Unusual DNA Structure and DNA Damage Recognition: Structure and Dynamic Markers

Nucleic acids play a central role in many biological processes, including information storage, gene expression, serving as messengers or structural components and even catalysis. Their diverse roles have made them targets of interest to diagnose and treat an array of human disorders such as infections, degenerative diseases and cancer. Nature has evolved proteins and ligands that recognize specific nucleic acid sequences or structures and control their function, demonstrating that this can be efficiently accomplished. This has led to the development of wide variety of synthetic molecules that selectively bind to nucleic acids. In turn, this has precipitated numerous studies which showed that nucleic acid structures and their dynamic properties must be understood in order to efficiently target specific sequences or structures

Rapidly Characterizing the Fast Dynamics of RNA Genetic Circuitry with Cell-Free Transcription Translation (TX-TL) Systems

RNA regulators are emerging as powerful tools to engineer synthetic genetic networks or rewire existing ones. A potential strength of RNA networks is that they may be able to propagate signals on time scales that are set by the fast degradation rates of RNAs. However, a current bottleneck to verifying this potential is the slow design-build-test cycle of evaluating these networks in vivo. Here, we adapt an Escherichia coli-based cell-free transcription-translation (TX-TL) system for rapidly prototyping RNA networks. We used this system to measure the response time of an RNA transcription cascade to be approximately five minutes per step of the cascade. We also show that this response time can be adjusted with temperature and regulator threshold tuning. Finally, we use TX-TL to prototype a new RNA network, an RNA single input module, and show that this network temporally stages the expression of two genes in vivo

Circulating tumour cell associated microRNA profiles change during chemoradiation and are predictive of response in locally advanced rectal cancer

Locally advanced rectal cancer (LARC) has traditionally been treated with trimodality therapy consisting of neoadjuvant radiation +/− chemotherapy, surgery, and adjuvant chemotherapy. There is currently a clinical need for biomarkers to predict treatment response and outcomes, especially during neoadjuvant therapy. Liquid biopsies in the form of circulating tumour cells (CTCs) and circulating nucleic acids in particular microRNAs (miRNA) are novel, the latter also being highly stable and clinically relevant regulators of disease. We studied a prospective cohort of 52 patients with LARC, and obtained samples at baseline, during treatment, and post-treatment. We enumerated CTCs during chemoradiation at these three time-points, using the IsofluxTM (Fluxion Biosciences Inc., Alameda, CA, USA) CTC Isolation and detection platform. We then subjected the isolated CTCs to miRNA expression analyses, using a panel of 106 miRNA candidates. We identified CTCs in 73% of patients at baseline; numbers fell and miRNA expression profiles also changed during treatment. Between baseline and during treatment (week 3) time-points, three microRNAs (hsa-miR-95, hsa-miR-10a, and hsa-miR-16-1*) were highly differentially expressed. Importantly, hsa-miR-19b-3p and hsa-miR-483-5p were found to correlate with good response to treatment. The latter (hsa-miR-483-5p) was also found to be differentially expressed between good responders and poor responders. These miRNAs represent potential predictive biomarkers, and thus a potential miRNA-based treatment strategy. In this study, we demonstrate that CTCs are present and can be isolated in the non-metastatic early-stage cancer setting, and their associated miRNA profiles can potentially be utilized to predict treatment response

Plasma fibronectin supports hemostasis and regulates thrombosis

Plasma fibronectin (pFn) has long been suspected to be involved in hemostasis; however, direct evidence has been lacking. Here, we demonstrated that pFn is vital to control bleeding in fibrinogen-deficient mice and in WT mice given anticoagulants. At the site of vessel injury, pFn was rapidly deposited and initiated hemostasis, even before platelet accumulation, which is considered the first wave of hemostasis. This pFn deposition was independent of fibrinogen, von Willebrand factor, β3 integrin, and platelets. Confocal and scanning electron microscopy revealed pFn integration into fibrin, which increased fibrin fiber diameter and enhanced the mechanical strength of clots, as determined by thromboelastography. Interestingly, pFn promoted platelet aggregation when linked with fibrin but inhibited this process when fibrin was absent. Therefore, pFn may gradually switch from supporting hemostasis to inhibiting thrombosis and vessel occlusion following the fibrin gradient that decreases farther from the injured endothelium. Our data indicate that pFn is a supportive factor in hemostasis, which is vital under both genetic and therapeutic conditions of coagulation deficiency. By interacting with fibrin and platelet β3 integrin, pFn plays a self-limiting regulatory role in thrombosis, suggesting pFn transfusion may be a potential therapy for bleeding disorders, particularly in association with anticoagulant therapy

Phase Ia Clinical Evaluation of the Safety and Immunogenicity of the Plasmodium falciparum Blood-Stage Antigen AMA1 in ChAd63 and MVA Vaccine Vectors

Traditionally, vaccine development against the blood-stage of Plasmodium falciparum infection has focused on recombinant protein-adjuvant formulations in order to induce high-titer growth-inhibitory antibody responses. However, to date no such vaccine encoding a blood-stage antigen(s) alone has induced significant protective efficacy against erythrocytic-stage infection in a pre-specified primary endpoint of a Phase IIa/b clinical trial designed to assess vaccine efficacy. Cell-mediated responses, acting in conjunction with functional antibodies, may be necessary for immunity against blood-stage P. falciparum. The development of a vaccine that could induce both cell-mediated and humoral immune responses would enable important proof-of-concept efficacy studies to be undertaken to address this question

Simulating the vibrational quantum dynamics of molecules using photonics

Advances in control techniques for vibrational quantum states in molecules present new challenges for modelling such systems, which could be amenable to quantum simulation methods. Here, by exploiting a natural mapping between vibrations in molecules and photons in waveguides, we demonstrate a reprogrammable photonic chip as a versatile simulation platform for a range of quantum dynamic behaviour in different molecules. We begin by simulating the time evolution of vibrational excitations in the harmonic approximation for several four-atom molecules, including H2CS, SO3, HNCO, HFHF, N4 and P4. We then simulate coherent and dephased energy transport in the simplest model of the peptide bond in proteins—N-methylacetamide—and simulate thermal relaxation and the effect of anharmonicities in H2O. Finally, we use multi-photon statistics with a feedback control algorithm to iteratively identify quantum states that increase a particular dissociation pathway of NH3. These methods point to powerful new simulation tools for molecular quantum dynamics and the field of femtochemistry

How sulphate-reducing microorganisms cope with stress: lessons from systems biology

Sulphate-reducing microorganisms (SRMs) are a phylogenetically diverse group of anaerobes encompassing distinct physiologies with a broad ecological distribution. As SRMs have important roles in the biogeochemical cycling of carbon, nitrogen, sulphur and various metals, an understanding of how these organisms respond to environmental stresses is of fundamental and practical importance. In this Review, we highlight recent applications of systems biology tools in studying the stress responses of SRMs, particularly Desulfovibrio spp., at the cell, population, community and ecosystem levels. The syntrophic lifestyle of SRMs is also discussed, with a focus on system-level analyses of adaptive mechanisms. Such information is important for understanding the microbiology of the global sulphur cycle and for developing biotechnological applications of SRMs for environmental remediation, energy production, biocorrosion control, wastewater treatment and mineral recovery

Current and emerging developments in subseasonal to decadal prediction

Weather and climate variations of subseasonal to decadal timescales can have enormous social, economic and environmental impacts, making skillful predictions on these timescales a valuable tool for decision makers. As such, there is a growing interest in the scientific, operational and applications communities in developing forecasts to improve our foreknowledge of extreme events. On subseasonal to seasonal (S2S) timescales, these include high-impact meteorological events such as tropical cyclones, extratropical storms, floods, droughts, and heat and cold waves. On seasonal to decadal (S2D) timescales, while the focus remains broadly similar (e.g., on precipitation, surface and upper ocean temperatures and their effects on the probabilities of high-impact meteorological events), understanding the roles of internal and externally-forced variability such as anthropogenic warming in forecasts also becomes important. The S2S and S2D communities share common scientific and technical challenges. These include forecast initialization and ensemble generation; initialization shock and drift; understanding the onset of model systematic errors; bias correct, calibration and forecast quality assessment; model resolution; atmosphere-ocean coupling; sources and expectations for predictability; and linking research, operational forecasting, and end user needs. In September 2018 a coordinated pair of international conferences, framed by the above challenges, was organized jointly by the World Climate Research Programme (WCRP) and the World Weather Research Prograame (WWRP). These conferences surveyed the state of S2S and S2D prediction, ongoing research, and future needs, providing an ideal basis for synthesizing current and emerging developments in these areas that promise to enhance future operational services. This article provides such a synthesis