Transfer of knowledge from model organisms to evolutionarily distant non-model organisms: The coral Pocillopora damicornis membrane signaling receptome

With the ease of gene sequencing and the technology available to study and manipulate non-model organisms, the extension of the methodological toolbox required to translate our understanding of model organisms to non-model organisms has become an urgent problem. For example, mining of large coral and their symbiont sequence data is a challenge, but also provides an opportunity for understanding functionality and evolution of these and other non-model organisms. Much more information than for any other eukaryotic species is available for humans, especially related to signal transduction and diseases. However, the coral cnidarian host and human have diverged over 700 million years ago and homologies between proteins in the two species are therefore often in the gray zone, or at least often undetectable with traditional BLAST searches. We introduce a two-stage approach to identifying putative coral homologues of human proteins. First, through remote homology detection using Hidden Markov Models, we identify candidate human homologues in the cnidarian genome. However, for many proteins, the human genome alone contains multiple family members with similar or even more divergence in sequence. In the second stage, therefore, we filter the remote homology results based on the functional and structural plausibility of each coral candidate, shortlisting the coral proteins likely to have conserved some of the functions of the human proteins. We demonstrate our approach with a pipeline for mapping membrane receptors in humans to membrane receptors in corals, with specific focus on the stony coral, P. damicornis. More than 1000 human membrane receptors mapped to 335 coral receptors, including 151 G protein coupled receptors (GPCRs). To validate specific sub-families, we chose opsin proteins, representative GPCRs that confer light sensitivity, and Toll-like receptors, representative non-GPCRs, which function in the immune response, and their ability to communicate with microorganisms. Through detailed structure-function analysis of their ligand-binding pockets and downstream signaling cascades, we selected those candidate remote homologues likely to carry out related functions in the corals. This pipeline may prove generally useful for other non-model organisms, such as to support the growing field of synthetic biology

Hydroxyapatite-TiO2-SiO2-Coated 316L Stainless Steel for Biomedical Application

This study investigated the effectiveness of titania (TiO2) as a reinforcing phase in the hydroxyapatite (HAP) coating and silica (SiO2) single-layer as a bond coat between the TiO2-reinforced hydroxyapatite (TiO2/HAP) top layer and 316L stainless steel (316L SS) substrate on the corrosion resistance and mechanical properties of the underlying 316L SS metallic implant. Single-layer of SiO2 film was first deposited on 316L SS substrate and studied separately. Water contact angle measurements, X-ray photoelectron spectroscopy (XPS) and Fourier transform infrared (FTIR) spectrophotometer analysis were used to evaluate the hydroxyl group reactivity at the SiO2 outer surface. The microstructural and morphological results showed that the reinforcement of HAP coating with TiO2 and SiO2 reduced the crystallite size and the roughness surface. Indeed, the deposition of 50 vol. % TiO2-reinforced hydroxyapatite layer enhanced the hardness and the elastic modulus of the HAP coating, the introduction of SiO2 inner-layer on the surface of the 316L SS allowed the improvement of the bonding strength and the corrosion resistance as confirmed by scratch studies, nanoindentation and cyclic voltammetry tests

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

Authentication on the Edge: Distributed Authentication for a Global Open Wi-Fi Network

A global-scale, outdoor Internet access infrastructure with low infrastructure costs is finally attainable. Emerging projects are leveraging the proliferation of private Wi-Fi networks to build an access infrastructure from autonomous, independently owned Internet connections. These open Wi-Fi networks aggregate the broadband Internet installations at homes and other private properties into a globalscale shared infrastructure for ubiquitous Internet access. To ensure the traceability and accountability required by the broadband ISPs and private owners of these Wi-Fi networks authentication and authorization are needed. This paper describes Authentication on the Edge, a localized and distributed authentication method for open Wi-Fi networks. Three main ideas are used to adapt to the variability and unreliability of these networks: the use of certificate-based authentication, the distribution of certificate revocation list segments to all entities, and the self organization of access points into a social look-up network. Authentication on the edge combines centralized administration and operator assistance with distributed algorithms to confine the authentication to the edge of the network. These methods achieve the scalability needed for the overwhelming size and volume of a global network and increase resiliency against temporary failures of the infrastructure. Overall authentication delays are reduced by as much as 71% compared to existing authentication schemes applied in the same scenario. Analysis of SMS traces from a large cellular provider show that the social network backend will satisfy all authentication requests as a fallback mechanism.

Metadherin Is a Prognostic Apoptosis Modulator in Mesothelioma Induced via NF-κB-Mediated Signaling

Therapies against malignant pleural mesothelioma (MPM) have yielded disappointing results, in part, because pathologic mechanisms remain obscure. In searching for rational molecular targets, we identified metadherin (MTDH), a multifunctional gene associated with several tumor types but previously unrecognized in MPM. Cox proportional hazards regression analysis delineated associations between higher MTDH expression and lower patient survival from three independent MPM cohorts (n = 349 patients). Through in vitro assays with overexpression and downregulation constructs in MPM cells, we characterized the role of MTDH. We confirmed in vivo the phenotype of altered MTDH expression in a murine xenograft model. Transcriptional regulators of MTDH were identified by chromatin immunoprecipitation. Overexpression of both MTDH mRNA (12-fold increased) and protein levels was observed in tumor tissues. MTDH stable overexpression significantly augmented proliferation, invasiveness, colony formation, chemoresistance, and an antiapoptosis phenotype, while its suppression showed opposite effects in MPM cells. Interestingly, NF-κB and c-Myc (in a feed-forward loop motif) contributed to modulating MTDH expression. Knockdown of MTDH expression profoundly retarded xenograft tumor growth. Thus, our findings support the notion that MTDH integrates upstream signals from certain transcription factors and mediates pathogenic interactions contributing to MPM traits. MTDH represents a new MPM-associated gene that can contribute to insights of MPM biology and, as such, suggest other treatment strategies

Residual Stress, Thermomechanics & Infrared Imaging, Hybrid Techniques and Inverse Problems, Volume 8Proceedings of the 2013 Annual Conference on Experimental and Applied Mechanics /

IX, 377 p. 326 illus., 207 illus. in color.onlin

Low level of tonic interferon signalling is associated with enhanced susceptibility to SARS-CoV-2 variants of concern in human lung organoids

ABSTRACTThere is tremendous heterogeneity in the severity of COVID-19 disease in the human population, and the mechanisms governing the development of severe disease remain incompletely understood. The emergence of SARS-CoV-2 variants of concern (VOC) Delta (B.1.617.2) and Omicron (B.1.1.529) further compounded this heterogeneity. Virus replication and host cell damage in the distal lung is often associated with severe clinical disease, making this an important site to consider when evaluating pathogenicity of SARS-CoV-2 VOCs. Using distal human lung organoids (hLOs) derived from multiple human donors, we compared the fitness and pathogenicity of SARS-CoV-2 VOC Delta and Omicron, along with an ancestral clade B variant D614G, and evaluated donor-dependent differences in susceptibility to infection. We observed substantial attenuation of Omicron in hLOs and demonstrated enhanced susceptibility to Omicron and D614G replication in hLOs from one donor. Transcriptomic analysis revealed that increased susceptibility to SARS-CoV-2 infection in these hLOs was associated with reduced tonic interferon signaling activity at baseline. We show that hLOs can be used to model heterogeneity of SARS-CoV-2 pathogenesis in humans, and propose that variability in tonic interferon signaling set point may impact susceptibility to SARS-CoV-2 VOCs and subsequent COVID-19 disease progression