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The peptide editor TAPBPR is the newest member of the major histocompatibility complex class I (MHC-I) antigen processing and presentation pathway. Since 2013, studies have explored the functions and mechanisms of action of this tapasin homolog. Here, we review the key insights gained from structural studies of the TAPBPR:MHC-I complex and the involvement of the TAPBPR loop in peptide exchange. However, despite recent advances, the question still remains: why do we need TAPBPR? The recent appreciation that different MHC-I allotypes vary in their ability to interact with TAPBPR, together with a role for TAPBPR in alternative presentation pathways highlights that much remains unknown concerning the biological need for TAPBPR.

Over the last decades, the intense need for more robust and lightweight structures, together with the dramatic improvement of computational power, had, as a result, the introduction of simulations in the traditional product development. As a simulation, it is considered any computer process that imitates a real system by generating similar responses over time. Simulations allow the designers to create virtual prototypes that can speed up the design phase and, thus, the product development time in total. This design paradigm shift is called simulation-based design (SBD) and includes several simulations and optimization techniques. The most notable of these techniques are; computer-aided design (CAD), finite element analysis (FEA), topology optimization (TO), and parametric optimization (PO). A combined SBD methodology, including these techniques, is presented here. This methodology is a two-stage optimization process. During the first stage, traditional compliance TO using the SIMP approach was conducted, while at the second, a PO with an evolutionary algorithm was applied. The presented methodology is focused on the optimization of composite laminates. In particular, an angle-ply laminated beam made by carbon fiber reinforced polymer (FRP) was used as a case study and optimized both for its topology and fibers’ direction. The results of this research are presented and tested using a commercial example. The suggested methodology resulted in a lighter and more robust design solution. These design solutions can be constructed either by conventional manufacturing processes (CMP) or by additive manufacturing (AM). Designers looking for interesting and lightweight composited structures can exploit the results found in this paper. The implemented process can easily be modified in order to cover any possible optimization of FRP products.

From observations of colloidal tracer particles in fibrin undergoing gelation, we introduce an analytical framework that allows the determination of the probability density function for a stochastic process beyond fractional Brownian motion. Using passive microrheology via videomicroscopy, mean square displacements of tracer particles suspended in fibrin at different ageing times are obtained. The anomalous diffusion is then described by a damped white noise process with memory, with analytical results closely matching experimental plots of mean square displacements and probability density function. We further show that the white noise functional stochastic approach applied to passive microrheology reveals the existence of a gelation parameter μ which elucidates the dynamics of constrained tracer particles embedded in a time-dependent soft material. In addition, we found that microstructural heterogeneity of particle environments decreases as the ageing time increases. This study offers experimental insights on the ageing of fibrin gels while presenting a white noise functional stochastic approach that could be applied to other systems exhibiting non-Markovian diffusive behavior.

The recombinant yellow fever-17D-dengue virus, live, attenuated, tetravalent dengue vaccine (CYD-TDV) is licensed in several dengue-endemic countries. Although the vaccine provides protection against dengue, the level of protection differs by serotype and warrants further investigation. We characterized the antigenic properties of each vaccine virus serotype using highly neutralizing human monoclonal antibodies (hmAbs) that bind quaternary structure-dependent epitopes. Specifically, we monitored the binding of dengue virus-1 (DENV-1; 1F4), DENV-2 (2D22) or DENV-3 (5J7) serotype-specific or DENV-1-4 cross-reactive (1C19) hmAbs to the four chimeric yellow fever-dengue vaccine viruses (CYD-1-4) included in phase III vaccine formulations using a range of biochemical and functional assays (dot blot, ELISA, surface plasmon resonance and plaque reduction neutralization assays). In addition, we used the "classic" live, attenuated DENV-2 vaccine serotype, immature CYD-2 viruses and DENV-2 virus-like particles as control antigens for anti-serotype-2 reactivity. The CYD vaccine serotypes were recognized by each hmAbs with the expected specificity, moreover, surface plasmon resonance indicated a high functional affinity interaction with the CYD serotypes. In addition, the hmAbs provided similar protection against CYD and wild-type dengue viruses in the in vitro neutralization assay. Overall, these findings demonstrate that the four CYD viruses used in clinical trials display key conformational and functional epitopes targeted by serotype-specific and/or cross-reactive neutralizing human antibodies. More specifically, we showed that CYD-2 displays serotype- specific epitopes present only on the mature virus. This indicates that the CYD-TDV has the ability to elicit antibody specificities which are similar to those induced by the wild type DENV. Future investigations will be needed to address the nature of CYD-TDV-induced responses after vaccine administration, and how these laboratory markers relate to vaccine efficacy and safety.

Chronic graft-versus-host disease (cGVHD) targets include the oral mucosa and salivary glands after allogeneic hematopoietic stem cell transplant (HSCT). Without incisional biopsy, no diagnostic test exists to confirm oral cGVHD. Consequently, therapy is often withheld until severe manifestations develop. This proteomic study examined saliva and human salivary gland for a biomarker profile at first onset of oral cGVHD prior to initiation of topical steroid therapy. Whole saliva collected at onset of biopsy-proven oral GVHD was assessed using liquid chromatography coupled tandem mass spectrometry with identification of 569 proteins, of which 77 significantly changed in abundance. ZG16B, a secretory lectin protein, was reduced 2-fold in oral cGVHD saliva (p < 0.05), and significantly decreased in salivary gland secretory cells affected by cGVHD. Single-cell RNAseq analysis of healthy MSG localized ZG16B expression to two discreet acinar cell populations. Reduced ZG16B expression may indicate specific cGVHD activity and possibly general salivary gland dysfunction.

Sphingomyelin nanosystems have already shown to be promising carriers for efficient delivery of anticancer drugs. For further application in the treatment of pancreatic tumor, the investigation on relevant in vitro models able to reproduce its physio-pathological complexity is mandatory. Accordingly, a 3D heterotype spheroid model of pancreatic tumor has been herein constructed to investigate the potential of bare and polyethylene glycol-modified lipid nanosystems in terms of their ability to penetrate the tumor mass and deliver drugs. Regardless of their surface properties, the lipid nanosystems successfully diffused through the spheroid without inducing toxicity, showing a clear safety profile. Loading of the bare nanosystems with a lipid prodrug of gemcitabine was used to evaluate their therapeutic potential. While the nanosystems were more effective than the free drug on 2D cell monocultures, this advantage, despite their efficient penetration capacity, was lost in the 3D tumor model. The latter, being able to mimic the tumor and its microenvironment, was capable to provide a more realistic information on the cell sensitivity to treatments. These results highlight the importance of using appropriate 3D tumor models as tools for proper in vitro evaluation of nanomedicine efficacy and their timely optimisation, so as to identify the best candidates for later in vivo evaluation.

Vaccine thermostability is key to successful global immunization programs as it may have a significant impact on the continuous cold-chain maintenance logistics, as well as affect vaccine potency. Modern biological and biophysical techniques were combined to in-depth characterize the thermostability of a formulated rabies virus (RABV) in terms of antigenic and genomic titer, virus particle count and aggregation state. Tunable resistive pulse sensing (TRPS) and nanoparticle tracking analysis (NTA) were used to count virus particles while simultaneously determining their size distribution. RABV antigenicity was assessed by NTA using a monoclonal antibody that recognize a rabies glycoprotein (G protein) conformational epitope, enabling to specifically count antigenic rabies viruses. Agreement between antigenicity results from NTA and conventional method, as ELISA, was demonstrated. Additionally, NTA and ELISA showed mirrored loss of RABV antigenicity during forced degradation studies performed between 5 °C and 45 °C temperature exposure for one month. Concomitant with decreased antigenicity, emergence of RABV particle populations larger than those expected for rabies family viruses was observed, suggesting RABV aggregation induced by thermal stress. Finally, using a kinetic-based modeling approach to explore forced degradation antigenicity data (NTA, ELISA), a two-step model accurately describing antigenicity loss was identified. This model predicted a RABV shelf-life of more than 3 years at 5 °C; significant loss of antigenicity was predicted for samples maintained several months at ambient temperature. This thorough characterization of RABV forced degradation study originally provided a time-temperature mapping of RABV stability.

Accepted manuscript version. Published version available at https://doi.org/10.1016/j.jrurstud.2018.03.005. Accepted manuscript version, licensed CC BY-NC-ND 4.0. Many rural communities experience new growth through in-migration. In Herøy, Northern Norway, this is a result of increased labour migration in the fishing industry and a comprehensive effort by the municipality to encourage migrant workers to settle there. This paper addresses the ambiguities of creating stability through mobility. Through a case study from Herøy, we explore the complex relations between migrants' mobile economic practices and social integration processes by analysing how migrants engage with Herøy's landscape in multiple manners. This landscape entails networks of people and relations, materialities, dreams and hopes. Studying engagement, in addition to contestations and intersecting trajectories, we analyse how the landscape of those on the move is interrelated with that of those “being moved through”. We argue that creating stability in rural communities by encouraging migrant settlement requires going beyond economic integration – emphasising the more versatile and vulnerable processes of relating to unfamiliar places and worlds. It also requires an understanding of stability that embraces uncertainty and opens up towards various forms of belonging.

Summary Chronic graft-versus-host disease (cGVHD) targets include the oral mucosa and salivary glands after allogeneic hematopoietic stem cell transplant (HSCT). Without incisional biopsy, no diagnostic test exists to confirm oral cGVHD. Consequently, therapy is often withheld until severe manifestations develop. This proteomic study examined saliva and human salivary gland for a biomarker profile at first onset of oral cGVHD prior to initiation of topical steroid therapy. Whole saliva collected at onset of biopsy-proven oral GVHD was assessed using liquid chromatography–coupled tandem mass spectrometry with identification of 569 proteins, of which 77 significantly changed in abundance. ZG16B, a secretory lectin protein, was reduced 2-fold in oral cGVHD saliva (p, Graphical abstract, Highlights • Salivary glands are targets of chronic graft-versus-host disease (cGVHD) • Saliva and salivary glands at onset of oral cGVHD have reduced ZG16B protein • ZG16b gene expression localizes to two types of salivary gland excretory cells • ZG16B expression loss may indicate cGVHD activity or general salivary gland damage, Pathophysiology; Proteomics; Transcriptomics

The shear behavior of reinforced concrete (RC) beams has been a major research area for a long time. Since the shear response of RC beams is affected by different factors, many researchers have reported that the nature of shear behavior is complicated. One of these factors worth investigating is the inclination of shear reinforcements. This paper investigated the effect of the orientation of stirrups on the shear capacity of RC beams as the shear-span-to-depth ratio (a/d) varies. The contribution of concrete compressive strength was also studied. An experimental program investigating 21 RC beams has been conducted. The test results revealed that the shear capacity increases as the arrangement of stirrup changes from conventional vertical arrangement to inclined arrangement. However, the increment is high in beams with (a/d) ratio of 2.2 than beams with (a/d) ratio of 2.6, which are relatively slender. Shear capacity also increases as concrete compressive strength increase, which shows that concrete contribution to the shear capacity of beams should be taken in to account. In addition to the experimental test, the beams were analyzed numerically by using a general-purpose finite element package, Abaqus. The shear capacity of reinforced concrete beams obtained from the numerical analysis is in a good agreement with the experimental result. The results obtained by numerical analysis and experimental tests are compared to analytically calculated values by using shear provisions of ACI 318-14 and EN-2. Both ACI 318-14 and EN-2 are generally conservative in predicting the shear capacity of RC beams. However, the conservativeness of these codes reduced as a/d ratio of the beams increase., Orientation of stirrups, shear-span-to-depth ratio, shear capacity of RC beams, concrete compressive strength, diagonal splitting

Understanding the dynamic transcriptional landscape throughout organ development will provide a template for regenerative therapies. Here, we generated a single-cell RNAseq atlas of murine submandibular glands identifying transcriptional profiles associated with cellular heterogeneity during landmark developmental events: endbud formation, branching morphogenesis, cytodifferentiation, maturation, and homeostasis. Trajectory inference analysis predicts unexpected lineage relationships during development, early specification of myoepithelial and basal duct cells, and suggests plasticity among acinar and duct populations. We identify transcription factors correlated with acinar differentiation including upregulation of Spdef, Etv1, and Xbp1, and loss of Ybx1, Eno1 and Atf3/4. Furthermore, we characterize two intercalated duct subsets defined by either Gfra3 and Kit, or Gstt1. This organ-specific atlas can be used to investigate specific cell functions and comparative studies predicting common mechanisms involved in development of branching organs.

Background It remains unknown whether infliximab (IFX) successfully can be discontinued once Crohn's disease (CD) patients have attained sustained, complete clinical, biochemical, and endoscopic remission. No randomized, placebo (PBO) controlled trial has previously assessed this. Methods This double-blind, randomized, PBO-controlled multicenter trial enrolled patients with luminal CD who had been treated with standard IFX maintenance therapy for at least 1 year, in complete remission at the time of inclusion defined as CD Activity Index (CDAI) 150 with an increase in CDAI >70-point from baseline over two consecutive weeks; or definitive clinical relapse requiring immediate intervention as judged by treating physician) in the intention-to-treat population. Results The study population comprised 115 patients (n=54 female; age median 34 years [IQR 26-50]; disease duration median 6 years [3-12]; IFX treatment duration median 23 months [16-39]). All patients were in combined clinical- (CDAI median 41 [IQR 15-66]), biochemical- (CRP median 3mg/L [IQR 2-4]), and endoscopic- (Simple Endoscopic Score for CD median 0, [IQR 0-0] (n=99)) remission. Patients were randomized to continued IFX therapy (n=59) or to start PBO infusions (n=56) (Figure 1). Time to relapse was significantly shorter among patients who discontinued IFX as compared to those continuing IFX (p 150) the figures were 47% in the PBO group vs. 98% in IFX group (p Conclusion This first double-blinded placebo-controlled RCT of IFX withdrawal in Crohn's disease patients strongly suggests that discontinuation of IFX leads to a considerable risk of relapse despite combined clinical, biochemical, and endoscopic remission. Download : Download high-res image (53KB) Download : Download full-size image Download : Download high-res image (56KB) Download : Download full-size image

This paper discusses finite element analysis of crack propagation in pavement slabs-on-grade with aggregate interlock joints, using the finite element package ABAQUS ®6.9-2. The fracture process is idealized using nonlinear fracture mechanics approach implemented through cohesive elements. Load transfer at the joint is achieved by aggregate interlock mechanism simulated in accordance with Walraven’s nonlinear constitutive relations. The proposed discretization is first verified by comparing the pre-crack responses with experimental and numerical results published by independent researchers. Then the discretization is extended to post-crack analysis of slab responses. Parametric studies are conducted concerning the effects of joint opening and aggregate size on post-crack pavement responses. It is observed that load transfer efficiency with respect to load, vertical and crack mouth opening displacements decreases almost linearly with increasing joint opening. Aggregate size is found to have a negligible effect when the initial joint opening is small. On the other hand, as initial joint opening increases, larger aggregate particles result in stiffer joint behavior. A daytime temperature profile is observed to reduce both the peak load supported by the slab system and the load transfer efficiency of the joint, while a nighttime temperature distribution results in modest increases in these metrics. It is concluded that the proposed approach lays a computational basis for further exploration of fracture analysis in jointed slab-on-grade systems. The step-by-step methodology implemented in this study may contribute to the ongoing development of rational failure criteria that can replace the statistical/empirical algorithms currently used in pavement design procedures.

A large number of breast cancers are characterized by amplification and overexpression of the chromosome segment surrounding the HER2 (ERBB2) oncogene. As the HER2 amplicon at 17q12 contains multiple genes, we have systematically explored the role of the HER2 co-amplified genes in breast cancer cell growth and their relation to trastuzumab resistance. We integrated array comparative genomic hybridization (aCGH) data of the HER2 amplicon from 71 HER2 positive breast tumors and 10 cell lines with systematic functional RNA interference analysis of 23 core amplicon genes with several phenotypic endpoints in a panel of trastuzumab responding and non-responding HER2 positive breast cancer cells. In this Data in Brief we give a detailed description of the experimental procedures and the data analysis methods used in the study (1).

SummarySmall noncoding miRNAs represent underexplored targets of genomic aberrations and emerging therapeutic targets. The 3q26.2 amplicon is among the most frequent genomic aberrations in multiple cancer lineages including ovarian and breast cancers. We demonstrate that hsa-miR-569 (hereafter designated as miR569), which is overexpressed in a subset of ovarian and breast cancers, at least in part due to the 3q26.2 amplicon, alters cell survival and proliferation. Downregulation of TP53INP1 expression by miR569 is required for the effects of miR569 on survival and proliferation. Targeting miR569 sensitizes ovarian and breast cancer cells overexpressing miR569 to cisplatin by increasing cell death both in vitro and in vivo. Thus targeting miR569 could potentially benefit patients with the 3q26.2 amplicon and subsequent miR569 elevation.

Regional development – including in the Arctic – relies heavily on in-migration, skills acquisition and international expertise. This paper is based on a qualitative study (Part of the fieldwork was undertaken with Dr. T. Fossland, University of Tromso.) of highly skilled immigrants in Tromso, Norway, undertaken while migrants attended the Global Future talent mobilisation programme. It builds on migrant narratives and observations, showing both women and men migrate for non-work reasons – often marriage or love. While previous studies focused on women as dependent migrants and described the ‘de-skilling’ of highly skilled migrants during migration, this study addresses the mechanisms which make entering labour markets a problem, prior to the deskilling, for men and women. Acknowledging that love migration is grounded in processes outside the labour market, and that migrants enter a specific local labour market, I employ a contextual perspective focused on gender and place. Theories on the transfer of skills are added to understand the processes of accessing and exclusion from skilled labour markets. The study finds gendered expectations and norms affect both women and men’s participation in labour markets. It shows how both the scale and structure of a local labour market are important in understanding exclusion processes and that going beyond language proficiency, localised knowledge and access to local non-migrant networks seem necessary to make skills relevant. These findings strengthen our understanding of migrants’ exclusion, and the spatial , social and cultural embeddedness of skills.

The present study describes the coupling between optical properties and the dynamics of phytoplankton distribution and photosynthetic capacity in the Lysefjord during an exceptional coastal upwelling. At the mouth of the fjord, transparent Coastal water was “piled up” against the sill, while more turbid Fjord water from the outer fjord system was flowing over the sill, creating the intermediate layer which extended further into the fjord. This was reflected by high spectral attenuation coefficients in the upper 10 m of the fjord. Outside the sill, clear water with low spectral attenuation coefficients were found below sill depth down to at least 30 m, while the attenuation coefficients inside the sill were significantly higher between 10 and 20 m. About 4–7 km outwards from the head of the fjord clearer deep basin water was entering the upper layer due to the upwelling which could be traced up to 7 m, bounded by the 7.5 °C and the 31 salinity isolines. In the outer part of the fjord waters with a high chl a content and photosynthetic capacity were observed below the outflowing surface layer containing “old water” from the inner part of the fjord, which was characterized by low nutrient and chl a concentrations. Maximum quantum efficiencies (0.5) were encountered within this subsurface layer. Quantum efficiencies exceeded 0.3 when nitrate and silicate concentrations increased above 2 mmol m −3 . About 50% of the PAR light attenuation (0–30 m) was caused by chl a , and the 1% light depth varied between 27 and 35 m along the transect. Due to the influence of freshwater outlets, non-pigmented particles were more abundant in the inner part of the fjord than in the outer part. Colored dissolved organic matter (CDOM) contributed strongly to absorption within the upper 10 m at wavelengths below 470 nm while scattering was the major attenuation contributor for wavelengths above 600 nm. With respect to possible climate change effects on the growth of phytoplankton in Norwegian fjords, our results indicate that the alteration of coastal wind patterns due to its impact on coastal – fjord water exchanges, is probably more important than increased temperature and/or increased precipitation.

Resumen Recientes evidencias clinicas y experimentales sugieren que los efectos de las estatinas se extienden mas alla del descenso del colesterol de baja densidad (c-LDL) y pueden disminuir la respuesta inflamatoria que caracteriza a la aterosclerosis, al bajar la concentracion de citocinas. Objetivo El objetivo del estudio fue evaluar los efectos antiinflamatorios de la simvastatina midiendo marcadores inflamatorios de riesgo cardiovascular como: proteina C reactiva (PCR), factor de necrosis tumoral α (TNFα), interleucina (IL) 1, IL-6, superoxido dismutasa (SOD) y 8-isoprostano F2α, ademas de efectos sobre la disminucion del colesterol total, del c-LDL, de los trigliceridos, sobre el colesterol de alta densidad (c-HDL), y sobre parametros metabolicos como la glucemia y el acido urico. Materiales y metodos Estudio prospectivo, observacional y analitico de una serie de casos. La poblacion incluyo pacientes de la Policlinica Pempaire de Maracaibo y del Hospital Vargas de Caracas; un total de 21 pacientes de ambos sexos que como criterio de inclusion presentaban hipercolesterolemia. Resultados A las 8 semanas se observo disminucion del colesterol total, LDL, TNFα, IL-6, PCR y glucemia, ademas de aumento de HDL y de SOD. Conclusion En corto tiempo las estatinas disminuyen la inflamacion gracias a la disminucion del TNFα y mejoran el estado oxidativo al aumentar la SOD, lo que puede mejorar la disfuncion de HDL.

Specific cytopathologic changes represent an important tool for the identification of a viral infection. After primary infection, generally during childhood, BK and JC polyomaviruses often remain latent within the urinary tract and can reactivate along life. These reactivations are usually encountered in immunosuppressed patients. In renal transplanted recipients, BK virus may cause a polyomavirus nephropathy inducing sometimes graft loss. A good morphologic sign of reactivation is characterized by the shedding in urine of viral-infected cells called decoy cells. The latter are easily identified in urine from renal transplanted patients but in other circumstances, they may be misdiagnosed as high-grade urothelial carcinoma cells. Correct cytological identification of decoy cells, confirmation of the diagnosis by urine PCR analysis and use of immunocytochemistry with anti-SV40 antibody are of good value for differential diagnosis in most cases. However, polyomavirus reactivation and urothelial carcinoma cells may be observed in the same urine specimen. The possible involvement of BK or JC virus in the pathogenesis of human urogenital tumors has been suggested by some studies but is not yet conclusively resolved.

International audience; Thanks to their design characteristics (i.e., colors, brightness, opacity, etc.) and/or physical properties (i.e., durability, low thermal conductivity, tightness, etc.), glazes find numerous applications, from art ornamenting to protection against corrosion. Glazing consists in coating a substrate by fusing various mineral substances over it. This is a low cost process and hence can be applied on large surfaces. Conventional glazing process needs a relatively high temperature treatment (i.e., up to 1400 °C) that heat-sensitive substrates do not sustain. Thermal spraying may be a good solution to prevent the substrate from thermal degradation. Flame spraying was considered as the spray technique due to its low operating cost and the possibility to adapt the glaze transition temperature to the operating parameters. When spraying glazes, the coating formation mechanism is different from the one encountered with crystallized ceramic materials. Indeed, the high surface tension of those feedstock prevents the particles from being totally spread (i.e., “dewetting” phenomena). Here, the coating results from the coalescence of impinging particles to form a monolayer. The effects of glaze morphology on coatings were studied in this paper. Chemical analysis also permitted to determine the influence of spray parameters on glaze compositions, that can affect glazes thermal properties and hence modify coating structures. At last, the effects of operating parameters on coating architecture were analyzed by experimental design.