Behavior of epoxy bonded bars in concrete affected by alkali-silica reaction

Installation of drilled-in epoxy-bonded reinforcing bars is generally an effective strengthening method to increase the flexural and shear capacities of deficient concrete structures. However, most of the available studies characterizing the bond behavior of epoxy bonded bars in concrete have been carried out on sound concrete elements—that is, without any pathological material damage. This raises the question of bond capacities in existing damaged elements. This study investigates the influence of alkali-silica reaction (ASR) on the capacity of post-installed reinforcing bars. ASR is a deleterious mechanism that causes expansion and cracking in the affected concrete elements. Pullout tests on post-installed reinforcing bars having embedded lengths of 2db, 4db, and 5db with 15M reinforcing bars (db = 15.9 mm [0.626 in.]) have demonstrated a drop-in bond strength when concrete is affected by ASR. In addition, the study revealed that the progression of concrete expansion due to ASR may lead to some confinement of the post-installed reinforcing bar and possibly increases the bond strength

Intronic Binding Sites for hnRNP A/B and hnRNP F/H Proteins Stimulate Pre-mRNA Splicing

hnRNP A/B proteins modulate the alternative splicing of several mammalian and viral pre-mRNAs, and are typically viewed as proteins that enforce the activity of splicing silencers. Here we show that intronic hnRNP A/B–binding sites (ABS) can stimulate the in vitro splicing of pre-mRNAs containing artificially enlarged introns. Stimulation of in vitro splicing could also be obtained by providing intronic ABS in trans through the use of antisense oligonucleotides containing a non-hybridizing ABS-carrying tail. ABS-tailed oligonucleotides also improved the in vivo inclusion of an alternative exon flanked by an enlarged intron. Notably, binding sites for hnRNP F/H proteins (FBS) replicate the activity of ABS by improving the splicing of an enlarged intron and by modulating 5′ splice-site selection. One hypothesis formulated to explain these effects is that bound hnRNP proteins self-interact to bring in closer proximity the external pair of splice sites. Consistent with this model, positioning FBS or ABS at both ends of an intron was required to stimulate splicing of some pre-mRNAs. In addition, a computational analysis of the configuration of putative FBS and ABS located at the ends of introns supports the view that these motifs have evolved to support cooperative interactions. Our results document a positive role for the hnRNP A/B and hnRNP F/H proteins in generic splicing, and suggest that these proteins may modulate the conformation of mammalian pre-mRNAs

Agent-based modelling reveals the role of the tumor microenvironment on the short-term success of combination temozolomide/immune checkpoint blockade to treat glioblastoma

Glioblastoma is the most common and deadly primary brain tumor in adults. All glioblastoma patients receiving standardof- care surgery-radiotherapy-chemotherapy (i.e., temozolomide (TMZ)) recur, with an average survival time of only 15 months. New approaches to the treatment of glioblastoma, including immune checkpoint blockade and oncolytic viruses, offer the possibility of improving glioblastoma outcomes and have as such been under intense study. Unfortunately, these treatment modalities have thus far failed to achieve approval. Recently, in an attempt to bolster efficacy and improve patient outcomes, regimens combining chemotherapy and immune checkpoint inhibitors have been tested in trials. Unfortunately, these efforts have not resulted in significant increases to patient survival. To better understand the various factors impacting treatment outcomes of combined TMZ and immune checkpoint blockade, we developed a systems-level, computational model that describes the interplay between glioblastoma, immune, and stromal cells with this combination treatment. Initializing our model to spatial resection patient samples labeled using imaging mass cytometry, our model's predictions show how the localization of glioblastoma cells, influence therapeutic success. We further validated these predictions in samples of brain metastases from patients given they generally respond better to checkpoint blockade compared with primary glioblastoma. Ultimately, our model provides novel insights into the mechanisms of therapeutic success of immune checkpoint inhibitors in brain tumors and delineates strategies to translate combination immunotherapy regimens more effectively into the clinic.</p