Application of ITC-Based Characterization of Thermodynamic and Kinetic Association of Ligands With Proteins in Drug Design

A comprehensive characterization of the thermodynamic and kinetic profiling of ligands binding to a given target protein is crucial for the hit selection as well as the hit-to-lead-to-drug evolution. Isothermal titration calorimetry (ITC), widely known as an invaluable tool to measure the thermodynamic data, has recently found its way to determine the binding kinetics too. The extensive application of ITC in measurement of both thermodynamic and kinetic data manifests unique roles of ITC in drug discovery and development. This mini-review concentrates on elaborating how to gain the thermodynamic and kinetic data using ITC, highlighting the importance of these data in lead discovery and optimization, and intends to provide an overview of the technical and conceptual advances that offer unprecedented access to protein–ligand recognition by ITC measurement

Network embeddedness, entrepreneurial bricolage, and family farm sustainability

Family farm sustainability is an essential guarantee for increasing the resilience of food systems. Based on the network embeddedness theory and entrepreneurial bricolage theory, an exploratory longitudinal case study was adopted. The value-creating behaviors of family farms in different entrepreneurial periods were described and a process model of family farms sustainability with network embeddedness and entrepreneurial bricolage was constructed. The study revealed that family farms faced resource constraints such as shortage of element resources, insufficient market resources and lack of knowledge resources during the induction, start-up, and growth periods, respectively. In order to overcome resource constraints in different entrepreneurial periods, family farms employed multiple network embeddedness ways including relational embeddedness, structural embeddedness and cognitive embeddedness to seek help from actors in the rural social network. Family farms embedded in multiple networks used the entrepreneurial bricolage strategy of “element bricolage – market bricolage – institutional bricolage” to continuously acquire production elements, improve brand awareness, optimize processing techniques and promote the convergence of three industries. Family farms benefited from a win-win result with actors through network embeddedness and entrepreneurial bricolage, and created economic, social and ecological values eventually. The study offers fresh insights into the dynamics of rural entrepreneurship

Engineering the genomes of wild insect populations: Challenges, and opportunities provided by synthetic Medea selfish genetic elements

Advances in insect transgenesis and our knowledge of insect physiology and genomics are making it possible to create transgenic populations of beneficial or pest insects that express novel traits. There are contexts in which we may want the transgenes responsible for these traits to spread so that all individuals within a wild population carry them, a process known as population replacement. Transgenes of interest are unlikely to confer an overall fitness benefit on those who carry them. Therefore, an essential component of any population replacement strategy is the presence of a drive mechanism that will ensure the spread of linked transgenes. We discuss contexts in which population replacement might be desirable and the requirements a drive system must satisfy to be both effective and safe. We then describe the creation of synthetic Medea elements, the first selfish genetic elements synthesized de novo, with the capability of driving population replacement, in this case in Drosophila. The strategy used to create Drosophila Medea is applicable to a number of other insect species and the Medea system satisfies key requirements for scientific and social acceptance. Finally, we highlight several challenges to implementing population replacement in the wild

The C-terminal motif of SiAGO1b is required for the regulation of growth, development and stress responses in foxtail millet (\u3ci\u3eSetaria italica\u3c/i\u3e (L.) P. Beauv)

Foxtail millet (Setaria italica (L.) P. Beauv), which belongs to the Panicoideae tribe of the Poaceae, is an important grain crop widely grown in Northern China and India. It is currently developing into a novel model species for functional genomics of the Panicoideae as a result of its fully available reference genome sequence, small diploid genome (2n=18, ~510 Mb), short life cycle, small stature and prolific seed production. Argonaute 1 (AGO1), belonging to the argonaute (AGO) protein family, recruits small RNAs and regulates plant growth and development. Here, we characterized an AGO1 mutant (siago1b) in foxtail millet, which was induced by ethyl methanesulfonate treatment. The mutant exhibited pleiotropic developmental defects, including dwarfing stem, narrow and rolled leaves, smaller panicles and lower rates of seed setting. Map-based cloning analysis demonstrated that these phenotypic variations were attributed to a C–A transversion, and a 7-bp deletion in the C-terminus of the SiAGO1b gene in siago1b. Yeast two-hybrid assays and BiFC experiments revealed that the mutated region was an essential functional motif for the interaction between SiAGO1b and SiHYL1. Furthermore, 1598 differentially expressed genes were detected via RNAseq- based comparison of SiAGO1b and wild-type plants, which revealed that SiAGO1b mutation influenced multiple biological processes, including energy metabolism, cell growth, programmed death and abiotic stress responses in foxtail millet. This study may provide a better understanding of the mechanisms by which SiAGO1b regulates the growth and development of crops

The C-terminal motif of SiAGO1b is required for the regulation of growth, development and stress responses in foxtail millet (\u3ci\u3eSetaria italica\u3c/i\u3e (L.) P. Beauv)

Foxtail millet (Setaria italica (L.) P. Beauv), which belongs to the Panicoideae tribe of the Poaceae, is an important grain crop widely grown in Northern China and India. It is currently developing into a novel model species for functional genomics of the Panicoideae as a result of its fully available reference genome sequence, small diploid genome (2n=18, ~510 Mb), short life cycle, small stature and prolific seed production. Argonaute 1 (AGO1), belonging to the argonaute (AGO) protein family, recruits small RNAs and regulates plant growth and development. Here, we characterized an AGO1 mutant (siago1b) in foxtail millet, which was induced by ethyl methanesulfonate treatment. The mutant exhibited pleiotropic developmental defects, including dwarfing stem, narrow and rolled leaves, smaller panicles and lower rates of seed setting. Map-based cloning analysis demonstrated that these phenotypic variations were attributed to a C–A transversion, and a 7-bp deletion in the C-terminus of the SiAGO1b gene in siago1b. Yeast two-hybrid assays and BiFC experiments revealed that the mutated region was an essential functional motif for the interaction between SiAGO1b and SiHYL1. Furthermore, 1598 differentially expressed genes were detected via RNAseq- based comparison of SiAGO1b and wild-type plants, which revealed that SiAGO1b mutation influenced multiple biological processes, including energy metabolism, cell growth, programmed death and abiotic stress responses in foxtail millet. This study may provide a better understanding of the mechanisms by which SiAGO1b regulates the growth and development of crops

Carbonate contourite drifts in the southwest South China Sea: Sedimentary, paleoceanographic and economic implications

Contourite drifts are significant sedimentary features and provide clues for the reconstruction of paleoceanography and paleoenvironment. Although they have been increasingly identified in the world’s ocean, shallow-water contourite drifts (< 300 m depth) remain poorly understood and the examples are rare. This study documents a Middle Miocene shallow-water contourite depositional system in the southwest South China Sea by interpreting seismic reflection data and calibrating results with the previous chronological framework. The depositional system consisted of six mounded drifts and six moats. The contourite features were generated in seismic unit III (16-10.5 Ma) and distributed adjacent to carbonate reefs. They were formed on the proto-continental shelf (50-200 m depth) and shaped by the wind-driven currents. Changes in the sedimentary stacking patterns suggest three evolutionary stages of the contourite features. Stage I represents the growth of the Middle Miocene contourite depositional system between 16 and 10.5 Ma. Stage II marks the termination of carbonate drifts and the burial of the Late Miocene sedimentation during 10.5-5.3 Ma. Stage III started with the development of modern deep-water sedimentary systems since 5.3 Ma. The contourite features are compared with the examples on other South China Sea margins. Significant changes in the paleoceanography occurred at 10.5 Ma and 6.5-5.3 Ma when the dominated bottom currents shifted from the monsoonal wind-driven currents to the North Pacific waters, and then the modern circulation system. The Middle Miocene mounded drifts were likely sourced by the coarse-grained carbonate sands. Fluid flow escaped from the coarse-grained contourite layers and natural gas leakage occurs on the seafloor. Shallow-water carbonate contourite drifts can be served as a good gas reservoir and have great economic potential

Case report: Intraretinal hyperflow microinfiltration lesions on swept-source optical coherence tomography angiography as a potential biomarker of primary vitreoretinal lymphoma

Primary vitreoretinal lymphoma (PVRL) is often associated with central nervous system involvement, contributing to a heightened mortality rate, thus imaging features that are characteristic enough to be potential biomarkers of PVRL are important, either in diagnosis or in assessment of disease activity. This report details the case of a 68-year-old male who presented with blurred vision in both eyes persisting for 2 months. Fundus examination demonstrated vitreous opacity and multiple subretinal yellow nodular lesions of varying sizes in the peripheral fundus of both eyes. Multiple vertical hyperreflective lesions in the neural retina of posterior pole, indistinct outer retina borders in the fovea, and hyperreflective lesions in the sub-retinal pigment epithelium (RPE) space of the peripheral retina were demonstrated on swept-source optical coherence tomography (SS-OCT) of the left eye. Hyperflow signals corresponding to the vertical hyperreflective lesions were detected on swept-source optical coherence tomography angiography (SS-OCTA) images of retinal deep capillary plexus (DCP) layer. Notably, the hyperflow signals, precisely located around retinal vessels from the nerve fiber layer to the outer plexiform layer, were postulated to stem from the dilation of infiltrated retinal vessels. Vitreous pathological results of the left eye confirmed the diagnosis of PVRL. Treatments with intravitreal methotrexate injections led to a marked improvement of best-corrected visual acuity (BCVA) and regression of the hyperflow microinfiltration lesions demonstrated on SS-OCTA. In conclusion, SS-OCTA effectively delineated the vertical hyperreflective lesions and corresponding hyperflow signals in the posterior pole macular region of a patient with PVRL. These lesions significantly diminished following intravitreal methotrexate injections. We speculated that the specific hyperflow signals on SS-OCTA could act as a potential biomarker of PVRL, and SS-OCTA holds promise in facilitating early diagnosis and monitoring therapeutic responses in PVRL cases

A Synthetic Maternal-Effect Selfish Genetic Element Drives Population Replacement in Drosophila

One proposed strategy for controlling the transmission of insect-borne pathogens uses a drive mechanism to ensure the rapid spread of transgenes conferring disease refractoriness throughout wild populations. Here, we report the creation of maternal-effect selfish genetic elements in Drosophila that drive population replacement and are resistant to recombination-mediated dissociation of drive and disease refractoriness functions. These selfish elements use microRNA-mediated silencing of a maternally expressed gene essential for embryogenesis, which is coupled with early zygotic expression of a rescuing transgene