.
To investigate the behavior of silicone oil (SiO) at a steady equilibrium and during saccades in pseudophakic highly myopic eyes with posterior staphyloma with and without an encircling band and compare it to behavior in emmetropic eyes. The SiO-retina contact area and shear stress were calculated by computational fluid dynamics.
A numerical model of an emmetropic eye and a myopic eye with and without scleral band underwent a saccade of 50°/0.137 s. The vitreous chamber surface was divided into superior and inferior 180° sectors lens, pre-equator, post-equator, and macula. SiO-retina contact was evaluated as a function of fill percentages between 80% and 90% for standing, 45° upward tilt, and supine patients. Maximum and average shear stress were calculated.
Overall, SiO-retina contact ranged between 40% and 83%; fill percentage varied between 80% and 95%. Neither the encircling scleral band nor the staphyloma significantly affected the SiO-retina contact area, although the presence of a scleral band proved disadvantageous when gazing 45° upward. The inferior retina-SiO contact remained below 40% despite 95% SiO fill. The SS significantly increased at the scleral band indentation and decreased elsewhere. The staphyloma greatly reduced shear stress at the macula.
The presence of a myopic staphyloma reduces shear stress at the macula but does not alter SiO-retina contact significantly. The apposition of a 360° scleral band may reduce SiO-retina contact at least in some postures and increases the SS at the indentation.
Assessing SiO-retina contact when vitreous chamber geometry changes according to pathologic or iatrogenic modifications allows accurate prediction of real-life tamponade behavior and helps explain surgical outcomes.
Assessing SiO-retina contact when vitreous chamber geometry changes according to pathologic or iatrogenic modifications allows accurate prediction of real-life tamponade behavior and helps explain surgical outcomes.
To characterize macular blood flow connectivity in vivo using high-resolution optical coherence tomography (HighRes OCT).
Cross-sectional, observational study. Dense (6-µm interscan distance) perifoveal HighRes OCT raster scans were performed on healthy participants. To mitigate the limitations of projection-resolved OCT-angiography, flow and structural data were used to observe the vascular structures of the superficial vascular complex (SVC) and the deep vascular complex. Vascular segmentation and rendering were performed using Imaris 9.5 software. Inflow and outflow patterns were classified according to vascular diameter and branching order from superficial arteries and veins, respectively.
Eight eyes from eight participants were included in this analysis, from which 422 inflow and 459 outflow connections were characterized. Arteries had direct arteriolar connections to the SVC (78%) and to the intermediate capillary plexus (ICP, 22%). Deep capillary plexus (DCP) inflow derived from small-diameter vessels succeeding ICP arterioles. The most prevalent outflow pathways coursed through superficial draining venules (74%). DCP draining venules ordinarily merged with ICP draining venules and drained independently of superficial venules in 21% of cases. The morphology of DCP draining venules in structural HighRes OCT is distinct from other vessels crossing the inner nuclear layer and can be used to identify superficial veins.
Vascular connectivity analysis supports a hybrid circuitry of blood flow within the human parafoveal macula.
Characterization of parafoveal macular blood flow connectivity in vivo using a precise segmentation of HighRes OCT is consistent with ground-truth microscopy studies and shows a hybrid circuitry.
Characterization of parafoveal macular blood flow connectivity in vivo using a precise segmentation of HighRes OCT is consistent with ground-truth microscopy studies and shows a hybrid circuitry.
Emotion-Focused Skills Training (EFST) is a 12-week parental program based on Emotion-Focused Therapy, developed to improve children and adolescents' mental health problems.
In a randomized clinical dismantling study, including parents of 236 children and adolescents (ages 6-13, M
8.9, 60.6% boys, 95.8% Caucasian) with externalizing and/or internalizing problems within clinical range, we examined the efficacy of two versions of EFST one
condition (n=120) involving emotionally evocative techniques and two-chair interventions, and one
condition (n=116) involving didactic teaching of emotion skills. Both groups received a 2-day group training and 6hours of individual supervision. Outcomes were parent- and teacher-reported symptoms at baseline, posttreatment, and 4-, 8-, and 12-month follow-up. Analyses were conducted using multilevel growth curve modeling and Bayesian post hoc analysis.
EFST showed efficacy in reducing parent-reported externalizing (
=-1.72,
<.001,
=1.0) and internalizing (
=-1.71,
<.001,
=0.9) symptoms, and teacher-reported externalizing (
=-.96,
<.001,
=0.4), but not internalizing (
=-.13,
>.05,
=0.2) symptoms. Multilevel analyses showed nonsignificant differences between conditions (all
's >.05), although a Bayesian longitudinal sensitivity analysis indicated a better outcome for the
condition.
EFST showed efficacy in symptom reduction for children and adolescents with internalizing and externalizing symptoms. Outcomes were maintained over 12months for both conditions, supporting EFST as a transdiagnostic parental approach for early intervention.
EFST showed efficacy in symptom reduction for children and adolescents with internalizing and externalizing symptoms. Outcomes were maintained over 12 months for both conditions, supporting EFST as a transdiagnostic parental approach for early intervention.Considerable implant materials are prone to cause a severe inflammatory reaction due to poor histocompatibility, which leads to various complications and implant failure. Surface coating modification of these implant materials is one of the most important techniques to settle this problem. However, fabricating a coating with both adequate adhesiveness and excellent biocompatibility remains a challenge. Inspired by the adhesion mechanism of mussels, a series of mussel-inspired polyurethanes (PU-LDAs) were synthysized through a step growth polymerization based on hexamethylene diisocyanate as a hard segment, polytetra-methylene-ether-glycol as a soft segment, lysine-dopamine (LDA) and butanediol as chain extenders with different mole ratios.The coatings of PU-LDAs were applied to various substrates, such as stainless steel, glass and PP using a facile one-step coating process. The introduction of 3,4-dihydroxyphenylalanine (DOPA) groups can greatly improve the adhesion ability of the coatings to the substrates demonstrated by a 180° peel test.
