A machine-assisted approach for the preparation of follow-on pharmaceutical compound libraries

Follow-on drugs represent the majority of new drug introductions and show improved properties to the pioneer drug. In order to fast-follow, R&D needs to be able to quickly generate a library of analogues that can then be screened for desired properties. Here we have designed a hybrid machine-assisted approach which makes use of both multi-step continuous flow processing and robotic microwave reactors to generate a library of indoles over two technology steps (four reaction steps; diazotization, reduction, unmasking of the hydrazine and Fischer indole reaction). This ‘machine’ is then used to prepare a small library of hitherto unreported analogues of the 5-HT agonist Zolmitriptan in good yields, thus demonstrating that the integration and use of machines is a powerful tool to expedite drug discovery

The lymphocyte secretome from young adults enhances skeletal muscle proliferation and migration, but effects are attenuated in the secretome of older adults.

Older people experience skeletal muscle wasting, in part due to impaired proliferative capacity of quiescent skeletal muscle satellite cells which can be reversed by exposure to young blood. To investigate the role of immune cells in muscle regeneration, we isolated lymphocytes from whole blood of young and older healthy volunteers and cultured them with, or without, anti-CD3/CD28 activators to induce release of cytokines, interleukins, and growth factors into the media. The secreted proteins were collected to prepare a conditioned media, which was subsequently used to culture C2C12 myoblasts. The conditioned media from the activated young lymphocytes increased the rate of proliferation of myoblasts by around threefold (P < 0.005) and caused an approximate fourfold (P < 0.005) increase in migration compared with nonactivated lymphocyte control media. These responses were characterized by minimal myotube formation (2%), low fusion index (5%), low myosin heavy chain content, and substantial migration. In contrast, myoblasts treated with conditioned media from activated old lymphocytes exhibited a high degree of differentiation, and multi-nucleated myotube formation that was comparable to control conditions, thus showing no effect on proliferation or migration of myoblasts. These results indicate that secreted proteins from lymphocytes of young people enhance the muscle cell proliferation and migration, whereas secreted proteins from lymphocytes of older people may contribute to the attenuated skeletal muscle satellite cell proliferation and migration

Mammary epithelium permeability during established lactation: associations with cytokine levels in human milk

Objective: The cytokine profile of human milk may be a key indicator of mammary gland health and has been linked to infant nutrition, growth, and immune system development. The current study examines the extent to which mammary epithelium permeability (MEP) is associated with cytokine profiles during established lactation within a sample of US mothers. Methods: Participants were drawn from a previous study of human milk cytokines. The present analysis includes 162 participants (98 Black, 64 White) with infants ranging from 1 to 18 months of age. Levels of cytokines were determined previously. Here we measure milk sodium (Na) and potassium (K) levels with ion-selective probes. Two approaches were used to define elevated MEP: Na levels ≥10  mmol/L and Na/K ratios greater than 0.6. Associations between maternal–infant characteristics, elevated MEP, and twelve analytes (IL-6, IL-8, TNFα, IL-1β, FASL, VEGFD, FLT1, bFGF, PLGF, EGF, leptin, adiponectin) were examined using bivariate associations, principal components analysis, and multivariable logistic regression models. Results: Elevated MEP was observed in 12 and 15% of milk samples as defined by Na and Na/K cutoffs, respectively. The odds of experiencing elevated MEP (defined by Na ≥  10  mmol/L) were higher among Black participants and declined with older infant age. All cytokines, except leptin, were positively correlated with either Na or the Na/K ratio. A pro-inflammatory factor (IL-6, IL-8, TNFα, IL-1β, EGF) and a tissue remodeling factor (FASL, VEGFD, FLT1, bFGF, PLGF, adiponectin) each contributed uniquely to raising the odds of elevated MEP as defined by either Na or the Na/K ratio. Conclusion: This exploratory analysis of MEP and cytokine levels during established lactation indicates that elevated MEP may be more common in US populations than previously appreciated and that individuals identifying as Black may have increased odds of experiencing elevated MEP based on current definitions. Research aimed at understanding the role of MEP in mammary gland health or infant growth and development should be prioritized

From regional pulse vaccination to global disease eradication: insights from a mathematical model of Poliomyelitis

Mass-vaccination campaigns are an important strategy in the global fight against poliomyelitis and measles. The large-scale logistics required for these mass immunisation campaigns magnifies the need for research into the effectiveness and optimal deployment of pulse vaccination. In order to better understand this control strategy, we propose a mathematical model accounting for the disease dynamics in connected regions, incorporating seasonality, environmental reservoirs and independent periodic pulse vaccination schedules in each region. The effective reproduction number, $R_e$, is defined and proved to be a global threshold for persistence of the disease. Analytical and numerical calculations show the importance of synchronising the pulse vaccinations in connected regions and the timing of the pulses with respect to the pathogen circulation seasonality. Our results indicate that it may be crucial for mass-vaccination programs, such as national immunisation days, to be synchronised across different regions. In addition, simulations show that a migration imbalance can increase $R_e$ and alter how pulse vaccination should be optimally distributed among the patches, similar to results found with constant-rate vaccination. Furthermore, contrary to the case of constant-rate vaccination, the fraction of environmental transmission affects the value of $R_e$ when pulse vaccination is present.Comment: Added section 6.1, made other revisions, changed titl

Elevated arousal at time of decision-making is not the arbiter of risk avoidance in chickens

The somatic marker hypothesis proposes that humans recall previously experienced physiological responses to aid decision-making under uncertainty. However, little is known about the mechanisms used by non-human animals to integrate risk perception with predicted gains and losses. We monitored the behaviour and physiology of chickens when the choice between a high-gain (large food quantity), high-risk (1 in 4 probability of receiving an air-puff) option (HGRAP) or a low-gain (small food quantity), no-risk (of an air-puff) (LGNAP) option. We assessed when arousal increased by considering different stages of the decision-making process (baseline, viewing, anticipation, reward periods) and investigated whether autonomic responses influenced choice outcome both immediately and in the subsequent trial. Chickens were faster to choose and their heart-rate significantly increased between the viewing and anticipation (post-decision, pre-outcome) periods when selecting the HGRAP option. This suggests that they responded physiologically to the impending risk. Additionally, arousal was greater following a HGRAP choice that resulted in an air-puff, but this did not deter chickens from subsequently choosing HGRAP. In contrast to human studies, we did not find evidence that somatic markers were activated during the viewing period, suggesting that arousal is not a good measure of avoidance in non-human animals

O- and N-glycosylation of serum immunoglobulin A is associated with IgA nephropathy and glomerular function.

BACKGROUND: IgA nephropathy (IgAN) is the most common primary glomerular disease worldwide and is a leading cause of renal failure. The disease mechanisms are not completely understood, but a higher abundance of galactose-deficient IgA is recognized to play a crucial role in IgAN pathogenesis. Although both types of human IgA (IgA1 and IgA2) have several N-glycans as post-translational modification, only IgA1 features extensive hinge-region O-glycosylation. IgA1 galactose deficiency on the O-glycans is commonly detected by a lectin-based method. To date, limited detail is known about IgA O- and N-glycosylation in IgAN. METHODS: To gain insights into the complex O- and N-glycosylation of serum IgA1 and IgA2 in IgAN, we used liquid chromatography-mass spectrometry (LC-MS) for the analysis of tryptic glycopeptides of serum IgA from 83 patients with IgAN and 244 age- and sex-matched healthy controls. RESULTS: Multiple structural features of N-glycosylation of IgA1 and IgA2 were associated with IgAN and glomerular function in our cross-sectional study. These features included differences in galactosylation, sialylation, bisection, fucosylation, and N-glycan complexity. Moreover, IgA1 O-glycan sialylation was associated with both the disease and glomerular function. Finally, glycopeptides were a better predictor of IgAN and glomerular function than galactose-deficient IgA1 levels measured by lectin-based ELISA. CONCLUSIONS: Our high-resolution data suggest that IgA O- and N-glycopeptides are promising targets for future investigations on the pathophysiology of IgAN and as potential noninvasive biomarkers for disease prediction and deteriorating kidney function

Entanglement dynamics of two-bipartite system under the influence of dissipative environments

An experimental scheme is suggested that permits a direct measure of entanglement in a two-qubit cavity system. It is realized in the cavity-QED technology utilizing atoms as flying qubits. With this scheme we generate two different measures of entanglement, namely logarithmic negativity and concurrence. The phenomenon of sudden death entanglement (ESD) in a bipartite system subjected to dissipative environment is examined. We show that the sudden death time of the entangled states depends on the initial preparation of the entangled state and the temperature of the reservoir.Comment: 21 pages, 13 figure

Transmission Dynamics of Shiga Toxin-Producing Escherichia coli in New Zealand Cattle from Farm to Slaughter

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Effect of under-reinforcement on the flexural strength of corroded beams

Reinforced concrete beams are normally designed as under-reinforced to provide ductile behaviour i.e. the tensile moment of resistance, Mt(0) is less than the moment of resistance of the compressive zone, Mc. The degree of under-reinforcement (Mt(0)/Mc ratio) can depend upon the preferences of the designer in complying with design and construction constraints, codes and availability of steel reinforcement diameters and length. Mt(0)/Mc is further influenced during service life by corrosion which decreases Mt(0). The paper investigates the influence of Mt(0)/Mc on the residual flexural strength of corroded beams and determines detailing parameters (e.g. size and percentage of steel reinforcement, cover) on Mt(0)/Mc. Corroded reinforced concrete beams (100 mm · 150 mm deep) with varying Mt(0)/Mc ratios were tested in flexure. The results of the investigation were combined with the results of similar work by other researchers and show that beams with lower Mt(0)/Mc ratios suffer lower flexural strength loss when subjected to tensile reinforcement corrosion. Cover to the main steel does not directly influence Mt(0)/Mc and, thus, the residual flexural strength of corroded beams is not normally affected by increased cover. A simplified expression for estimating the residual strength of corroded beams is also given