Epidemic management and control through risk-dependent individual contact interventions

Testing, contact tracing, and isolation (TTI) is an epidemic management and control approach that is difficult to implement at scale because it relies on manual tracing of contacts. Exposure notification apps have been developed to digitally scale up TTI by harnessing contact data obtained from mobile devices; however, exposure notification apps provide users only with limited binary information when they have been directly exposed to a known infection source. Here we demonstrate a scalable improvement to TTI and exposure notification apps that uses data assimilation (DA) on a contact network. Network DA exploits diverse sources of health data together with the proximity data from mobile devices that exposure notification apps rely upon. It provides users with continuously assessed individual risks of exposure and infection, which can form the basis for targeting individual contact interventions. Simulations of the early COVID-19 epidemic in New York City are used to establish proof-of-concept. In the simulations, network DA identifies up to a factor 2 more infections than contact tracing when both harness the same contact data and diagnostic test data. This remains true even when only a relatively small fraction of the population uses network DA. When a sufficiently large fraction of the population (≳ 75%) uses network DA and complies with individual contact interventions, targeting contact interventions with network DA reduces deaths by up to a factor 4 relative to TTI. Network DA can be implemented by expanding the computational backend of existing exposure notification apps, thus greatly enhancing their capabilities. Implemented at scale, it has the potential to precisely and effectively control future epidemics while minimizing economic disruption.     

Luliberin analogues exhibiting a cytotoxic effect on tumor cells in vitro

Luliberin analogues modified at the N-terminus were synthesized to search for drugs exerting a cytotoxic effect on cells of hormone-dependent tumors. A synthetic scheme effective in the preparation of analogues containing fatty acid residues was proposed. The cytotoxic effect of the peptides was studied on a number of cell lines of human tumors in vitro. The dependence of the antitumor effect on the length of peptide chain, amino acid sequence, and structure of the N-terminal group was demonstrated. Modification with palmitic acid was found to result in highly active compounds in the case of analogues containing more than ten aa, whereas modifications with lauric, caproic, or trimethylacetic acid led to compounds with significantly lower activities. Analogues of luliberin containing a palmitic acid residue and effectively inhibiting the growth of tumor cells in vitro were synthesized.     

Possible correlations between the level of alcoholic motivation and the electrophysiological structure of sleep in the rat

Using modified Porsolt's method, the electrophysiological sleep pattern was studied in normal conditions and after a single intraperitoneal ethanol injection to noninbred male albino rats divided into 2 groups ("high activity" and "low activity" rats). Voluntary alcohol intake in these rats was measured during free choice between 10% ethanol and water for 20 days. "Low activity" rats were characterized by a statistically significant 3.4-fold higher level of ethanol consumption and 2.7-fold longer REM-sleep stage, as compared to "high activity" animals. In "low activity" animals ethanol (1 g/k, 10% solution, i. p.) inhibits and in "high activity" rats it increases REM-sleep stage, thus removing differences in the sleep pattern in the two groups of rats. The data obtained suggest a possible role of REM-sleep in the development of alcohol motivation.     

Effect of chronic administration of ethanol on the blood-brain barrier permeability of 14C-tyrosine and horseradish peroxidase in rats

Chronic 10-days oral ethanol administration in doses 8-11 g/kg per day has been shown to increase blood-brain barrier penetration for peripherally administered 14C-tyrosine in Wistar heavy- and light-drinker rats. No changes in BBB permeability for horseradish peroxidase has been found. Chronic effect of ethanol on BBB systems of specific and unspecific transport in rats heavy- and light-drinkers is discussed.     

Incorporation of N‐amidino‐pyroglutamic acid into peptides using intramolecular cyclization of α‐guanidinoglutaric acid

N‐terminal modification of peptides by unnatural amino acids significantly affects their enzymatic stability, conformational properties and biological activity. Application of N‐amidino‐amino acids, positively charged under physiological conditions, can change peptide conformation and its affinity to the corresponding receptor. In this article, we describe synthesis of short peptides, containing a new building block—N‐amidino‐pyroglutamic acid. Although direct guanidinylation of pyroglutamic acid and oxidation of N‐amidino‐proline using RuO₄ did not produce positive results, N‐amidino‐Glp‐Phe‐OH was synthesized on Wang polymer by cyclization of α‐guanidinoglutaric acid residue. In the course of synthesis, it was found that literature procedure of selective Boc deprotection using TMSOTf/TEA reagent is accompanied by concomitant side reaction of triethylamine alkylation by polymer linker fragment. It should be mentioned that independently from cyclization time and coupling agent (DIC or HCTU), the lactam formation was incomplete. Separation of the cyclic product from the linear precursor was achieved by HPLC in ammonium formate buffer at pH 6. HPLC analysis showed N‐amidino‐Glp‐Phe‐OH stability at acidic and physiological pH and fast ring opening in water solution at pH 9. The suggested method of N‐amidino‐Glp residue formation can be applied in the case of short peptide chains, whereas synthesis of longer ones will require fragment condensation approach. Copyright © 2009 European Peptide Society and John Wiley & Sons, Ltd.     

Effect of pharmacological substances on the altered permeability of the hemato-encephalic barrier for 14C-tyrosine due to ethanol

It has been demonstrated that membrane-stabilizing agents, chlorpromazine and alpha-tocopherol, have no effect on the increased blood-brain barrier permeability for 14C-tyrosine, induced by a single injection of ethanol at a dose of 2 and 4 g/kg. Dopaminergic antagonist haloperidol prevented the increase of blood-brain barrier permeability induced by a single injection of 2 g/kg of ethanol and diminished the elevated barrier permeability caused by chronic 10-day alcoholization of animals, including abstinent ones. The role of membrane and neuromediator components in the mechanisms regulating blood-brain barrier functions is discussed.