TTCF4LAMMPS: A toolkit for simulation of the non-equilibrium behaviour of molecular fluids at experimentally accessible shear rates

Program summary: Program title: TTCF4LAMMPS CPC Library link to program files: https://doi.org/10.17632/hh2rkcxbrf.1 Developer's repository link: https://github.com/edwardsmith999/TTCF4LAMMPS Licensing provisions: GNU General Public License 3 Programming language: Python 3 Nature of problem: Measuring the nonequilibrium behaviour of bulk and confined fluids under experimentally accessible strain rates in non-equilibrium molecular dynamics (NEMD) simulations. Solution method: Creating a Python-based code that utilises the transient-time correlation function method and the LAMMPS software to enable the bulk fluid properties (e.g. viscosity) and confined fluid interfacial properties (e.g. shear stress and slip velocity) to be computed at low shear rates with NEMD.Data availability: All data used in this work are freely reproducible using the program provided. The source files are also available at the link https://github.com/edwardsmith999/TTCF4LAMMPS.We present TTCF4LAMMPS, a toolkit for performing non-equilibrium molecular dynamics (NEMD) simulations to study the fluid behaviour at low shear rates using the LAMMPS software. By combining direct NEMD simulations and the transient-time correlation function (TTCF) technique, we study the fluid response to shear rates spanning 15 orders of magnitude. We present two examples for simple monatomic systems: one consisting of a bulk liquid and another with a liquid layer confined between two solid walls. The small bulk system is suitable for testing on personal computers, while the larger confined system requires high-performance computing (HPC) resources. We demonstrate that the TTCF formalism can successfully detect the system response for arbitrarily weak external fields. We provide a brief mathematical explanation for this feature. Although we showcase the method for simple monatomic systems, TTCF can be readily extended to study more complex molecular fluids. Moreover, in addition to shear flows, the method can be extended to investigate elongational or mixed flows as well as thermal or electric fields. The high computational cost needed for the method is offset by the two following benefits: i) the cost is independent of the magnitude of the external field, and ii) the simulations can be made highly efficient on HPC architectures by exploiting the parallel design of the algorithm. We expect the toolkit to be useful for computational researchers striving to study the nonequilibrium behaviour of fluids under experimentally-accessible conditions.We thank the Australian Research Council for a grant obtained through the Discovery Projects Scheme (Grant No. DP200100422) and The Royal Society for support via International Exchanges, Grant No. IES/R3/170/233. J.P.E. was supported by the Royal Academy of Engineering (RAEng) through their Research Fellowships scheme. D.D. was supported through a Shell/RAEng Research Chair in Complex Engineering Interfaces. The authors acknowledge the Swinburne OzSTAR Supercomputing facility and the Imperial College London Research Computing Service (DOI:https://doi.org/10.14469/hpc/2232) for providing computational resources for this work. We thank Debra Bernhardt and Stephen Sanderson (University of Queensland) for useful discussions regarding the implementation of SLLOD in LAMMPS

Insulin and serine metabolism as sex-specific hallmarks of Alzheimer's disease in the human hippocampus

Healthy aging is an ambitious aspiration for humans, but neurodegenerative disorders, such as Alzheimer's disease (AD), strongly affect quality of life. Using an integrated omics approach, we investigate alterations in the molecular composition of postmortem hippocampus samples of healthy persons and individuals with AD. Profound differences are apparent between control and AD male and female cohorts in terms of up- and downregulated metabolic pathways. A decrease in the insulin response is evident in AD when comparing the female with the male group. The serine metabolism (linked to the glycolytic pathway and generating the N-methyl-D-aspartate [NMDA] receptor coagonist D-serine) is also significantly modulated: the D-Ser/total serine ratio represents a way to counteract age-related cognitive decline in healthy men and during AD onset in women. These results show how AD changes and, in certain respects, almost reverses sex-specific proteomic and metabolomic profiles, highlighting how different pathophysiological mechanisms are active in men and women

Mucosal immune response after the booster dose of the BNT162b2 COVID-19 vaccine

Background: To date, only a few studies reported data regarding the development of mucosal immune response after the BNT162b2-booster vaccination. Methods: Samples of both serum and saliva of 50 healthcare workers were collected at the day of the booster dose (T3) and after two weeks (T4). Anti-S1-protein IgG and IgA antibody titres and the neutralizing antibodies against the Wuhan wild-type Receptor-Binding Domain in both serum and saliva were measured by quantitative and competitive ELISA, respectively. Data were compared with those recorded after the primary vaccination cycle (T2). Neutralizing antibodies against the variants of concern were measured in those individuals with anti-Wuhan neutralizing antibodies in their saliva. Findings: After eight months from the second dose, IgG decreased in both serum (T2GMC: 23,838.5 ng/ml; T3GMC: 1473.8 ng/ml) and saliva (T2GMC: 12.9 ng/ml; T3GMC: 0.3 ng/ml). Consistently, serum IgA decreased (T2GMC: 48.6 ng/ml; T3GMC: 6.4 ng/ml); however, salivary IgA showed a different behaviour and increased (T2GMC: 0.06 ng/ml; T3GMC: 0.41 ng/ml), indicating a delayed activation of mucosal immunity. The booster elicited higher titres of both IgG and IgA when compared with the primary cycle, in both serum (IgG T4GMC: 98,493.9 ng/ml; IgA T4GMC: 187.5 ng/ml) and saliva (IgG T4GMC: 21.9 ng/ml; IgA T4GMC: 0.65 ng/ml). Moreover, the booster re-established the neutralizing activity in the serum of all individuals, not only against the Wuhan wild-type antigen (N = 50; INH: 91.6%) but also against the variants (Delta INH: 91.3%; Delta Plus INH: 89.8%; Omicron BA.1 INH: 85.1%). By contrast, the salivary neutralizing activity was high against the Wuhan antigen in 72% of individuals (N = 36, INH: 62.2%), but decreased against the variants, especially against the Omicron BA.1 variant (Delta N = 27, INH: 43.1%; Delta Plus N = 24, INH: 35.2%; Omicron BA.1 N = 4; INH: 4.7%). This was suggestive for a different behaviour of systemic immunity observed in serum with respect to mucosal immunity described in saliva (Wald chi-square test, 3 df of interaction between variants and sample type = 308.2, p < 0.0001). Interpretation: The BNT162b2-booster vaccination elicits a strong systemic immune response but fails in activating an effective mucosal immunity against the Omicron BA.1 variant. Funding: This work was funded by the Department of Medicine and Surgery, University of Insubria, and supported by Fondazione Umberto Veronesi (COVID-19 Insieme per la ricerca di tutti, 2020), Italy

Biotic and environmental stress induces nitration and changes in structure and function of the sea urchin major yolk protein toposome

The major yolk protein toposome plays crucial roles during gametogenesis and development of sea urchins. We previously found that nitration of toposome increases in the gonads of a Paracentrotus lividus population living in a marine protected area affected by toxic blooms of Ostreospsis cf. ovata, compared to control populations. This modification is associated with ovatoxin accumulation, high levels of nitric oxide in the gonads, and a remarkable impairment of progeny development. However, nothing is known about the environmental-mediated-regulation of the structure and biological function of toposome. Here, we characterize through wide-ranging biochemical and structural analyses the nitrated toposome of sea urchins exposed to the bloom, and subsequently detoxified. The increased number of nitrated tyrosines in toposome of sea urchins collected during algal bloom induced structural changes and improvement of the Ca2+-binding affinity of the protein. After 3 months' detoxification, ovatoxin was undetectable, and the number of nitric oxide-modified tyrosines was reduced. However, the nitration of specific residues was irreversible and occurred also in embryos treated with metals, used as a proxy of environmental pollutants. The structural and functional changes of toposome caused by nitration under adverse environmental conditions may be related to the defective development of sea urchins' progeny

Lipid accumulation in human breast cancer cells injured by iron depletors

Background: Current insights into the effects of iron deficiency in tumour cells are not commensurate with the importance of iron in cell metabolism. Studies have predominantly focused on the effects of oxygen or glucose scarcity in tumour cells, while attributing insufficient emphasis to the inadequate supply of iron in hypoxic regions. Cellular responses to iron deficiency and hypoxia are interlinked and may strongly affect tumour metabolism. Methods: We examined the morphological, proteomic, and metabolic effects induced by two iron chelators-deferoxamine (DFO) and di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT)-on MDA-MB-231 and MDA-MB-157 breast cancer cells. Results: These chelators induced a cytoplasmic massive vacuolation and accumulation of lipid droplets (LDs), eventually followed by implosive, non-autophagic, and non-apoptotic death similar to methuosis. Vacuoles and LDs are generated by expansion of the endoplasmic reticulum (ER) based on extracellular fluid import, which includes unsaturated fatty acids that accumulate in LDs. Typical physiological phenomena associated with hypoxia are observed, such as inhibition of translation, mitochondrial dysfunction, and metabolic remodelling. These survival-oriented changes are associated with a greater expression of epithelial/mesenchymal transcription markers. Conclusions: Iron starvation induces a hypoxia-like program able to scavenge nutrients from the extracellular environment, and cells assume a hypertrophic phenotype. Such survival strategy is accompanied by the ER-dependent massive cytoplasmic vacuolization, mitochondrial dysfunctions, and LD accumulation and then evolves into cell death. LDs containing a greater proportion of unsaturated lipids are released as a consequence of cell death. The consequence of the disruption of iron metabolism in tumour tissue and the effects of LDs on intercellular communication, cancer-inflammation axis, and immunity remain to be explored. Considering the potential benefits, these are crucial subjects for future mechanistic and clinical studies