The Oxidative Inactivation of Tissue Inhibitor of Metalloproteinase-1 (TIMP-1) by Hypochlorous Acid (HOCl) is Suppressed by Anti-Rheumatic Drugs

Tissue inhibitors of metalloproteinases (TIMPs) prevent uncontrolled connective tissue destruction by limiting the activity of matrix metalloproteinases (MMPs). That TIMPs should be susceptible to oxidative inactivation is suggested by their complex tertiary structure which is dependent upon 6 disulphide bonds. We examined the oxidative inactivation of human recombinant TIMP-1 (hr TIMP-1) by HOCl and the inhibition of this process by anti-rheumatic agents.

TIMP-1 was exposed to HOCl in the presence of a variety of disease modifying anti-rheumatic drugs. TIMP-1 activity was measured by its ability to inhibit BC1 collagenase activity as measured by a fluorimetric assay using the synthetic pEptide substrate (DNP-Pro-Leu-Ala-Leu-Trp-Ala-Arg), best cleaved by MMP-1.

The neutrophil derived oxidant HOCl, but not the derived oxidant N-chlorotaurine, can inactivate TIMP-1 at concentrations achieved at sites of inflammation. Anti-rheumatic drugs have the ability to protect hrTIMP-1 from inactivation by HOCl. For D-penicil-lamine, this effect occurs at plasma levels achieved with patients taking the drug but for other anti-rheumatic drugs tested this occurs at relatively high concentrations that are unlikely to be achieved in vivo, except possibly in a microenvironment. These results are in keeping with the concept that biologically derived oxidants can potentiate tissue damage by inactivating key but susceptible protein inhibitors such as TIMP-1 which form the major local defence against MMP induced tissue breakdown.     

Autism-related dietary preferences mediate autism-gut microbiome associations

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BET inhibition blocks inflammation-induced cardiac dysfunction and SARS-CoV-2 infection

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Structure Basis for Shaping the Nse4 Protein by the Nse1 and Nse3 Dimer within the Smc5/6 Complex

The Smc5/6 complex facilitates chromosome replication and DNA break repair. Within this complex, a subcomplex composed of Nse1, Nse3 and Nse4 is thought to play multiple roles through DNA binding and regulating ATP-dependent activities of the complex. However, how the Nse1-Nse3-Nse4 subcomplex carries out these multiple functions remain unclear. To address this question, we determine the crystal structure of the Xenopus laevis Nse1-Nse3-Nse4 subcomplex at 1.7 Å resolution and examine how it interacts with DNA. Our structural analyses show that the Nse1-Nse3 dimer adopts a closed conformation and forms three interfaces with a segment of Nse4, forcing it into a Z-shaped conformation. The Nse1-Nse3-Nse4 structure provides an explanation for how the lung disease immunodeficiency and chromosome breakage syndrome-causing mutations could dislodge Nse4 from Nse1-Nse3. Our DNA binding and mutational analyses reveal that the N-terminal and the middle region of Nse4 contribute to DNA interaction and cell viability. Integrating our data with previous crosslink mass spectrometry data, we propose potential roles of the Nse1-Nse3-Nse4 complex in binding DNA within the Smc5/6 complex.     

Nanomechanics of Drug-target Interactions and Antibacterial Resistance Detection

The cantilever sensor, which acts as a transducer of reactions between model bacterial cell wall matrix immobilized on its surface and antibiotic drugs in solution, has shown considerable potential in biochemical sensing applications with unprecedented sensitivity and specificity^1-5. The drug-target interactions generate surface stress, causing the cantilever to bend, and the signal can be analyzed optically when it is illuminated by a laser. The change in surface stress measured with nano-scale precision allows disruptions of the biomechanics of model bacterial cell wall targets to be tracked in real time. Despite offering considerable advantages, multiple cantilever sensor arrays have never been applied in quantifying drug-target binding interactions.Here, we report on the use of silicon multiple cantilever arrays coated with alkanethiol self-assembled monolayers mimicking bacterial cell wall matrix to quantitatively study antibiotic binding interactions. To understand the impact of vancomycin on the mechanics of bacterial cell wall structures^1,6,7. We developed a new model¹ which proposes that cantilever bending can be described by two independent factors; i) namely a chemical factor, which is given by a classical Langmuir adsorption isotherm, from which we calculate the thermodynamic equilibrium dissociation constant (K_d) and ii) a geometrical factor, essentially a measure of how bacterial peptide receptors are distributed on the cantilever surface. The surface distribution of peptide receptors (p) is used to investigate the dependence of geometry and ligand loading. It is shown that a threshold value of p ~10% is critical to sensing applications. Below which there is no detectable bending signal while above this value, the bending signal increases almost linearly, revealing that stress is a product of a local chemical binding factor and a geometrical factor combined by the mechanical connectivity of reacted regions and provides a new paradigm for design of powerful agents to combat superbug infections.     

Three-dimensional model on thermal response of skin subject to laser heating

A three-dimensional (3D) multilayer model based on the skin physical structure is developed to investigate the transient thermal response of human skin subject to laser heating. The temperature distribution of the skin is modeled by the bioheat transfer equation, and the influence of laser heating is expressed as a source term where the strength of the source is a product of a Gaussian shaped incident irradiance, an exponentially shaped axial attenuation, and a time function. The water evaporation and diffusion is included in the model by adding two terms regarding the heat loss due to the evaporation and diffusion, where the rate of water evaporation is determined based on the theory of laminar boundary layer. Cryogen spray cooling (CSC) in laser therapy is studied, as well as its effect on the skin thermal response. The time-dependent equation is discretized using the finite difference method with the Crank–Nicholson scheme and the stability of the numerical method is analyzed. The large sparse linear system resulted from discretizing the governing partial differential equation is solved by a GMRES solver and the expected simulation results are obtained.     

Decreased Hardness of Dietary Fiber-Rich Foods by the Enzyme-Infusion Method

A novel technique is reported for softening plant tissues while retaining their shape by impregnating them with macerating enzymes under reduced pressure after defrosting the frozen plants. Samples were removed immediately from the enzyme solution after the freeze-infusion treatment, and the hardness was measured. Six enzymes and three enzymes were respectively chosen from 18 commercial enzymes for softening burdock roots and bamboo shoots. The tissue degradation due to impregnation of the tissues with the enzymes and the reaction time were investigated. Burdock roots and bamboo shoots were progressively softened during the reaction: the hardness reached 1.0×10⁴ N/m² or less. The water-soluble dietary fiber contents increased as a result of the freeze-infusion treatment. This softening technique, which retained the food shape, could enhance the production of food products for elderly persons and those under nursing care. Foods produced by this method can replace current minced and liquid dietary components.     

‘We eat meat every day’: ecology and economy of dietary change among Oaxacan migrants from Mexico to New Jersey

Abstract

In the late twentieth and early twenty-first centuries, the USA has experienced large-scale and continuing immigration from around the world, especially Latin America and, within Latin America, from Mexico. One dimension of these transnational processes is dietary change. In this paper, we qualitatively assess the effects of migration from Oaxaca, Mexico to central New Jersey on the ecology and economy of dietary patterns. We explore multiple factors at the micro and macro levels. Data come from focus groups held among Mexican migrants in New Jersey, and in Oaxaca among people from their sending communities. Economic constraints and lack of culturally appropriate foods are larger barriers to healthy eating than lack of knowledge about appropriate diets. We end with recommendations for nutrition education and interventions.     

Importance of fire in influencing the occurrence of snakes in an upland region of arid Australia

In arid Australia, changes to historic fire regimes may now produce more large‐scale wildfire events. The impacts of these fires on fauna communities are poorly known. We sought to test the impacts of fire on the occurrence of two arid‐zone snake species, the desert death adder (Acanthophis pyrrhus) and monk snake (Parasuta monachus), specialist inhabitants of hummock grassland and mulga shrubland, respectively. We also examined the influence of fire on the occurrence of a habitat generalist, the sympatric Stimson's python (Antaresia stimsoni). Under an Information‐Theoretic framework we modelled the occurrence of each species with a range of habitat variables, including fire history, using logistic regression. As predicted, the two habitat specialists were more likely to be encountered at locations that had a lower percentage of surrounding area burnt in the most recent wildfires (2002), while fire variables failed to predict the occurrence of the habitat generalist. Acanthophis pyrrhus, already predisposed to endangerment through a suite of life‐history characteristics, may be at increased risk through accidental and deliberate burning and fragmentation of old‐growth hummock grasslands. We stress the importance of prescribed burning and natural fire breaks in maintaining areas of old‐growth hummock grassland across the landscape.