The role of pre-existing Precambrian structures in the development of Rukwa Rift Basin, southwest Tanzania

This study has been supported by BG Group Tanzania (now Shell) under the initiative of the University of Dar es Salaam (Tanzania) - University of Aberdeen (United Kingdom) - BG Group Tanzania (now Shell). Tanzania Petroleum Development Corporation (TPDC) provided aeromagnetic data used in this study at no cost. We are grateful to the editors and anonymous reviewers for detailed and constructive reviews that improved the manuscript.Peer reviewedPostprin

Novel targets for immune-checkpoint inhibition in cancer.

Immune-checkpoint inhibitors have revolutionized cancer therapy, yet many patients either do not derive any benefit from treatment or develop a resistance to checkpoint inhibitors. Intrinsic resistance can result from neoantigen depletion, defective antigen presentation, PD-L1 downregulation, immune-checkpoint ligand upregulation, immunosuppression, and tumor cell phenotypic changes. On the other hand, extrinsic resistance involves acquired upregulation of inhibitory immune-checkpoints, leading to T-cell exhaustion. Current data suggest that PD-1, CTLA-4, and LAG-3 upregulation limits the efficacy of single-agent immune-checkpoint inhibitors. Ongoing clinical trials are investigating novel immune-checkpoint targets to avoid or overcome resistance. This review provides an in-depth analysis of the evolving landscape of potentially targetable immune-checkpoints in cancer. We highlight their biology, emphasizing the current understanding of resistance mechanisms and focusing on promising strategies that are under investigation. We also summarize current results and ongoing clinical trials in this crucial field that could once again revolutionize outcomes for cancer patients

A CD64/FcγRI-mediated mechanism hijacks PD-1 from PD-L1/2 interaction and enhances anti-PD-1 functional recovery of exhausted T cells.

Therapeutic monoclonal antibodies (mAb) targeting the immune checkpoint inhibitor programmed cell death protein 1 (PD-1) have achieved considerable clinical success in anti-cancer therapy through relieving T cell exhaustion. Blockade of PD-1 interaction with its ligands PD-L1 and PD-L2 is an important determinant in promoting the functional recovery of exhausted T cells. Here, we show that anti-PD-1 mAbs act through an alternative mechanism leading to the downregulation of PD-1 surface expression on memory CD4 <sup>+</sup> and CD8 <sup>+</sup> T cells. PD-1 receptor downregulation is a distinct process from receptor endocytosis and occurs in a CD14 <sup>+</sup> monocyte dependent manner with the CD64/Fcγ receptor I acting as the primary factor for this T cell extrinsic process. Importantly, downregulation of surface PD-1 strongly enhances antigen-specific functional recovery of exhausted PD-1 <sup>+</sup> CD8 <sup>+</sup> T cells. Our study demonstrates a novel mechanism for reducing cell surface levels of PD-1 and limiting the inhibitory targeting by PD-L1/2 and thereby enhancing the efficacy of anti-PD-1 Ab in restoring T cell functionality

Statistical Learning in Specific Language Impairment and Autism Spectrum Disorder: A Meta-Analysis

Impairments in statistical learning might be a common deficit among individuals with Specific Language Impairment (SLI) and Autism Spectrum Disorder (ASD). Using metaanalysis, we examined statistical learning in SLI (14 studies, 15 comparisons) and ASD (13 studies, 20 comparisons) to evaluate this hypothesis. Effect sizes were examined as a function of diagnosis across multiple statistical learning tasks (Serial Reaction Time, Contextual Cueing, Artificial Grammar Learning, Speech Stream, Observational Learning, and Probabilistic Classification). Individuals with SLI showed deficits in statistical learning relative to age-matched controls. In contrast, statistical learning was intact in individuals with ASD relative to controls. Effect sizes did not vary as a function of task modality or participant age. Our findings inform debates about overlapping socialcommunicative difficulties in children with SLI and ASD by suggesting distinct underlying mechanisms. In line with the procedural deficit hypothesis (Ullman and Pierpont, 2005), impaired statistical learning may account for phonological and syntactic difficulties associated with SLI. In contrast, impaired statistical learning fails to account for the social-pragmatic difficulties associated with ASD

Mechanical Response of a Lined Pipe Under Dynamic Impact

An experimental and numerical investigation on the mechanical response of a lined pipe (compound pipe) under a dynamic impact is presented. The influence of the impact energy has been studied in terms of the depth of the dent formed, and of the strains and residual stresses. To this end, a three-dimensional explicit dynamic non-linear finite element model has been developed and successfully validated against the results of impact-test experiments conducted on pipes made of AISI 10305 steel, with and without the AISI304 stainless steel liner. The validation was made by comparing numerically computed strains with those measured by strain gauges, as well as in terms of permanent deformation. The model is then utilized to evaluate the residual stresses, the amount of energy dissipation and the velocity of impact process as a function of different pipes (i.e. with or without liner) and of the free drop heights.Design for Resource and Energy efficiency in cerAMic kiln

Human melanomas and ovarian cancers overexpressing mechanical barrier molecule genes lack immune signatures and have increased patient mortality risk.

We have identified eight genes whose expression in human melanoma metastases and ovarian cancers is associated with a lack of Th1 immune signatures. They encode molecules with mechanical barrier function in the skin and other normal tissues and include filaggrin (FLG), tumor-associated calcium signal transducer 2 (TACSTD2), and six desmosomal proteins (DST, DSC3, DSP, PPL, PKP3, and JUP). This association has been validated in an independent series of 114 melanoma metastases. In these, DST expression alone is sufficient to identify melanomas without immune signatures, while FLG and the other six putative barrier molecules are overexpressed in a different subset of melanomas lacking immune signatures. Similar associations have been identified in a set of 186 ovarian cancers. RNA-seq data from 471 melanomas and 307 ovarian cancers in the TCGA database further support these findings and also reveal that overexpression of barrier molecules is strongly associated with early patient mortality for melanoma (p = 0.0002) and for ovarian cancer (p < 0.01). Interestingly, this association persists for FLG for melanoma (p = 0.012) and ovarian cancer (p = 0.006), whereas DST overexpression is negatively associated with CD8(+) gene expression, but not with patient survival. Thus, overexpression of FLG or DST identifies two distinct patient populations with low immune cell infiltration in these cancers, but with different prognostic implications for each. These data raise the possibility that molecules with mechanical barrier function in skin and other tissues may be used by cancer cells to protect them from immune cell infiltration and immune-mediated destruction

Evaluating Literacy Sensitive Client Education Materials for the SMMART Clinic

This master’s project was completed in collaboration with the St. Mary’s Medical and Rehabilitative Therapies (SMMART) Clinic, located on the campus of St. Catherine University in St. Paul, Minnesota. Through the completion of literature reviews, a needs assessment, and project activities, nine graduate occupational therapy students analyzed the needs of this clinic and aimed to improve client care. The SMMART clinic serves primarily Spanish-speaking clients who are low-income, uninsured, or underinsured. This population often faces obstacles in accessing primary health care and rehabilitation, including language and literacy-related barriers. Occupational therapy can play an important role in addressing these barriers and providing high quality care and education that is sensitive to clients’ literacy and language preferences

Does native Trypanosoma cruzi calreticulin mediate growth inhibition of a mammary tumor during infection?

Indexación: Web of Science.Background: For several decades now an antagonism between Trypanosoma cruzi infection and tumor development has been detected. The molecular basis of this phenomenon remained basically unknown until our proposal that T. cruzi Calreticulin (TcCRT), an endoplasmic reticulum-resident chaperone, translocated-externalized by the parasite, may mediate at least an important part of this effect. Thus, recombinant TcCRT (rTcCRT) has important in vivo antiangiogenic and antitumor activities. However, the relevant question whether the in vivo antitumor effect of T. cruzi infection is indeed mediated by the native chaperone (nTcCRT), remains open. Herein, by using specific modified anti-rTcCRT antibodies (Abs), we have neutralized the antitumor activity of T. cruzi infection and extracts thereof, thus identifying nTcCRT as a valid mediator of this effect. Methods: Polyclonal anti-rTcCRT F(ab')(2) Ab fragments were used to reverse the capacity of rTcCRT to inhibit EAhy926 endothelial cell (EC) proliferation, as detected by BrdU uptake. Using these F(ab')(2) fragments, we also challenged the capacity of nTcCRT, during T. cruzi infection, to inhibit the growth of an aggressive mammary adenocarcinoma cell line (TA3-MTXR) in mice. Moreover, we determined the capacity of anti-rTcCRT Abs to reverse the antitumor effect of an epimastigote extract (EE). Finally, the effects of these treatments on tumor histology were evaluated. Results: The rTcCRT capacity to inhibit ECs proliferation was reversed by anti-rTcCRT F(ab')(2) Ab fragments, thus defining them as valid probes to interfere in vivo with this important TcCRT function. Consequently, during infection, these Ab fragments also reversed the in vivo experimental mammary tumor growth. Moreover, anti-rTcCRT Abs also neutralized the antitumor effect of an EE, again identifying the chaperone protein as an important mediator of this anti mammary tumor effect. Finally, as determined by conventional histological parameters, in infected animals and in those treated with EE, less invasive tumors were observed while, as expected, treatment with F(ab')(2) Ab fragments increased malignancy. Conclusion: We have identified translocated/externalized nTcCRT as responsible for at least an important part of the anti mammary tumor effect of the chaperone observed during experimental infections with T. cruzi.http://bmccancer.biomedcentral.com/articles/10.1186/s12885-016-2764-