Cultural and Intellectual Responses to the Black Death

From the fall of the Roman Empire to the Age of Translations, Western Europe endeavored to rise above the so-called cultural and intellectual Dark Ages. That advancement was threatened with the arrival of the Black Death in 1347. Chapter one details the correlation between the spread of the plague and the location of the first universities. It also examines the expansion of the university system throughout the continent in the wake of the plague. The second chapter looks at the cultural, especially religious, explanations of and responses to the Black Death. It examines how medieval society used the religious tools at their disposal to combat the evils of the plague

Adoption of the governmental affordable medicines programme by ukrainians.

Ensuring that the local population has access to medicines is one of the functions of a modern democratic state and an important element of social policy. The question of the affordability of medicines to the public is extremely important. This is also due to the fact that, unlike in European countries, Ukraine did not have a system of medicines reimbursement. To date, the reimbursement Affordable Medicines Programme has been in effect since April 2017 and is applicable to patients with cardiovascular disease, bronchial asthma, and type II diabetes. In total, 258 medicines are included in the Programme, 64 of which can be obtained free of charge and the others with a small extra payment. The respondents' perceptions of the Programme were conducted through a secondary analysis based on the third wave of the «Health Index. Ukraine» which was held in 2018 by the International Renaissance Foundation, the School of Public Health of the National University of Kyiv Mohyla Academy, and the Kyiv International Institute of Sociology. This study aims to present the results of the research of the attitude of Ukrainians to the government Affordable Medicines Programme and their perception of its implementation. The total number of respondents to this survey totaled more than 10,000 household rep­resentatives. The results of the research indicate a positive assessment of the respondents who participated in the survey «Health Index. Ukraine» (76% in 2018), which is confirmed by other research of the Kyiv International Institute of Sociology (63% in 2019) and by international experts. The results of the survey do not allow us to draw any official conclusions about the impact of the Programme on the health of Ukrainians, but during the interview 60.6% of the respondents said that the Programme «helped improve health»; in addition, positive changes in health were indicated by the most financially vulne­rable categories of the population. It is also noted that 80–82% of prescriptions were reimbursed to Programme participants

Mother’s perceptions of healthy diet for children in Ukraine

Численні хронічні захворювання можна запобігти, запровадивши та впровадивши політику здорового харчування, орієнтовану на дітей дошкільного віку в період формування звичок на все життя. Підкреслюється, що роль матері є вирішальною для харчування дошкільника. Важливо було провести дослідження, щоб дослідити сприйняття матерів здорового харчування дітей у малих містах України. У дослідженні застосовано якісну методологію напівструктурованих інтерв’ю з використанням стратегії «сніжної кулі» та підходів максимальної варіаційної вибірки для опитування матерів дітей дошкільного віку в Лубнах (Полтавська область, Україна), включно з експертами з охорони здоров’я місцевого та національного рівнів. Як інструмент дослідження було розроблено тематичне керівництво. Він базується на категоріях аналізу. Дослідження показує, що серед опитаних матерів та експертів у галузі охорони здоров’я існують різні погляди на здорове харчування. Попередні дослідження також підтвердили, що уявлення матерів про здорову дієту для дітей тісно пов’язані з соціально-демографічними характеристиками, які були виявлені в статті. Спільним для всіх опитаних матерів було уявлення про вживання свіжих фруктів та овочів як додатковий компонент раціону дитини, а не основу. Жодна з матерів не знала повністю рекомендацій Всесвітньої організації охорони здоров’я щодо здорового харчування. На підставі отриманих результатів робимо висновок, що матерів дітей дошкільного віку в Лубнах за уявленнями про здорове харчування можна розділити на три основні типи: 1) консервативний тип (матері, які віддають перевагу традиційному харчуванню дітей і мають високий рівень довіри до медичної допомоги). лікарі та установи в Лубнах); 2) лояльний тип (матері мають такі ж уявлення про здорове харчування, як і консервативні, але з високою лояльністю до шкідливої їжі в раціоні дітей); 3) критичний тип (матері, які повідомили про відмінні від консервативних уявлень про здорове харчування та, як правило, мають низький рівень довіри до лікарів та закладів у Лубнах). Дослідження представляє результати, актуальні для Лубнів та Полтавської області в Україні. Потрібні подальші дослідження, щоб отримати більше даних для кращого розуміння уявлень про здорове харчування дітей в Україні.Multiple chronic diseases could be prevented by introducing and implementing healthy diet policies oriented for preschool children in the time of setting life-long habits. The role of mothers is highlighted to be crucial for a preschooler’s diet. It was important to conduct research to explore and investigate mothers’ perceptions of healthy diet for children in small towns in Ukraine. The study applies the qualitative methodology of semi-structured interviews using the strategy of a snowball and maximum variation sampling approaches interviewing mothers of preschool children in Lubny (Poltava Region, Ukraine) including local- and national-level health experts. As the research instrument, a topic guide was developed. It is based on the categories of analysis. The study displays that there is a variety of perceptions around healthy diet among interviewed mothers and health experts. It was also confirmed by previous studies that the mothers’ perceptions of a healthy diet for children are highly linked to socio-demographic characteristics which was found in the article. Common for all interviewed mothers was the perception about fresh fruits and vegetables consumption as the additional component of the child’s diet, but not the basis. None of the mothers was fully aware of World Health Organisation recommendations for a healthy diet. Based on the results, we conclude that mothers of preschool children in Lubny may be grouped into three main types by their perceptions about healthy diet: 1) the conservative type (mothers who prefer traditional meals for children and have a high level of trust to medical doctors and institutions in Lubny); 2) the loyal type (mothers have the same perceptions about healthy diet as conservative yet with a high loyalty to junk food in children’s diet); 3) the critical type (mothers who reported different from conservative type perceptions about healthy diet and tend to have low level of trust to the medical doctors and institutions in Lubny). The study represents findings relevant for Lubny and Poltava Region in Ukraine. Further research is needed to provide more data for a better understanding of perceptions about a healthy diet for children in Ukraine

The 5' untranslated region of the major immediate early mRNA is necessary for efficient human cytomegalovirus replication

The human cytomegalovirus (HCMV) immediate early 1 (IE1) and IE2 proteins are critical regulators of virus replication. Both proteins are needed to efficiently establish lytic infection, and nascent expression of IE1 and IE2 is critical for reactivation from latency. The regulation of IE1 and IE2 protein expression is thus a central event in the outcome of HCMV infection. Transcription of the primary transcript encoding both IE1 and IE2 is well studied, but relatively little is known about the posttranscriptional mechanisms that control IE1 and IE2 protein synthesis. The mRNA 5' untranslated region (5' UTR) plays an important role in regulating mRNA translation. Therefore, to better understand the control of IE1 and IE2 mRNA translation, we examined the role of the shared 5' UTR of the IE1 and IE2 mRNAs (MIE 5' UTR) in regulating translation. In a cell-free system, the MIE 5' UTR repressed translation, as predicted based on its length and sequence composition. However, in transfected cells we found that the MIE 5' UTR increased the expression of a reporter gene and enhanced its association with polysomes, demonstrating that the MIE 5' UTR has a positive role in translation control. We also found that the MIE 5' UTR was necessary for efficient IE1 and IE2 translation during infection. Replacing the MIE 5' UTR with an unstructured sequence of the same length decreased IE1 and IE2 protein expression despite similar levels of IE1 and IE2 mRNA and reduced the association of the IE1 and IE2 mRNAs with polysomes. The wild-type MIE 5'-UTR sequence was also necessary for efficient HCMV replication. Together these data identify the shared 5' UTR of the IE1 and IE2 mRNAs as an important regulator of HCMV lytic replication

Lipin-1 contributes to IL-4 mediated macrophage polarization

Macrophage responses contribute to a diverse array of pathologies ranging from infectious disease to sterile inflammation. Polarization of macrophages determines their cellular function within biological processes. Lipin-1 is a phosphatidic acid phosphatase in which its enzymatic activity contributes to macrophage pro-inflammatory responses. Lipin-1 also possesses transcriptional co-regulator activity and whether this activity is required for macrophage polarization is unknown. Using mice that lack only lipin-1 enzymatic activity or both enzymatic and transcriptional coregulator activities from myeloid cells, we investigated the contribution of lipin-1 transcriptional co-regulator function toward macrophage wound healing polarization. Macrophages lacking both lipin-1 activities did not elicit IL-4 mediated gene expression to levels seen in either wild-type or lipin-1 enzymatically deficient macrophages. Furthermore, mice lacking myeloid-associated lipin-1 have impaired full thickness excisional wound healing compared to wild-type mice or mice only lacking lipin-1 enzymatic activity from myeloid cell. Our study provides evidence that lipin-1 transcriptional co-regulatory activity contributes to macrophage polarization and influences wound healin

Deletion of the Human Cytomegalovirus US17 Gene Increases the Ratio of Genomes per Infectious Unit and Alters Regulation of Immune and Endoplasmic Reticulum Stress Response Genes at Early and Late Times after Infection

Human cytomegalovirus (HCMV) employs numerous strategies to combat, subvert, or co-opt host immunity. One evolutionary strategy for this involves capture of a host gene and then its successive duplication and divergence, forming a family of genes, many of which have immunomodulatory activities. The HCMV US12 family consists of 10 tandemly arranged sequence-related genes in the unique short (US) region of the HCMV genome (US12 to US21). Each gene encodes a protein possessing seven predicted transmembrane domains, patches of sequence similarity with cellular G-protein-coupled receptors, and the Bax inhibitor 1 family of antiapoptotic proteins. We show that one member, US17, plays an important role during virion maturation. Microarray analysis of cells infected with a recombinant HCMV isolate with a US17 deletion (the ΔUS17 mutant virus) revealed blunted host innate and interferon responses at early times after infection (12 h postinfection [hpi]), a pattern opposite that previously seen in the absence of the immunomodulatory tegument protein pp65 (pUL83). Although the ΔUS17 mutant virus produced numbers of infectious particles in fibroblasts equal to the numbers produced by the parental virus, it produced \u3e3-fold more genome-containing noninfectious viral particles and delivered increased amounts of pp65 to newly infected cells. These results suggest that US17 has evolved to control virion composition, to elicit an appropriately balanced host immune response. At later time points (96 hpi), ΔUS17 mutant-infected cells displayed aberrant expression of several host endoplasmic reticulum stress response genes and chaperones, some of which are important for the final stages of virion assembly and egress. Our results suggest that US17 modulates host pathways to enable production of virions that elicit an appropriately balanced host immune response

The human cytomegalovirus UL55 (gB) and UL75 (gH) glycoprotein ligands initiate the rapid activation of Sp1 and NF-kappaB during infection.

The cellular transcription factors Sp1 and NF-kappaB were upregulated shortly after the binding of purified live or UV-inactivated human cytomegalovirus (HCMV) to the cell surface. The rapid time frame of transcription factor induction is similar to that seen in other systems in which cellular factors are induced following receptor-ligand engagement. This similarity suggested that a cellular receptor-viral ligand interaction might be involved in Sp1 and NF-kappaB activation during the earliest stages of HCMV infection. To focus on the possible role viral ligands play in initiating cellular events following infection, we first used purified viral membrane extracts to demonstrate that constituents on the membrane are responsible for cellular activation. Additionally, these studies showed, through the use of neutralizing antibodies, that the viral membrane mediators of this activation are the major envelope glycoproteins gB (UL55) and gH (UL75). To confirm these results, neutralizing anti-gB and -gH antibodies were used to block the interactions of these glycoproteins on whole purified virus with their cell surface receptors. In so doing, we found that Sp1 and NF-kappaB induction was inhibited. Lastly, through the use of purified viral gB protein and an anti-idiotypic antibody that mimics the image of the viral gH protein, it was found that the engagement of individual viral ligands with their appropriate cell surface receptors was sufficient to activate cellular Sp1 and NF-kappaB. These results support our hypothesis that HCMV glycoproteins mediate an initial signal transduction pathway which leads to the upregulation of host cell transcription factors and suggests a model wherein the orderly sequence of virus-mediated changes in cellular activation initiates with viral binding via envelope glycoproteins to the cognate cellular receptor(s)

The role of protein tyrosine phosphorylation in integrin-mediated gene induction in monocytes

Integrin-mediated cell adhesion, or cross-linking of integrins using antibodies, often results in the enhanced tyrosine phosphorylation of certain intracellular proteins, suggesting that integrins may play a role in signal transduction processes. In fibroblasts, platelets, and carcinoma cells, a novel tyrosine kinase termed pp125FAK has been implicated in integrin-mediated tyrosine phosphorylation. In some cell types, integrin ligation or cell adhesion has also been shown to result in the increased expression of certain genes. Although it seems reasonable to hypothesize that integrin-mediated tyrosine phosphorylation and integrin-mediated gene induction are related, until now, there has been no direct evidence supporting this hypothesis. In the current report, we explore the relationship between integrin- mediated tyrosine phosphorylation and gene induction in human monocytes. We demonstrate that monocyte adherence to tissue culture dishes or to extracellular matrix proteins is followed by a rapid and profound increase in tyrosine phosphorylation, with the predominant phosphorylated component being a protein of 76 kD (pp76). Tyrosine phosphorylation of pp76 and other monocyte proteins can also be triggered by incubation of monocytes with antibodies to the integrin beta 1 subunit, or by F(ab')2 fragments of such antibodies, but not by F(ab) fragments. The ligation of beta 1 integrins with antibodies or F(ab')2 fragments also induces the expression of immediate-early (IE) genes such as IL-1 beta. When adhering monocytes are treated with the tyrosine kinase inhibitors genistein or herbimycin, both phosphorylation of pp76 and induction of IL-1 beta message are blocked in a dose-dependent fashion. Similarly, treatment with genistein or herbimycin can block tyrosine phosphorylation of pp76 and IL-1 beta message induction mediated by ligation of beta 1 integrin with antibodies. These observations suggest that protein tyrosine phosphorylation is an important aspect of integrin-mediated IE gene induction in monocytes. The cytoplasmic tyrosine kinase pp125FAK, although important in integrin signaling in other cell types, seems not to play a role in monocytes because this protein could not be detected in these cells

OR14I1 is a receptor for the human cytomegalovirus pentameric complex and defines viral epithelial cell tropism

A human cytomegalovirus (HCMV) pentameric glycoprotein complex (PC), gH-gL-UL128-UL130-UL131A, is necessary for viral infection of clinically relevant cell types, including epithelial cells, which are important for interhost transmission and disease. We performed genome-wide CRISPR/Cas9 screens of different cell types in parallel to identify host genes specifically required for HCMV infection of epithelial cells. This effort identified a multipass membrane protein, OR14I1, as a receptor for HCMV infection. This olfactory receptor family member is required for HCMV attachment, entry, and infection of epithelial cells and is dependent on the presence of viral PC. OR14I1 is required for AKT activation and mediates endocytosis entry of HCMV. We further found that HCMV infection of epithelial cells is blocked by a synthetic OR14I1 peptide and inhibitors of adenylate cyclase and protein kinase A (PKA) signaling. Identification of OR14I1 as a PC-dependent HCMV host receptor associated with epithelial tropism and the role of the adenylate cyclase/PKA/AKT-mediated signaling pathway in HCMV infection reveal previously unappreciated targets for the development of vaccines and antiviral therapies

The role of protein tyrosine phosphorylation in integrin-mediated gene induction in monocytes.

Integrin-mediated cell adhesion, or cross-linking of integrins using antibodies, often results in the enhanced tyrosine phosphorylation of certain intracellular proteins, suggesting that integrins may play a role in signal transduction processes. In fibroblasts, platelets, and carcinoma cells, a novel tyrosine kinase termed pp125FAK has been implicated in integrin-mediated tyrosine phosphorylation. In some cell types, integrin ligation or cell adhesion has also been shown to result in the increased expression of certain genes. Although it seems reasonable to hypothesize that integrin-mediated tyrosine phosphorylation and integrin-mediated gene induction are related, until now, there has been no direct evidence supporting this hypothesis. In the current report, we explore the relationship between integrin- mediated tyrosine phosphorylation and gene induction in human monocytes. We demonstrate that monocyte adherence to tissue culture dishes or to extracellular matrix proteins is followed by a rapid and profound increase in tyrosine phosphorylation, with the predominant phosphorylated component being a protein of 76 kD (pp76). Tyrosine phosphorylation of pp76 and other monocyte proteins can also be triggered by incubation of monocytes with antibodies to the integrin beta 1 subunit, or by F(ab')2 fragments of such antibodies, but not by F(ab) fragments. The ligation of beta 1 integrins with antibodies or F(ab')2 fragments also induces the expression of immediate-early (IE) genes such as IL-1 beta. When adhering monocytes are treated with the tyrosine kinase inhibitors genistein or herbimycin, both phosphorylation of pp76 and induction of IL-1 beta message are blocked in a dose-dependent fashion. Similarly, treatment with genistein or herbimycin can block tyrosine phosphorylation of pp76 and IL-1 beta message induction mediated by ligation of beta 1 integrin with antibodies. These observations suggest that protein tyrosine phosphorylation is an important aspect of integrin-mediated IE gene induction in monocytes. The cytoplasmic tyrosine kinase pp125FAK, although important in integrin signaling in other cell types, seems not to play a role in monocytes because this protein could not be detected in these cells