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The first purpose of this study was to examine the prevalence of risk for comorbid reading and mathematics disabilities (RMD) at start of first grade, when measured in a representative sample of 3,062 students with first-grade fluency measures (word reading; computation). The second purpose was to examine the utility of these measures for predicting RMD status within a sample of 577 students when RMD status was assessed at the end of second grade in terms of reading and math accuracy. When set at or below the 16 th percentile, first-grade risk for RMD was two times more common than chance; at or below the 7 th percentile, it was five times more common. Logistic regression showed that the two first-grade fluency measures accurately distinguished students with and without RMD in second grade; however, when cut scores were set to capture 85% of students with RMD, false positives were high. Overall, the results provide support for the use of fluency measures as an initial gating procedure in first grade, but additional gating steps appear necessary in the screening process to reduce false positives.

Therapeutic blockade of the immune checkpoint proteins programmed cell death protein 1 (PD-1) and cytotoxic T lymphocyte antigen 4 (CTLA4) has transformed cancer treatment. However, the overall response rate to these treatments is low, suggesting that immune checkpoint activation is not the only mechanism leading to dysfunctional anti-tumour immunity. Here we show that butyrophilin-like protein 2 (BTNL2) is a potent suppressor of the anti-tumour immune response. Antibody-mediated blockade of BTNL2 attenuates tumour progression in multiple in vivo murine tumour models, resulting in prolonged survival of tumour-bearing mice. Mechanistically, BTNL2 interacts with local γδ T cell populations to promote IL-17A production in the tumour microenvironment. Inhibition of BTNL2 reduces the number of tumour-infiltrating IL-17A-producing γδ T cells and myeloid-derived suppressor cells, while facilitating cytotoxic CD8 + T cell accumulation. Furthermore, we find high BTNL2 expression in several human tumour samples from highly prevalent cancer types, which negatively correlates with overall patient survival. Thus, our results suggest that BTNL2 is a negative regulator of anti-tumour immunity and a potential target for cancer immunotherapy., (© 2022. The Author(s).)

Although genome-wide association studies have identified the gene RNF186 encoding an E3 ubiquitin-protein ligase as conferring susceptibility to ulcerative colitis, the exact function of this protein remains unclear. In the present study, we demonstrate an important role for RNF186 in macroautophagy/autophagy activation in colonic epithelial cells and intestinal homeostasis. Mechanistically, RNF186 acts as an E3 ubiquitin-protein ligase for EPHB2 and regulates the ubiquitination of EPHB2. Upon stimulation by ligand EFNB1 (ephrin B1), EPHB2 is ubiquitinated by RNF186 at Lys892, and further recruits MAP1LC3B for autophagy. Compared to control mice, rnf186 -/- and ephb2 -/- mice have a more severe phenotype in the DSS-induced colitis model, which is due to a defect in autophagy in colon epithelial cells. More importantly, treatment with ephrin-B1-Fc recombinant protein effectively relieves DSS-induced mouse colitis, which suggests that ephrin-B1-Fc may be a potential therapy for human inflammatory bowel diseases. Abbreviations : ACTB: actin beta; ATG5: autophagy related 5; ATG16L1: autophagy related 16 like 1; ATP: adenosine triphosphate; Cas9: CRISPR associated protein 9; CD: Crohn disease; CQ: chloroquine; Csf2 : colony stimulating factor 2; Cxcl1 : c-x-c motif chemokine ligand 1; DMSO: dimethyl sulfoxide; DSS: dextran sodium sulfate; EFNB1: ephrin B1; EPHB2: EPH receptor B2; EPHB3: EPH receptor B3; EPHB2 K788R : lysine 788 mutated to arginine in EPHB2; EPHB2 K892R : lysine 892 mutated to arginine in EPHB2; ER: endoplasmic reticulum; FITC: fluorescein isothiocyanate; GFP: green fluorescent protein; GWAS: genome-wide association studies; HRP: horseradish peroxidase; HSPA5/BiP: heat shock protein family A (Hsp70) member 5; IBD: inflammatory bowel diseases; Il1b : interleukin 1 beta; Il6 : interleukin 6; IRGM:immunity related GTPase M; i.p.: intraperitoneally; IPP: inorganic pyrophosphatase; KD: knockdown; KO: knockout; MAP1LC3B: microtubule associated protein 1 light chain 3 beta; MTOR: mechanistic target of rapamycin kinase; NOD2: nucleotide binding oligomerization domain containing 2; PI3K: phosphoinositide 3-kinase; PtdIns3K: class III phosphatidylinositol 3-kinase; RNF186: ring finger protein 186; RNF186 A64T : alanine 64 mutated to threonine in RNF186; RNF186 R179X : arginine 179 mutated to X in RNF186; RPS6: ribosomal protein S6; Tnf : tumor necrosis factor; SQSTM1: sequestosome 1; Ub: ubiquitin; UBE2D2: ubiquitin conjugating enzyme E2 D2; UBE2H: ubiquitin conjugating enzyme E2 H; UBE2K: ubiquitin conjugating enzyme E2 K; UBE2N: ubiquitin conjugating enzyme E2 N; UC: ulcerative colitis; ULK1:unc-51 like autophagy activating kinase 1; WT: wild type.

Opportunistic fungal infections have become one of the leading causes of death among immunocompromised patients, resulting in an estimated 1.5 million deaths each year worldwide. The molecular mechanisms that promote host defense against fungal infections remain elusive. Here, we find that Myosin IF (MYO1F), an unconventional myosin, promotes the expression of genes that are critical for antifungal innate immune signaling and proinflammatory responses. Mechanistically, MYO1F is required for dectin-induced α-tubulin acetylation, acting as an adaptor that recruits both the adaptor AP2A1 and α-tubulin N - acetyltransferase 1 to α-tubulin; in turn, these events control the membrane-to-cytoplasm trafficking of spleen tyrosine kinase and caspase recruitment domain-containing protein 9 Myo1f-deficient mice are more susceptible than their wild-type counterparts to the lethal sequelae of systemic infection with Candida albicans Notably, administration of Sirt2 deacetylase inhibitors, namely AGK2, AK-1, or AK-7, significantly increases the dectin-induced expression of proinflammatory genes in mouse bone marrow-derived macrophages and microglia, thereby protecting mice from both systemic and central nervous system C. albicans infections. AGK2 also promotes proinflammatory gene expression in human peripheral blood mononuclear cells after Dectin stimulation. Taken together, our findings describe a key role for MYO1F in promoting antifungal immunity by regulating the acetylation of α-tubulin and microtubules, and our findings suggest that Sirt2 deacetylase inhibitors may be developed as potential drugs for the treatment of fungal infections., Competing Interests: The authors declare no competing interest., (Copyright © 2021 the Author(s). Published by PNAS.)

IL-17A plays an essential role in the pathogenesis of many autoimmune diseases, including psoriasis and multiple sclerosis. Act1 is a critical adaptor in the IL-17A signaling pathway. In this study, we report that an anti-sense long noncoding RNA, TRAF3IP2-AS1 , regulates Act1 expression and IL-17A signaling by recruiting SRSF10, which downregulates the expression of IRF1, a transcriptional factor of Act1. Interestingly, we found that a psoriasis-susceptible variant of TRAF3IP2-AS1 A4165G (rs13210247) is a gain-of-function mutant. Furthermore, we identified a mouse gene E130307A14-Rik that is homologous to TRAF3IP2-AS1 and has a similar ability to regulate Act1 expression and IL-17A signaling. Importantly, treatment with lentiviruses expressing E130307A14-Rik or SRSF10 yielded therapeutic effects in mouse models of psoriasis and experimental autoimmune encephalomyelitis. These findings suggest that TRAF3IP2-AS1 and/or SRSF10 may represent attractive therapeutic targets in the treatment of IL-17-related autoimmune diseases, such as psoriasis and multiple sclerosis., (Copyright © 2021 by The American Association of Immunologists, Inc.)

The TAGAP gene locus has been linked to several infectious diseases or autoimmune diseases, including candidemia and multiple sclerosis. While previous studies have described a role of TAGAP in T cells, much less is known about its function in other cell types. Here we report that TAGAP is required for Dectin-induced anti-fungal signaling and proinflammatory cytokine production in myeloid cells. Following stimulation with Dectin ligands, TAGAP is phosphorylated by EPHB2 at tyrosine 310, which bridges proximal Dectin-induced EPHB2 activity to downstream CARD9-mediated signaling pathways. During Candida albicans infection, mice lacking TAGAP mount defective immune responses, impaired Th17 cell differentiation, and higher fungal burden. Similarly, in experimental autoimmune encephalomyelitis model of multiple sclerosis, TAGAP deficient mice develop significantly attenuated disease. In summary, we report that TAGAP plays an important role in linking Dectin-induced signaling to the promotion of effective T helper cell immune responses, during both anti-fungal host defense and autoimmunity.

The purpose of this study was to explore interactions between limited English proficiency (LEP) status, as a function of risk status (low math performance at the start of the school year), on computation and word-problem solving performance. Among 260 1st-grade students, classified as at-risk (AR) or not at-risk (NAR) for math disability, we compared the performance of LEP students to native English-speaking peers. A series of 2-way ANOVAs were conducted on computation and word-problem solving skill at 2 time points, fall and spring of 1st-grade. On fall computation measures, there was no main effect for LEP status and no interaction between LEP and risk status. On spring computation, a main effect for LEP status had emerged, but again no interaction. By contrast, on fall word-problem solving, there was an interaction between LEP and risk status; however, this interaction was no longer significant by spring. Results suggest that language proficiency is an important factor in the development of computation and word-problem solving skill. Implications for future research are discussed.

Rotational 3-breed crossbred cows of Montbéliarde, Viking Red, and Holstein (CB) were compared with Holstein (HO) cows for alternative measures of feed efficiency as well as income over feed cost (IOFC) and residual feed intake (RFI) during the first 150 d of first, second, and third lactations. Primiparous and multiparous CB (n = 63 and n = 43, respectively) and HO (n = 60 and n = 37, respectively) cows were fed the same total mixed ration twice daily with refusals weighed once daily. Feed was analyzed for dry matter content, net energy for lactation, and crude protein content. Body weight (BW) was recorded twice weekly. Daily production of milk, fat, and protein were estimated from monthly test days with best prediction. Measures of efficiency from 4 to 150 d in milk (DIM) were feed conversion efficiency (FCE), defined as fat plus protein production (kg) per kilogram of dry matter intake (DMI); ECM/DMI, defined as kilograms of energy-corrected milk (ECM) per kilogram of DMI; net energy for lactation efficiency (NE L E), defined as ECM (kg) per megacalorie of net energy for lactation intake; crude protein efficiency (CPE), defined as true protein production (kg) per kilogram of crude protein intake; and DMI/BW, defined as DMI (kg) per kilogram of BW. The IOFC was defined as revenue from fat plus protein production minus feed cost. The RFI from 4 to 150 DIM for each lactation was the residual error remaining from regression of DMI on milk energy output (Mcal), metabolic BW, and energy required for change in BW (Mcal). Statistical analysis of measures of feed efficiency and RFI for primiparous cows included the fixed effects of year of calving and breed group. For multiparous cows, statistical analysis included breed as a fixed effect and cow as a repeated effect nested within breed group. Primiparous CB cows had higher means for FCE (+5.5%), ECM/DMI (+4.0%), NE L E (+4.0%), and CPE (+5.2%) and a lower mean DMI/BW (-5.3%) than primiparous HO cows. Primiparous CB cows ($875) also had higher mean IOFC than primiparous HO cows ($825). In addition, mean RFI from 4 to 150 DIM was significantly lower (more desirable) for primiparous CB cows than HO cows. Likewise, multiparous CB cows had higher means for FCE (+8.2%), ECM/DMI (+5.9%), NE L E (+5.8%), and CPE (+8.1%) and a lower mean for DMI/BW (-4.8%) than multiparous HO cows. Multiparous CB cows ($1,296) also had a higher mean for IOFC than multiparous HO cows ($1,208) and a lower mean for RFI from 4 to 150 DIM than HO cows., (Copyright © 2019 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.)

Rotational crossbred cows of the Montbéliarde, Viking Red, and Holstein (HO) breeds (CB) were compared with HO cows for dry matter intake (DMI), body weight (BW), cow height, body condition score (BCS), and production during the first 150 d of first, second, and third lactations. Primiparous and multiparous CB (n = 63 and 43, respectively) and HO (n = 60 and 37, respectively) cows calved from September 2014 to June 2017. Cows were fed the same total mixed ration twice daily, with refusals weighed once daily. The BW was recorded twice weekly, and height at the withers and the hips was recorded monthly. The BCS was evaluated weekly. The fat plus protein production from 4 to 150 d in milk was calculated from monthly test days using best prediction. Primiparous and multiparous cows were analyzed separately. Statistical analysis for primiparous cows included the fixed effects of year of calving and breed group, and the analysis for multiparous cows included the fixed effect of breed group and the repeated effect of cow nested within breed group. Primiparous CB cows (2,807 kg) had lower mean DMI than HO cows (2,948 kg) from 4 to 150 d in milk of first lactation. Mean BW was not different for the CB (562 kg) and HO (556 kg) cows, but primiparous CB cows had mean wither height that was 4.0 cm shorter and mean hip height that was 2.0 cm shorter than that of HO cows. Primiparous CB cows (3.46) had higher mean BCS compared with HO cows (3.20). Mean fat plus protein production did not differ for the primiparous CB and HO cows (331 vs. 329 kg, respectively). Multiparous CB cows (3,360 kg) also had lower mean DMI than HO cows (3,592 kg) and did not differ (636 kg) from HO cows (644 kg) for mean BW. The CB cows had mean wither height that was 3.5 cm shorter than that of HO cows, but mean hip height did not differ for multiparous CB (145.2 cm) and HO (146.4 cm) cows. Mean BCS was higher for multiparous CB cows (3.25) than for HO cows (3.06), and mean fat plus protein production was not different for multiparous CB (445 kg) and HO (441 kg) cows. The lower DMI of the CB cows than HO cows resulted in less feed cost without loss of revenue from fat plus protein production., (Copyright © 2019 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.)

Although Act1 (adaptor for IL-17 receptors) is necessary for IL-17-mediated inflammatory responses, Act1- (but not Il17ra-, Il17rc-, or Il17rb-) deficient mice develop spontaneous SLE- and Sjögren's-like diseases. Here, we show that Act1 functions as a negative regulator in T and B cells via direct inhibition of STAT3. Mass spectrometry analysis detected an Act1-STAT3 complex, deficiency of Act1 (but not Il17ra-, Il17rc-, or Il17rb) results in hyper IL-23- and IL-21-induced STAT3 activation in T and B cells, respectively. IL-23R deletion or blockade of IL-21 ameliorates SLE- and Sjögren's-like diseases in Act1 -/- mice. Act1 deficiency results in hyperactivated follicular Th17 cells with elevated IL-21 expression, which promotes T-B cell interaction for B cell expansion and antibody production. Moreover, anti-IL-21 ameliorates the SLE- and Sjögren's-like diseases in Act1-deficient mice. Thus, IL-21 blocking antibody might be an effective therapy for treating SLE- and Sjögren's-like syndrome in patients containing Act1 mutation.

This study was designed to deepen insights on whether word-problem (WP) solving is a form of text comprehension (TC) and on the role of language in WPs. A sample of 325 second graders, representing high, average, and low reading and math performance, was assessed on (a) start-of-year TC, WP skill, language, nonlinguistic reasoning, working memory, and foundational skill (word identification, arithmetic) and (b) year-end WP solving, WP-language processing (understanding WP statements, without calculation demands), and calculations. Multivariate, multilevel path analysis, accounting for classroom and school effects, indicated that TC was a significant and comparably strong predictor of all outcomes. Start-of-year language was a significantly stronger predictor of both year-end WP outcomes than of calculations, whereas start-of-year arithmetic was a significantly stronger predictor of calculations than of either WP measure. Implications are discussed in terms of WP solving as a form of TC and a theoretically coordinated approach, focused on language, for addressing TC and WP-solving instruction.

NOTCH1 signalling contributes to defective remyelination by impairing differentiation of oligodendrocyte progenitor cells (OPCs). Here we report that IL-17 stimulation induces NOTCH1 activation in OPCs, contributing to Th17-mediated demyelinating disease. Mechanistically, IL-17R interacts with NOTCH1 via the extracellular domain, which facilitates the cleavage of NOTHC1 intracellular domain (NICD1). IL-17-induced NOTCH1 activation results in the interaction of IL-17R adaptor Act1 with NICD1, followed by the translocation of the Act1-NICD1 complex into the nucleus. Act1-NICD1 are recruited to the promoters of several NOTCH1 target genes (including STEAP4, a metalloreductase important for inflammation and cell proliferation) that are specifically induced in the spinal cord by Th17 cells. A decoy peptide disrupting the IL-17RA-NOTCH1 interaction inhibits IL-17-induced NOTCH1 activation and attenuates Th17-mediated experimental autoimmune encephalitis (EAE). Taken together, these findings demonstrate critical crosstalk between the IL-17 and NOTCH1 pathway, regulating Th17-induced inflammatory and proliferative genes to promote demyelinating disease.

The reactivities of butadiene, cyclopentadiene, furan, thiophene, pyrrole, and their 1-aza- and 2-aza-derivatives in Diels-Alder reactions with ethylene and fumaronitrile were investigated with density functional theory (M06-2X/6-311G(d,p)). The activation free energies for the Diels-Alder reactions of cyclic 1-azadienes are 10-14 kcal mol -1 higher than those of cyclic 2-azadienes, and the reaction free energies are 17-20 kcal mol -1 more endergonic. The distortion/interaction model shows that the increased activation energies of cyclic 1-azadienes originate from increased transition state distortion energies and unfavorable interaction energies, arising from addition to the nitrogen terminus of the C═N bond.

Lipopolysaccharide (LPS)-mediated activation of Toll-like receptors (TLRs) in hepatic macrophages and injury to hepatocytes are major contributors to the pathogenesis of alcoholic liver disease. However, the mechanisms by which TLR-dependent inflammatory responses and alcohol-induced hepatocellular damage coordinately lead to alcoholic liver disease are not completely understood. In this study, we found that mice deficient in interleukin-1 receptor-associated kinase M (IRAKM), a proximal TLR pathway molecule typically associated with inhibition of TLR signaling, were actually protected from chronic ethanol-induced liver injury. In bone marrow-derived macrophages challenged with low concentrations of LPS, which reflect the relevant pathophysiological levels of LPS in both alcoholic patients and ethanol-fed mice, the IRAKM Myddosome was preferentially formed. Further, the IRAKM Myddosome mediated the up-regulation of Mincle, a sensor for cell death. Mincle-deficient mice were also protected from ethanol-induced liver injury. The endogenous Mincle ligand spliceosome-associated protein 130 (SAP130) is a danger signal released by damaged cells; culture of hepatocytes with ethanol increased the release of SAP130. Ex vivo studies in bone marrow-derived macrophages suggested that SAP130 and LPS synergistically activated inflammatory responses, including inflammasome activation., Conclusion: This study reveals a novel IRAKM-Mincle axis that contributes to the pathogenesis of ethanol-induced liver injury. (Hepatology 2016;64:1978-1993)., (© 2016 by the American Association for the Study of Liver Diseases.)

Interleukin 1β (IL-1β) is critical for the in vivo survival, expansion and effector function of IL-17-producing helper T (T(H)17) cells during autoimmune responses, including experimental autoimmune encephalomyelitis (EAE). However, the spatiotemporal role and cellular source of IL-1β during EAE pathogenesis are poorly defined. In the present study, we uncovered a T cell-intrinsic inflammasome that drives IL-1β production during T(H)17-mediated EAE pathogenesis. Activation of T cell antigen receptors induced expression of pro-IL-1β, whereas ATP stimulation triggered T cell production of IL-1β via ASC-NLRP3-dependent caspase-8 activation. IL-1R was detected on T(H)17 cells but not on type 1 helper T (T(H)1) cells, and ATP-treated T(H)17 cells showed enhanced survival compared with ATP-treated T(H)1 cells, suggesting autocrine action of T(H)17-derived IL-1β. Together these data reveal a critical role for IL-1β produced by a T(H)17 cell-intrinsic ASC-NLRP3-caspase-8 inflammasome during inflammation of the central nervous system.

Background & Aims: Single immunoglobulin and toll-interleukin 1 receptor (SIGIRR), a negative regulator of the Toll-like and interleukin-1 receptor (IL-1R) signaling pathways, controls intestinal inflammation and suppresses colon tumorigenesis in mice. However, the importance of SIGIRR in human colorectal cancer development has not been determined. We investigated the role of SIGIRR in development of human colorectal cancer., Methods: We performed RNA sequence analyses of pairs of colon tumor and nontumor tissues, each collected from 68 patients. Immunoblot and immunofluorescence analyses were used to determine levels of SIGIRR protein in primary human colonic epithelial cells, tumor tissues, and colon cancer cell lines. We expressed SIGIRR and mutant forms of the protein in Vaco cell lines. We created and analyzed mice that expressed full-length (control) or a mutant form of Sigirr (encoding SIGIRR(N86/102S), which is not glycosylated) specifically in the intestinal epithelium. Some mice were given azoxymethane (AOM) and dextran sulfate sodium to induce colitis-associated cancer. Intestinal tissues were collected and analyzed by immunohistochemical and gene expression profile analyses., Results: RNA sequence analyses revealed increased expression of a SIGIRR mRNA isoform, SIGIRR(ΔE8), in colorectal cancer tissues compared to paired nontumor tissues. SIGIRR(ΔE8) is not modified by complex glycans and is therefore retained in the cytoplasm-it cannot localize to the cell membrane or reduce IL1R signaling. SIGIRR(ΔE8) interacts with and has a dominant-negative effect on SIGIRR, reducing its glycosylation, localization to the cell surface, and function. Most SIGIRR detected in human colon cancer tissues was cytoplasmic, whereas in nontumor tissues it was found at the cell membrane. Mice that expressed SIGIRR(N86/102S) developed more inflammation and formed larger tumors after administration of azoxymethane and dextran sulfate sodium than control mice; colon tissues from these mutant mice expressed higher levels of the inflammatory cytokines IL-17A and IL-6 had activation of the transcription factors STAT3 and NFκB. SIGIRR(N86/102S) expressed in colons of mice did not localize to the epithelial cell surface., Conclusion: Levels of SIGIRR are lower in human colorectal tumors, compared with nontumor tissues; tumors contain the dominant-negative isoform SIGIRR(ΔE8). This mutant protein blocks localization of full-length SIGIRR to the surface of colon epithelial cells and its ability to downregulate IL1R signaling. Expression of SIGIRR(N86/102S) in the colonic epithelium of mice increases expression of inflammatory cytokines and formation and size of colitis-associated tumors., (Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.)

We recently described the induction of noncanonical IL-1β processing via caspase-8 recruited to ripoptosome signaling platforms in myeloid leukocytes. Here, we demonstrate that activated NLRP3·ASC inflammasomes recruit caspase-8 to drive IL-1β processing in murine bone marrow-derived dendritic cells (BMDC) independent of caspase-1 and -11. Sustained stimulation (>2 h) of LPS-primed caspase-1-deficient (Casp1/11(-/-)) BMDC with the canonical NLRP3 inflammasome agonist nigericin results in release of bioactive IL-1β in conjunction with robust caspase-8 activation. This IL-1β processing and caspase-8 activation do not proceed in Nlrp3(-/-) or Asc(-/-) BMDC and are suppressed by pharmacological inhibition of caspase-8, indicating that caspase-8 can act as a direct IL-1β-converting enzyme during NLRP3 inflammasome activation. In contrast to the rapid caspase-1-mediated death of wild type (WT) BMDC via NLRP3-dependent pyroptosis, nigericin-stimulated Casp1/11(-/-) BMDC exhibit markedly delayed cell death via NLRP3-dependent apoptosis. Biochemical analyses of WT and Casp1/11(-/-) BMDC indicated that caspase-8 is proteolytically processed within detergent-insoluble ASC-enriched protein complexes prior to extracellular export during nigericin treatment. Although nigericin-stimulated caspase-1 activation and activity are only modestly attenuated in caspase-8-deficient (Casp8(-/-)Rip3(-/-)) BMDC, these cells do not exhibit the rapid loss of viability of WT cells. These results support a contribution of caspase-8 to both IL-1β production and regulated death signaling via NLRP3 inflammasomes. In the absence of caspase-1, NLRP3 inflammasomes directly utilize caspase-8 as both a pro-apoptotic initiator and major IL-1β-converting protease. In the presence of caspase-1, caspase-8 acts as a positive modulator of the NLRP3-dependent caspase-1 signaling cascades that drive both IL-1β production and pyroptotic death., (© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.)

IL-25 is a member of the IL-17 family of cytokines that promotes Th2 cell-mediated inflammatory responses. IL-25 signals through a heterodimeric receptor (IL-25R) composed of IL-17RA and IL-17RB, which recruits the adaptor molecule Act1 for downstream signaling. Although the role of IL-25 in potentiating type 2 inflammation is well characterized by its ability to activate the epithelium as well as T cells, the components of its signaling cascade remain largely unknown. In this study, we found that IL-25 can directly activate STAT5 independently of Act1. Furthermore, conditional STAT5 deletion in T cells or epithelial cells led to a defective IL-25-initiated Th2 polarization as well as defective IL-25 enhancement of Th2 responses. Finally, we found that STAT5 is recruited to the IL-25R in a ligand-dependent manner through unique tyrosine residues on IL-17RB. Together, these findings reveal a novel Act1-independent IL-25 signaling pathway through STAT5 activation., (Copyright © 2015 by The American Association of Immunologists, Inc.)

Objective: There are limited clinical treatments for temporomandibular joint (TMJ) pathologies, including degenerative disease, disc perforation and heterotopic ossification (HO). One barrier hindering the development of new therapies is that animal models recapitulating TMJ diseases are poorly established. The objective of this study was to develop an animal model for TMJ cartilage degeneration and disc pathology, including disc perforation and soft tissue HO., Methods: New Zealand white rabbits (n = 9 rabbits) underwent unilateral TMJ disc perforation surgery and sham surgery on the contralateral side. A 2.5 mm defect was created using a punch biopsy in rabbit TMJ disc. The TMJ condyles and discs were evaluated macroscopically and histologically after 4, 8 and 12 weeks. Condyles were blindly scored by four independent observers using OARSI recommendations for macroscopic and histopathological scoring of osteoarthritis (OA) in rabbit tissues., Results: Histological evidence of TMJ condylar cartilage degeneration was apparent in experimental condyles following disc perforation relative to sham controls after 4 and 8 weeks, including surface fissures and loss of Safranin O staining. At 12 weeks, OARSI scores indicated experimental condylar cartilage erosion into the subchondral bone. Most strikingly, HO occurred within the TMJ disc upon perforation injury in six rabbits after 8 and 12 weeks., Conclusion: We report for the first time a rabbit TMJ injury model that demonstrates condylar cartilage degeneration and disc ossification, which is indispensible for testing the efficacy of potential TMJ therapies., (Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Molecular ordering and charge transport have been studied computationally for 22 conjugated oligomers fabricated as crystal or thin-film semiconductors. Molecular dynamics (MD) simulations are employed to equilibrate crystal morphologies at 300 K. The paracrystalline order parameter, g, is calculated to characterize structural order in the materials. Charge-transport dynamics are predicted using kinetic Monte Carlo methods based on a charge-hopping mechanism described by the Marcus theory of electron transfer to calculate charge-transfer rates using the VOTCA package. We introduce an error function to assess the reliability of our computed values to reproduce experimental hole mobilities in both crystalline and thin-film morphologies of the 22 conjugated oligomers. For each of the oligomers, we compute hole mobility with three different theoretical models incorporating increasing measures of disorder: (1) a perfect crystal, based on the experimentally derived crystal structure, with no disorder, (2) an MD-equilibrated structure incorporating thermal disorder into the crystal structure, and (3) model 2 above but also incorporating energetic disorder arising from variations in site energies. For the series of known crystals with long-range order, we find that the perfect crystal model produces hole mobilities giving the best fit to experimental data. For the series of thin-film morphologies with short-range order, we observe that the presence of both thermal and energetic disorder is essential for accurate calculation. We also discuss the interplay between hole mobility and other charge-transport parameters in these morphologies, such as reorganization energy and energetic disorder.

The objective of the present study was to evaluate the antioxidant potential and the wound healing effect of the ethanolic extract of the bark of Calotropis procera. The antioxidant study was evaluated in vitro, using 2,2-diphenylpicrylhydrazyl (DPPH) and deoxyribose degradation assays. Wound healing was studied using excision and incision wound on normal and dexamethasone-suppressed wound healing rodent models. Alkaloids, flavonoids, proteins and phenols were screened in the extract used whereas saponins and true tannins were absent. The extract contains only 12.5 gallic acid equivalent and 399.54 rutin equivalent. It was found to inhibit DPPH and deoxyribose oxidation (IC50 = 24.24 and 5.40 respectively). In vivo study demonstrated a significant reduction in the epithelialization time (P < 0.001) to 17-18 days in normal and dexamethasone treated rats following the ethanolic extract of the bark of C. procera application. The same extract also significantly increased the breaking strength in dexamethasone treated rats. Histological examination of incision wounds of treated group showed matured extracellular matrix, numerous fibroblasts. This study illustrated an excellent potential of the bark of C. procera therapy on dermal wound healing, with a tentative mechanism of action related to improved collagen deposition and reduced inflammatory reaction.

The inflammasomes are multiprotein complexes that activate caspase-1 in response to infections and stress, resulting in the secretion of pro-inflammatory cytokines. Here we report that IκB kinase α (IKKα) is a critical negative regulator of apoptosis-associated specklike protein containing a C-terminal caspase-activation-andrecruitment (CARD) domain (ASC)-dependent inflammasomes. IKKα controls the inflammasome at the level of the adaptor ASC, which interacts with IKKα in the nucleus of resting macrophages in an IKKα kinase-dependent manner. Loss of IKKα kinase activity results in inflammasome hyperactivation. Mechanistically, the downstream nuclear effector IKK-related kinase (IKKi) facilitates translocation of ASC from the nucleus to the perinuclear area during inflammasome activation. ASC remains under the control of IKKα in the perinuclear area following translocation of the ASC/IKKα complex. Signal 2 of NLRP3 activation leads to inhibition of IKKα kinase activity through the recruitment of PP2A, allowing ASC to participate in NLRP3 inflammasome assembly. Taken together, these findings reveal a IKKi-IKKα-ASC axis that serves as a common regulatory mechanism for ASC-dependent inflammasomes.

The purpose of this research was to determine if there was a relationship between the leadership style of the nursing department head and the level of professional satisfaction and organizational commitment by nursing faculty members. The survey instrument was designed to measure the department heads' leadership style as perceived by the nursing faculty and assess the nursing faculty members' level of professional satisfaction and organizational commitment. Five schools of nursing in 2 Midwestern states, with a total of 52 full-time baccalaureate nursing faculty, were the focus of the inquiry. Findings support statistically significant relationships between the 3 variables of department head leadership, organizational commitment, and professional satisfaction. Implications for leadership style exhibited by the nursing department head are discussed.

Act1 is an essential adaptor in interleukin 17 (IL-17)-mediated signaling and is recruited to the receptor for IL-17 after stimulation with IL-17. Here we found that Act1 was a 'client' protein of the molecular chaperone hsp90. The D10N variant of Act1 (Act1(D10N)) that is linked to susceptibility to psoriasis was defective in its interaction with hsp90, which resulted in a global loss of Act1 function. Act1-deficient mice modeled the mechanistic link between loss of Act1 function and susceptibility to psoriasis. Although Act1 was necessary for IL-17-mediated inflammation, Act1-deficient mice had a hyperactive response of the T(H)17 subset of helper T cells and developed spontaneous IL-22-dependent skin inflammation. In the absence of IL-17 signaling, IL-22 was the main contributor to skin inflammation, which provides a molecular mechanism for the association of Act1(D10N) with psoriasis susceptibility.

Objective: To describe our experience with developing, implementing, and evaluating the educational effect of a school health experience for pediatric residents., Design: Descriptive., Setting: University-based pediatric residency program and five public elementary and middle schools in surrounding communities., Participants: Eleven pediatric residents., Intervention: A school health experience for pediatric residents was developed in response to the report of the American Academy of Pediatrics Task Force on Pediatric Education and the new training recommendations of the Residency Review Committee of the American Council for Graduate Medical Education. Residents spent 3 weeks in the schools engaged in teaching and observational activities., Main Outcome Measures: Questionnaires of residents' attitudes and knowledge, structured resident interviews, and teacher questionnaires., Results: Positive effect on resident's knowledge of school structure, child development, communication with children, school-related problems, and special education. Positive effects on resident's attitudes about teamwork between teachers and pediatricians and roles of pediatricians in schools. Teacher feedback showed acceptance by the school community., Conclusions: Pediatric residents benefit from exposure to children in school settings. Schools provide an opportunity to observe normal childhood development and behavior in a more natural setting than that provided in the hospital.