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Bruton's tyrosine kinase (BTK) is a Tec family kinase that plays an essential role in B-cell receptor (BCR) signaling as well as Fcγ receptor signaling in leukocytes. Pharmacological inhibition of BTK has been shown to be effective in treating hematological malignancies and is hypothesized to provide an effective strategy for the treatment of autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus. We report the discovery and preclinical properties of JNJ-64264681 (

Background: Accurate prediction of lymph node metastasis (LNM) status in patients with muscle-invasive bladder cancer (MIBC) before radical cystectomy can guide the use of neoadjuvant chemotherapy and the extent of pelvic lymph node dissection. We aimed to develop and validate a weakly-supervised deep learning model to predict LNM status from digitized histopathological slides in MIBC. Methods: We trained a multiple instance learning model with an attention mechanism (namely SBLNP) from a cohort of 323 patients in the TCGA cohort. In parallel, we collected corresponding clinical information to construct a logistic regression model. Subsequently, the score predicted by the SBLNP was incorporated into the logistic regression model. In total, 417 WSIs from 139 patients in the RHWU cohort and 230 WSIs from 78 patients in the PHHC cohort were used as independent external validation sets. Results: In the TCGA cohort, the SBLNP achieved an AUROC of 0.811 (95% confidence interval [CI], 0.771–0.855), the clinical classifier achieved an AUROC of 0.697 (95% CI, 0.661–0.728) and the combined classifier yielded an improvement to 0.864 (95% CI, 0.827–0.906). Encouragingly, the SBLNP still maintained high performance in the RHWU cohort and PHHC cohort, with an AUROC of 0.762 (95% CI, 0.725–0.801) and 0.746 (95% CI, 0.687–0.799), respectively. Moreover, the interpretability of SBLNP identified stroma with lymphocytic inflammation as a key feature of predicting LNM presence. Conclusions: Our proposed weakly-supervised deep learning model can predict the LNM status of MIBC patients from routine WSIs, demonstrating decent generalization performance and holding promise for clinical implementation.

Large-size AlN crystal homo-PVT process is distinguished by the growth of prismatic grains in a macroscopic 3-dimensional mode, and that overgrowth plays a key role in the merging of grains under a lateral overgrown c-plane surface.

Purpose Accurate estimation of the glomerular filtration rate (GFR) is clinically crucial for determining the status of obstruction, developing treatment strategies, and predicting prognosis in obstructive nephropathy (ON). We aimed to develop a deep learning-based system, named UroAngel, for non-invasive and convenient prediction of single-kidney function level. Methods We retrospectively collected computed tomography urography (CTU) images and emission computed tomography diagnostic reports of 520 ON patients. A 3D U-Net model was used to segment the renal parenchyma, and a logistic regression multi-classification model was used to predict renal function level. We compared the predictive performance of UroAngel with the Modification of Diet in Renal Disease (MDRD), Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations and two expert radiologists in an additional 40 ON patients to validate clinical effectiveness. Results UroAngel based on 3D U-Net convolutional neural network could segment the renal cortex accurately, with a Dice similarity coefficient of 0.861. Using the segmented renal cortex to predict renal function stage had high performance with an accuracy of 0.918, outperforming MDRD and CKD-EPI and two radiologists. Conclusion We proposed an automated 3D U-Net-based analysis system for direct prediction of single-kidney function stage from CTU images. UroAngel could accurately predict single-kidney function in ON patients, providing a novel, reliable, convenient, and non-invasive method.

[Image: see text] Bruton’s tyrosine kinase (BTK) is a cytoplasmic tyrosine kinase that plays a critical role in the activation of B cells, macrophages, and osteoclasts. Given the key role of these cell types in the pathology of autoimmune disorders, BTK inhibitors have the potential to improve treatment outcomes in multiple diseases. Herein, we report the discovery and characterization of a novel potent and selective covalent 4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide BTK inhibitor chemotype. Compound 27 irreversibly inhibits BTK by targeting a noncatalytic cysteine residue (Cys481) for covalent bond formation. Compound 27 is characterized by selectivity for BTK, potent in vivo BTK occupancy that is sustained after it is cleared from systemic circulation, and dose-dependent efficacy at reducing joint inflammation in a rat collagen-induced arthritis model.

In this paper, the growth of semi-polar GaN thick films was investigated on an m-plane sapphire by hydride vapor phase epitaxy (HVPE). By optimizing parameters of the HVPE process, both (11−22) and (10−13) semi-polar GaN films have been successfully obtained with a mirror surface and excellent crystal quality on different GaN templates grown by metal organic chemical vapor deposition (MOCVD), respectively. The influence of MO-GaN templates on the HVPE growth was further studied. The results revealed that the same plane of a semi-polar HVPE-GaN thick layer was grown on a single-phase template, such as GaN (11−22)HVPE on (11−22)MO-template and GaN (10−13)HVPE on (10−13)MO-template. However, on mixed-phase MO-templates, a single-phase (11−22) GaN thick layer was found to grow even if the original templates contain both (11−22) and (10−13) plane components. Meanwhile, in contrast with the difficult growth of GaN (10−13) with a smooth surface, it is easier to acquire GaN (11−22) thick layers by a HVPE method. A wider window for the growth of the (11−22) plane could partly explain the reason why the pure GaN (11−22) plane could be grown on mixed-phase ((11−22) & (10−13)) MO-templates. In order to explain this phenomenon, both formation energy (Ef) and migration barrier (Em) of these semi-polar faces were calculated. Our results indicated that the Ef of GaN (10−13) (−0.56 eV) is higher than that of (11−22) (−10.73 eV), and the Em of (10−13) (0.30 eV) is lower than that of (11−22) (1.89 eV). So the (11−22)-plane growth was more likely to be prevalent in competition between two phases.

Inhibition of the serine protease enteropeptidase (EP) opens a new avenue to the discovery of chemotherapeutics for the treatment of metabolic diseases. Camostat has been used clinically for treating chronic pancreatitis in Japan; however, the mechanistic basis of the observed clinical efficacy has not been fully elucidated. We demonstrate that camostat is a potent reversible covalent inhibitor of EP, with an inhibition potency (kinact/KI) of 1.5 × 104 M−1s−1. High-resolution liquid chromatography-mass spectrometry (LC-MS) showed addition of 161.6 Da to EP after the reaction with camostat, consistent with insertion of the carboxyphenylguanidine moiety of camostat. Covalent inhibition of EP by camostat is reversible, with an enzyme reactivation half-life of 14.3 hours. Formation of a covalent adduct was further supported by a crystal structure resolved to 2.19 A, showing modification of the catalytic serine of EP by a close analog of camostat, leading to formation of the carboxyphenylguanidine acyl enzyme identical to that expected for the reaction with camostat. Of particular note, minor structural modifications of camostat led to changes in the mechanism of inhibition. We observed from other studies that sustained inhibition of EP is required to effect a reduction in cumulative food intake and body weight, with concomitant improved blood glucose levels in obese and diabetic leptin-deficient mice. Thus, the structure-activity relationship needs to be driven by not only the inhibition potency but also the mechanistic and kinetic characterization. Our findings support EP as a target for the treatment of metabolic diseases and demonstrate that reversible covalent EP inhibitors show clinically relevant efficacy. SIGNIFICANCE STATEMENT Interest in targeted covalent drugs has expanded in recent years, particularly so for kinase targets, but also more broadly. This study demonstrates that reversible covalent inhibition of the serine protease enteropeptidase is a therapeutically viable approach to the treatment of metabolic diseases and that mechanistic details of inhibition are relevant to clinical efficacy. Our mechanistic and kinetic studies outline a framework for detailed inhibitor characterization that is proving essential in guiding discovery efforts in this area.

The gut microbiome is a malleable microbial community that can remodel in response to various factors, including diet, and contribute to the development of several chronic diseases, including atherosclerosis. We devised an in vitro screening protocol of the mouse gut microbiome to discover molecules that can selectively modify bacterial growth. This approach was used to identify cyclic D,L-α-peptides that remodeled the Western diet (WD) gut microbiome toward the low-fat-diet microbiome state. Daily oral administration of the peptides in WD-fed LDLr-/- mice reduced plasma total cholesterol levels and atherosclerotic plaques. Depletion of the microbiome with antibiotics abrogated these effects. Peptide treatment reprogrammed the microbiome transcriptome, suppressed the production of pro-inflammatory cytokines (including interleukin-6, tumor necrosis factor-α and interleukin-1β), rebalanced levels of short-chain fatty acids and bile acids, improved gut barrier integrity and increased intestinal T regulatory cells. Directed chemical manipulation provides an additional tool for deciphering the chemical biology of the gut microbiome and might advance microbiome-targeted therapeutics.

Although the tumor-stroma ratio (TSR) has prognostic value in many cancers, the traditional semi-quantitative visual assessment method has inter-observer variability, making it impossible for clinical practice. We aimed to develop a machine learning (ML) algorithm for accurately quantifying TSR in hematoxylin-and-eosin (H&E)-stained whole slide images (WSI) and further investigate its prognostic effect in patients with muscle-invasive bladder cancer (MIBC). We used an optimal cell classifier previously built based on QuPath open-source software and ML algorithm for quantitative calculation of TSR. We retrospectively analyzed data from two independent cohorts to verify the prognostic significance of ML-based TSR in MIBC patients. WSIs from 133 MIBC patients were used as the discovery set to identify the optimal association of TSR with patient survival outcomes. Furthermore, we performed validation in an independent external cohort consisting of 261 MIBC patients. We demonstrated a significant prognostic association of ML-based TSR with survival outcomes in MIBC patients (p < 0.001 for all comparisons), with higher TSR associated with better prognosis. Uni- and multivariate Cox regression analyses showed that TSR was independently associated with overall survival (p < 0.001 for all analyses) after adjusting for clinicopathological factors including age, gender, and pathologic stage. TSR was found to be a strong prognostic factor that was not redundant with the existing staging system in different subgroup analyses (p < 0.05 for all analyses). Finally, the expression of six genes (DACH1, DEEND2A, NOTCH4, DTWD1, TAF6L, and MARCHF5) were significantly associated with TSR, revealing possible potential biological relevance. In conclusion, we developed an ML algorithm based on WSIs of MIBC patients to accurately quantify TSR and demonstrated its prognostic validity for MIBC patients in two independent cohorts. This objective quantitative method allows application in clinical practice while reducing the workload of pathologists. Thus, it might be of significant aid in promoting precise pathology services in MIBC.

(1) Purpose: Although assessment of tumor-infiltrating lymphocytes (TILs) has been acknowledged to have important predictive prognostic value in muscle-invasive bladder cancer (MIBC), it is limited by inter- and intra-observer variability, hampering widespread clinical application. We aimed to evaluate the prognostic value of quantitative TILs score based on a machine learning (ML) algorithm to identify MIBC patients who might benefit from immunotherapy or the de-escalation of therapy. (2) Methods: We constructed an artificial neural network classifier for tumor cells, lymphocytes, stromal cells, and “ignore” cells from hematoxylin-and-eosin-stained slide images using the QuPath open source software. We defined four unique TILs variables based on ML to analyze TILs measurements. Pathological slide images from 133 MIBC patients were retrospectively collected as the discovery set to determine the optimal association of ML-read TILs variables with patient survival outcomes. For validation, we evaluated an independent external validation set consisting of 247 MIBC patients. (3) Results: We found that all four TILs variables had significant prognostic associations with survival outcomes in MIBC patients (p < 0.001 for all comparisons), with higher TILs score being associated with better prognosis. Univariate and multivariate Cox regression analyses demonstrated that electronic TILs (eTILs) variables were independently associated with overall survival after adjustment for clinicopathological factors including age, sex, and pathological stage (p < 0.001 for all analyses). Results analyzed in different subgroups showed that the eTILs variable was a strong prognostic factor that was not redundant with pre-existing clinicopathological features (p < 0.05 for all analyses). (4) Conclusion: ML-driven cell classifier-defined TILs variables were robust and independent prognostic factors in two independent cohorts of MIBC patients. eTILs have the potential to identify a subset of high-risk stage II or stage III-IV MIBC patients who might benefit from adjuvant immunotherapy.

(1) Background: Early diagnosis and treatment are essential to reduce the mortality rate of bladder cancer (BLCA). We aimed to develop deep learning (DL)-based weakly supervised models for the diagnosis of BLCA and prediction of overall survival (OS) in muscle-invasive bladder cancer (MIBC) patients using whole slide digitized histological images (WSIs). (2) Methods: Diagnostic and prognostic models were developed using 926 WSIs of 412 BLCA patients from The Cancer Genome Atlas cohort. We collected 250 WSIs of 150 BLCA patients from the Renmin Hospital of Wuhan University cohort for external validation of the models. Two DL models were developed: a BLCA diagnostic model (named BlcaMIL) and an MIBC prognostic model (named MibcMLP). (3) Results: The BlcaMIL model identified BLCA with accuracy 0.987 in the external validation set, comparable to that of expert uropathologists and outperforming a junior pathologist. The C-index values for the MibcMLP model on the internal and external validation sets were 0.631 and 0.622, respectively. The risk score predicted by MibcMLP was a strong predictor independent of existing clinical or histopathologic indicators, as demonstrated by univariate Cox (HR = 2.390, p < 0.0001) and multivariate Cox (HR = 2.414, p < 0.0001) analyses. The interpretability of DL models can help in the analysis of critical regions associated with tumors to enrich the information obtained from WSIs. Furthermore, the expression of six genes (ANAPC7, MAPKAPK5, COX19, LINC01106, AL161431.1 and MYO16-AS1) was significantly associated with MibcMLP-predicted risk scores, revealing possible potential biological correlations. (4) Conclusions: Our study developed DL models for accurately diagnosing BLCA and predicting OS in MIBC patients, which will help promote the precise pathological diagnosis of BLCA and risk stratification of MIBC to improve clinical treatment decisions.

A thin GaN transition layer (GTL) technology is proposed to control stress and reduce the dislocation density in the initial growth of GaN on an AlN nucleation layer on Si (111) substrates. The GTL has a thickness of 50 nm and is the thinnest transition layer reported for GaN growth on Si substrates. It is found that the density and aspect ratio of GaN islands markedly decrease and the size of GaN islands observably increases under GTL growth conditions. Therefore, the compressive stress relaxation in the initial GaN growth caused by island deformation and island coalescence can be significantly reduced and more compressive stress is built up in the GaN epilayer. Meanwhile, the dislocations originating from the AlN nucleation layer are inclined at an average angle as large as 37° and therefore, most of the dislocations interact and annihilate in the GTL. In this way, efficient stress control and dislocation reduction in the initial GaN growth are simultaneously realized. Moreover, thanks to great reduction of the dislocation density in the GTL, the compressive stress relaxation due to dislocation inclination in subsequent GaN growth is also significantly decreased. As a result, a 1.5 μm crack-free GaN epilayer, whose full width at half maximum (FWHM) values of the (002) and (102) X-ray rocking curves are 270 and 521 arcsec, respectively, is obtained. With a simple growth process, the quality of the GaN epilayer directly grown on the AlN nucleation layer is greatly improved, which demonstrates great application potential for the growth of a fully vertical device structure on Si substrates.

Unlike closely related GPCRs, protease-activated receptors (PAR1, PAR2, PAR3, and PAR4) have a predicted signal peptide at their N-terminus, which is encoded by a separate exon, suggesting that the signal peptides of PARs may serve an important and unique function, specific for PARs. In this report, we show that the PAR2 signal peptide, when fused to the N-terminus of IgG-Fc, effectively induced IgG-Fc secretion into culture medium, thus behaving like a classical signal peptide. The presence of PAR2 signal peptide has a strong effect on PAR2 cell surface expression, as deletion of the signal peptide (PAR2ΔSP) led to dramatic reduction of the cell surface expression and decreased responses to trypsin or the synthetic peptide ligand (SLIGKV). However, further deletion of the tethered ligand region (SLIGKV) at the N-terminus rescued the cell surface receptor expression and the response to the synthetic peptide ligand, suggesting that the signal peptide of PAR2 may be involved in preventing PAR2 from intracellular protease activation before reaching the cell surface. Supporting this hypothesis, an Arg36Ala mutation on PAR2ΔSP, which disabled the trypsin activation site, increased the receptor cell surface expression and the response to ligand stimulation. Similar effects were observed when PAR2ΔSP expressing cells were treated with protease inhibitors. Our findings indicated that these is a role of the PAR2 signal peptide in preventing the premature activation of PAR2 from intracellular protease cleavage before reaching the cells surface. The same mechanism may also apply to PAR1, PAR3, and PAR4.

Stress-induced self-separation is one of the most efficient process for preparing native GaN substrate. The control of GaN film thickness is the key point for GaN film separating from substrate completely. Considering the bowing of bilayer, we studied the radial stress in GaN film before separation. A shrunken circular delamination front model was proposed to derive the unrelaxed stress after separation, and the energy release rate for GaN/sapphire systems of different thicknesses was investigated during the whole separation process. A critical thickness about 500–700 μm was determined for separating 2-inch (5.08 cm) GaN film from a sapphire substrate. By precisely controlling the GaN film thickness around such critical thickness, the complete separation rate could be increased greatly to 74%, which is of great importance in realizing the industrialization of GaN substrate. Keywords: GaN, Stress-induced self-separation, Bilayer thick film, Residual stress, Fracture

The anisotropic extraction dependence of polarized light on propagation path in AlGaN-based deep-ultraviolet (DUV) light-emitting diodes (LEDs) is investigated by simulations and photoluminescence (PL) measurements. Theoretical calculations based on k⋅p approximation and Monte Carol ray tracing indicate that there are two kinds of polarized sources with different angular distributions in ~280 nm AlGaN-based LEDs, s-polarized (spherical-shaped) and p-polarized (dumbbell-shaped) sources, which have different extraction behaviors. It is found that the total light extraction intensities are improved with decreasing the propagation path, and the lateral surface extraction gradually becomes dominant. Moreover, the extraction intensity of s-polarized light improves more than that of p-polarized light when the propagation path decreases, leading to a greater polarization degree. Polarization-resolved PL measurements show that the polarization degree of extracted light from lateral facet of the AlGaN multiple quantum well sample can be enhanced from 1% to 17% as the average propagation path reduces by 0.6 mm, which is consistent with the simulation results of the anisotropic dependence of light extraction on propagation path. Our results are significant for understanding and modulating the anisotropic extraction behavior of polarized light to realize high efficiency AlGaN-based DUV LEDs.

The growth mechanism of exceptionally long N-polar GaN sub-micrometer (sub-μm) rods has not been revealed to date. In this work, we investigated the effects of the V/III molar ratio and HCl (diluted in carrier gas) on the lengthening of a MOCVD-GaN rod template by HVPE. It is found that a low V/III molar ratio and HCl (diluted in carrier gas) help form vertical sidewalls and suppress the lateral growth on the top part of exceptionally long GaN sub-μm rods. Simulation results revealed that the low V/III molar ratio leads to reactive species distributing almost exclusively on the top part of GaN rods, which can effectively prevent crystal growth on the bottom of GaN rods. Chlorine ions support the growth by etching the sidewalls. After growth, the diameter and length of each GaN rod are more than 1.5 μm and 70–80 μm, respectively. Finally, an empirical growth model was developed to account for the exceptionally long GaN sub-μm rods under HVPE growth.

In this paper, crack-free 2-inch bulk GaN wafer with the thickness up to 3 mm was obtained by HVPE homoepitaxy. A new method of acid wet etching was used to pre-treat GaN substrate before re-growth. The formation of the mesh-like subsurface crack and interface layer were found to be suppressed between the re-growth layer and as-grown GaN substrate. EDS and time varied contact angle measurement proved that chemical etching would decrease the oxygen related surface adsorption and increase atoms diffusion length during HVPE homoepitaxial growth. Moreover, Morphology, Low temperature photoluminescence measurements indicated a reduction in stress of wet etching treated as-grown GaN substrate due to etching effect on its N face. High quality bulk GaN with the dislocation density of 1×10 6 cm −2 was achieved by using wet etching and HVPE multiple re-growth. It would offer a simple method to obtain bulk GaN with thicker layer and high quality.

Synthesis of several 7-hydroxy oxysterols and their potential roles as signaling molecules in the innate and adaptive immune responses is discussed. Discovery of a new, fluorinated, synthetic analog of the 7α,25-dihydroxycholesterol-the endogenous ligand of GPR 183 (EBI2), a G-protein coupled receptor highly expressed upon Epstein-Barr virus infection is described. Fluoro oxysterol 12 showed good metabolic stability while maintaining excellent EBI2 agonist activity.

The uniformity of flow field inner the reactor plays a crucial role for hydride vapor phase epitaxy (HVPE) crystal growth and its more important for large scale substrate. A new nozzle structure was designed by adding a push and dilution (PD) gas pipe in the center of gas channels for a 4-inch HVPE (PD-HVPE) system. Experimental results showed that the thickness inhomogeneity of 46 μm 4-inch GaN layer could reach ±1.8% by optimizing PD gas, greatly improved from ±14% grown with conventional nozzle. The simulations of the internal flow field were consistent with our experiment, and the enhancement in uniformity should be attributed to the redistribution of GaCl and NH 3 upon the wafer induced by PD pipe. The full width at half maximum (FWHM) of X-ray diffraction rocking curves for the 4-inch GaN film were about 224 and 200 arcsec for (002) and (102) reflection. The dislocation density of as-grown GaN was about 6.4×10 7 cm −2 .

A magnetron sputtered AlN buffer layer is applied for preparing 2 in. free-standing (FS) GaN on the GaAs substrate by hydride vapor phase epitaxy (HVPE). The AlN buffer layer with excellent compactness can prevent As atoms from diffusing to the GaN growth surface. Thus it serves as an effective protective layer for GaAs substrate and also a seed layer for the deposition of GaN in the early stage of the high-temperature GaN growth. Benefiting from the decomposition property of GaAs at temperature higher than 900 °C, thick GaN film self-separated completely from GaAs substrate during growth. By this way, a 2 in. FS-GaN layer with the thickness of 1.3 mm is finally obtained after the long growth time about 20 h.

The wide-bandgap materials Al-rich AlGaN materials, and their applications on the deep UV LEDs, photodetectors, and power devices are reviewed. The physical properties including energy bandgap, optical properties, polarization properties, etc. are also discussed.

GPR139 is a Gq‐coupled receptor activated by the essential amino acids L‐tryptophan (L‐Trp) and L‐phenylalanine (L‐Phe). We carried out mutagenesis studies of the human GPR139 receptor to identify the critical structural motifs required for GPR139 activation. We applied site‐directed and high throughput random mutagenesis approaches using a double addition normalization strategy to identify novel GPR139 sequences coding receptors that have altered sensitivity to endogenous ligands. This approach resulted in GPR139 clones with gain‐of‐function, reduction‐of‐function or loss‐of‐function mutations. The agonist pharmacology of these mutant receptors was characterized and compared to wild‐type receptor using calcium mobilization, radioligand binding, and protein expression assays. The structure‐activity data were incorporated into a homology model which highlights that many of the gain‐of‐function mutations are either in or immediately adjacent to the purported orthosteric ligand binding site, whereas the loss‐of‐function mutations were largely in the intracellular G‐protein binding area or were disrupters of the helix integrity. There were also some reduction‐of‐function mutations in the orthosteric ligand binding site. These findings may not only facilitate the rational design of novel agonists and antagonists of GPR139, but also may guide the design of transgenic animal models to study the physiological function of GPR139.

Leukotrienes (LTs) and related species are proinflammatory lipid mediators derived from arachidonic acid (AA) that have pathological roles in autoimmune and inflammatory conditions, cardiovascular diseases, and cancer. 5-Lipoxygenase activating protein (FLAP) plays a critical accessory role in the conversion of AA to LTA4, and its subsequent conversion to LTC4 by LTC4 synthase. Pharmacological inhibition of FLAP results in a loss of LT production by preventing the biosynthesis of both LTB4 and LTC4, making it an attractive target for the treatment of inflammatory diseases in which LTs likely play a role. Small-molecule (SM) drugs often exhibit polypharmacology through various pathways, which may explain the differential therapeutic efficacies of compounds sharing structural similarity. We have profiled a series of SM FLAP modulators for their selectivity across enzymes of AA cascade in human whole blood (HWB), using a recently developed LC/MS (liquid chromatography-mass spectrometry)-based high-throughput lipidomics platform that monitors 122 eicosanoids in multiplex. Highly efficient data acquisition coupled with fast and accurate data analysis allowed facile compound profiling from ex vivo study samples. This platform allowed us to quantitatively map the effects of those SMs on the entire AA cascade, demonstrating its potential to discriminate structurally related compounds.

Aging in humans is associated with increased hyperglycemia and insulin resistance (collectively termed IR) and dysregulation of the immune system. However, the causative factors underlying their association remain unknown. Here, using "healthy" aged mice and macaques, we found that IR was induced by activated innate 4-1BBL+ B1a cells. These cells (also known as 4BL cells) accumulated in aging in response to changes in gut commensals and a decrease in beneficial metabolites such as butyrate. We found evidence suggesting that loss of the commensal bacterium Akkermansia muciniphila impaired intestinal integrity, causing leakage of bacterial products such as endotoxin, which activated CCR2+ monocytes when butyrate was decreased. Upon infiltration into the omentum, CCR2+ monocytes converted B1a cells into 4BL cells, which, in turn, induced IR by expressing 4-1BBL, presumably to trigger 4-1BB receptor signaling as in obesity-induced metabolic disorders. This pathway and IR were reversible, as supplementation with either A. muciniphila or the antibiotic enrofloxacin, which increased the abundance of A. muciniphila, restored normal insulin response in aged mice and macaques. In addition, treatment with butyrate or antibodies that depleted CCR2+ monocytes or 4BL cells had the same effect on IR. These results underscore the pathological function of B1a cells and suggest that the microbiome-monocyte-B cell axis could potentially be targeted to reverse age-associated IR.

We theoretically investigate the optical properties of conventional, normal (type A) parabolic and novel (type B) parabolic InGaN quantum well (QW) for blue light emitters. Two specially designed active layer structures by parabolic-shaped QW are proposed, and the optical characteristics of these two parabolic QW structures are calculated and compared to those of conventional QW structures. The electron–hole wavefunction overlap (Γe–hh) of type-B parabolic QWs is 2.8 times (69.6%) that in the conventional QW (24.8%), and the spontaneous emission rate is ninefold that of conventional QWs. The transparency carrier density of type-B parabolic QWs is much smaller than type-A parabolic or conventional QW. These results can be attributed to a higher indium index in the center of the type-B parabolic QWs, and that leads to better confinement of carriers wavefunctions.

We have developed a workflow to extract, separate, and semi-quantify bioactive oxysterols from mouse colon tissues and fecal matters using solid- and liquid-phase extractions, enzymatic and chemical modifications, and stable-isotope dilution LC/MS/MS. The method was applied to a dextran sodium sulphate (DSS)-induced mouse colitis model, which revealed that one particular dihydroxycholesterol (diOHC), 7α,25-diOHC, was significantly elevated in both colon tissue and fecal matters of mice with colitis compared to that in naive mice. The extent of 7α,25-diOHC elevation was positively correlated with colitis severity.

In this letter, a new simple method is introduced for obtaining freestanding GaN. The method combines hydride vapor phase epitaxy and heat-treatment of sapphire, which has been implemented to improve mechanical properties before the growth of GaN template by metalorganic chemical vapor deposition. After hydride vapor phase epitaxy on the GaN template, spontaneous separation took place inside the GaN layer at room temperature, in which process, a new phenomenon called delamination inside GaN layer was observed. The delamination was believed to be driven by the large thermal mismatch stress and the interface shear stress at the wafer edge. Two-inch-diameter freestanding GaN with high quality was thus obtained. The full width at half maximum for X-ray rocking curve were about 108 and 81 arcs for (0 0 2) and (1 0 2) reflections. The dislocation density of the freestanding GaN was about 3–7×106 cm−2.

The RAR-related orphan receptor gamma t (RORγt) is a nuclear receptor required for generating IL-17-producing CD4(+) Th17 T cells, which are essential in host defense and may play key pathogenic roles in autoimmune diseases. Oxysterols elicit profound effects on immune and inflammatory responses as well as on cholesterol and lipid metabolism. Here, we describe the identification of several naturally occurring oxysterols as RORγt agonists. The most potent and selective activator for RORγt is 7β, 27-dihydroxycholesterol (7β, 27-OHC). We show that these oxysterols reverse the inhibitory effect of an RORγt antagonist, ursolic acid, in RORγ- or RORγt-dependent cell-based reporter assays. These ligands bind directly to recombinant RORγ ligand binding domain (LBD), promote recruitment of a coactivator peptide, and reduce binding of a corepressor peptide to RORγ LBD. In primary cells, 7β, 27-OHC and 7α, 27-OHC enhance the differentiation of murine and human IL-17-producing Th17 cells in an RORγt-dependent manner. Importantly, we showed that Th17, but not Th1 cells, preferentially produce these two oxysterols. In vivo, administration of 7β, 27-OHC in mice enhanced IL-17 production. Mice deficient in CYP27A1, a key enzyme in generating these oxysterols, showed significant reduction of IL-17-producing cells, including CD4(+) and γδ(+) T cells, similar to the deficiency observed in RORγt knockout mice. Our results reveal a previously unknown mechanism for selected oxysterols as immune modulators and a direct role for CYP27A1 in generating these RORγt agonist ligands, which we propose as RORγt endogenous ligands, driving both innate and adaptive IL-17-dependent immune responses.

In order to solve the problems of GaN heteroepitaxy on sapphire substrate, some techniques were explored. Freestanding GaN substrates have been made by hydride vapor phase epitaxy (HVPE), laser lift-off (LLO), and chemical mechanical polishing techniques. Wafer bending and cracking in the HVPE growth were partly settled by pulsed flow modulation method. High-crystal quality was established for 1.2 mm thick GaN substrate by X-ray diffraction measurement, in which the full width of half maximum values were 72, 110 arcsec for (102), (002) peaks. A novel micro-size patterned sapphire substrate (PSS) and a nano PSS were also fabricated. High-power vertical structure light emitting diodes (VSLEDs) have been developed by Au–Sn eutectic wafer bonding, homemade micro-area LLO, and light extraction structure preparation. The high-injection-level active region with low temperature GaN sandwiched layers was used for low-efficiency droop. The light output power of VSLED was achieved as 400 mW driven at 350 mA, and the dominant wavelength is about 460 nm. The structures and properties of strain modulated superlattices (SLs) and quantum wells as well as advanced simulation of carriers transport across the electron blocking layer were investigated in laser diodes. The hole concentration was achieved as high as 1.6 × 1018 cm−3 in AlGaN/GaN SLs:Mg by inserting an AlN layer. High-quality AlGaN epilayers and structures were grown by MOCVD. Some device structures of UV LEDs and detectors were demonstrated. The emission wavelength of 262 nm UV LED has been successfully fabricated. At last, high-quality InN and InGaN materials for solar cell were grown by boundary-temperature-controlled epitaxy and growth-temperature-controlled epitaxy. Hall-effect measurement showed a recorded electron mobility of 3,280 cm2/(V s) and a residual electron concentration of 1.47 × 1017 cm−3 at 300 K.

e18337 Background: Over the past 4 years, we have conducted over 30 telepathology consultation cases from China covering a wide spectrum of cancers. Through our experience, we realized that the diagnostic accuracy and report integrity from Chinese pathologists is lower than US standards. which brings great concern about diagnosis, treatment and prognosis of cancer patients in China. Methods: Consultation cases were submitted by Chinese patients, their family members or physicians. Specifically, all clinical reports were sent for consultation including imaging studies, laboratory tests, pathology reports, and histology slides for review which covered a wide spectrum of malignant neoplasms, including lung, esophagus, stomach, colon, ovary, breast, prostate, neuroendocrine, melanoma, head/neck, and soft tissue sarcoma; for most cases (27/30) additional immunostaining or molecular tests were performed. All cases and reports were analyzed at top pathology institutions in the United States, including Memorial Sloan Kettering Cancer Center, Johns Hopkins Hospital, or Brigham Women’s Hospital/Beth Israel Medical Center. Following the review of the original materials, final diagnostic reports between the Chinese and US medical centers were compared for major discrepancies in diagnosis. Results: All consulted cases had major discrepancies in diagnosis (100%). Specifically, 75% of cases had improper cancer classifications or grading, 2 cases had improper quality control in immunostains rendering interpretation questionable; 3 cases lacked appropriate molecular tests; finally, 29/30 (97%) of cases lacked cancer staging based on CAP/AJCC/UICC TNM classification of cancer report protocols. Conclusions: Our consultation experiences demonstrated great discrepancies in malignant neoplasm diagnosis and reports among pathologists between the US and China. These findings raise concerns for Chinese patient’s clinical management and prognoses; moreover, they might help explain the observed difference in cancer patient's total 5-year survival between China and USA (40% vs 70%). These findings emphasize the importance of providing support and consultations for pathologists in China, especially those who practice in non-metropolitan, small county or rural local hospitals which lack updated information, technical and academic supports.