Biochemistry, Not Oncogenes, may Demystify and Defeat Cancer

The presence of mutated genes strongly correlates with the incidence of cancer. Decades of research, however, has not yielded any specific causative gene or set of genes for the vast majority of cancers. The Cancer Genome Atlas program was supposed to provide clarity but it only gave much more data without any accompanying insight into how the disease begins and progresses. It may be time to notice that epidemiological studies consistently show that the environment, not genes, has the principal role in causing cancer. Since carcinogenic chemicals in our food, drink, air and water are the primary culprits, we need to look at the biochemistry of cancer, with a focus on enzymes which invariably facilitate transformations in a cell. In particular, attention should be paid to the rate-limiting enzyme in DNA synthesis, ribonucleotide reductase (RnR) whose activity is tightly linked to tumor growth. Besides circumstantial evidence that cancer is induced at this enzyme’s vulnerable free-radical-containing active-site by various carcinogens, its role in initiating retinoblastoma and HPV-related cervical cancers is well documented. Blocking the activity of malignant RnR is a certain way to arrest cancer.

A Study on Decisional Factors for Service Life of Fire Trucks

The lifetime of fire trucks depends on their built-in pumps. A fire truck delivers water to the site of a fire accident via its pump that is composed of an impeller and a casing. As its service time increases, the clearance between the two elements increases. This causes leakage in the pump to increase beyond its limit and the pump can no longer fulfill its principal role. In general, fatigue, erosion, and corrosion are considered to be the major mechanisms for pump failure. From this study, it has been observed that fatigue is not the main factor for failure because of the small magnitude of stress it induces. Erosion by particles shows a high erosion rate of the suction area of the impeller. Cavitation, which is a key mechanism of corrosion, is observed at a suction depth of 7 m and is observed to widen at 7.1 m depth. Finally, the lifetime of the fire trucks is found to be affected by the motion of sucking the natural water of ponds, rivers, etc.

Alternative Vaccination Politics

Background The timely implementation of the vaccination campaign and sharp rules for vaccine administration can make a difference. The paper investigates the impact of alternative policies based on scientific vaccination priorities inspired by the extended statistics on Covid-19 fatalities. Methods In the case of Covid-19 vaccination, a principal role is played by promptly adopting a reverse-order of age approach (to target first the elderly) coupled to covering the high priority categories but postponing the low priority ones. We implemented an in silico vaccination simulator capable of comparing what happened in reality with what might have happened if alternative vaccination policies had been adopted. The immunization profile and the death distribution curve allowed measuring the distance between reality and alternative policies and finally quantifying the expected number of saved lives. Results The alternative approach to vaccination was applied to Italy and Lombardy that host 60 and 10 million residents respectively. In about 100 days of vaccination based on (a) a reverse-order of age policy (from 90 + to 80–89 to 70–79 year-olds, etc.), (b) vaccination of priority categories, (c) postponement of non-priority categories and reallocation of such doses to (a) and (b), the saved lives would have been 3969 in Italy (of which 799 in Lombardy). In the same period, Italy suffered 30,911 fatalities (of which 5,613 in Lombardy). Of those fatalities, about 12.8% in Italy and 14.2% in Lombardy might have been avoided if a different approach to vaccination had been applied. Even better results would have been achieved if the elderly vaccination had been anticipated a few days (which started only 53 days after the very beginning of the Italian vaccination campaign) or if the vaccination engine had performed better in terms of daily administered doses while respecting the available delivered doses. Conclusions A different approach to the vaccination politics based on sharp and straight policies based on scientific quantitative data of Covid-19 mortality as a function of age and comorbidities would have accomplished a better quantitative effect on extinguishing the pandemic and containing the fatalities toll.

Milestones in Molecular Mechanisms of Adipogenesis and Adipose Tissue Plasticity

This review focuses on the problem of adipogenesis mechanisms and the biological role of adipose tissue (AT) in the human body. Over the past decades, various types of adipocytes have been identified and characterized—white, brown, beige, yellow, and pink. An important feature of AT is a high plasticity and the ability to transdifferentiate and de-differentiate into another cell type. In this case, the pathway of transformation mostly depends on adipocytes’ cellular and metabolic microenvironment. The mechanisms of adipogenesis and the ways of its regulation remain not fully understood. The principal role in the terminal differentiation of preadipocytes is assigned to PPARγ and receptors activated by bone morphogenetic proteins, insulin, and cortisol. However, in chronic inflammation, adipogenesis is suppressed and old adipocytes increase the production of proinflammatory cytokines, which leads to the death of inflamed cells and hypertrophy of neighboring adipocytes. Thus, disruption of adipogenesis, premature aging of white adipocytes, perturbations in the metabolic and cellular microenvironment of preadipocytes, and early apoptosis of fat cells cause the development of insulin resistance and metabolically unhealthy obesity.

Immune Landscape of CMV Infection in Cancer Patients: From “Canonical” Diseases Toward Virus-Elicited Oncomodulation

Human Cytomegalovirus (HCMV) is an immensely pervasive herpesvirus, persistently infecting high percentages of the world population. Despite the apparent robust host immune responses, HCMV is capable of replicating, evading host defenses, and establishing latency throughout life by developing multiple immune-modulatory strategies. HCMV has coexisted with humans mounting various mechanisms to evade immune cells and effectively win the HCMV-immune system battle mainly through maintaining its viral genome, impairing HLA Class I and II molecule expression, evading from natural killer (NK) cell-mediated cytotoxicity, interfering with cellular signaling, inhibiting apoptosis, escaping complement attack, and stimulating immunosuppressive cytokines (immune tolerance). HCMV expresses several gene products that modulate the host immune response and promote modifications in non-coding RNA and regulatory proteins. These changes are linked to several complications, such as immunosenescence and malignant phenotypes leading to immunosuppressive tumor microenvironment (TME) and oncomodulation. Hence, tumor survival is promoted by affecting cellular proliferation and survival, invasion, immune evasion, immunosuppression, and giving rise to angiogenic factors. Viewing HCMV-induced evasion mechanisms will play a principal role in developing novel adapted therapeutic approaches against HCMV, especially since immunotherapy has revolutionized cancer therapeutic strategies. Since tumors acquire immune evasion strategies, anti-tumor immunity could be prominently triggered by multimodal strategies to induce, on one side, immunogenic tumor apoptosis and to actively oppose the immune suppressive microenvironment, on the other side.

TRANSFORMATION OF CURRENT ISSUES OF MODERN SOCIO-POLITICAL CHANGES

The article provides estimates of the “material standard of living” of the world’s population by periods (life expectancy, the volume of production of consumer goods, services, and products per capita). Many scientists and experts, politicians and, statesmen who have left their mark on world history have thought about the concept of progress. Most of them supported the idea of “progress” only from the bottom up. One described the pinnacle of progress as Chinese communism and, another called it “Western democracy.” This one-sided explanation reflects in the theory of five entities. (primitive, slavery, feudalism, capitalism and, communism or Western democracy). It emphasizes that all nations must go through these formations. The end of the twentieth century was characterized not only by the breakdown of the socialist system so “longawaited” in the West, the disappearance of the bipolar world and the emergence of world centers of power, unpredictable insane globalization with all the ensuing consequences, but, as it is obvious now, by the emergence of new, previously unseen threats and challenges not only to the sovereignty of individual countries but, above all, by threats to the existence of both each individual and by challenges to the existence of people itself. The first quarter of the 21st century, more than ever before, stuck out, exposed and, brought to the culmination point all painful problems - environmental, economic, geopolitical, socio-cultural, etc. The problem of adequate analysis and forecasting of these threats and challenges did not test, methodologically verified. The study made it possible to conclude that the issue of global and national security on earth is one of the main tasks of any state. And the understanding of the current requirements plays a principal role in preventing the emergence of a threat factor. Thus, understanding the period is one of the dominant needs in preventing the emergence of a threat factor

A conditioned place preference for heroin is signaled by increased dopamine and direct pathway activity and decreased indirect pathway activity in the nucleus accumbens

Initial drug use promotes the development of conditioned reinforcement, whereby the reinforcing properties of a drug become attributed to drug-associated stimuli, such as cues and contexts. A principal role for the nucleus accumbens (NAc) in the response to drug-associated stimuli has been well-documented. In particular, direct and indirect pathway medium spiny neurons (dMSNs and iMSNs) have been shown to bidirectionally regulate cue-induced heroin-seeking in rats expressing addiction-like phenotypes, and a shift in NAc activity towards the direct pathway has been shown in mice following cocaine conditioned place preference (CPP). However, how NAc signaling guides heroin CPP, and whether heroin alters the balance of signaling between dMSNs and iMSNs remains unknown. Moreover, the role of NAc dopamine signaling in heroin reinforcement remains unclear. Here, we integrate fiber photometry for in vivo monitoring of dopamine and dMSN/iMSN calcium activity with a heroin CPP procedure in rats to address these outstanding questions. We identify a sensitization-like response to heroin in the NAc, with prominent iMSN activity during initial heroin exposure and prominent dMSN activity following repeated heroin exposure. We demonstrate a ramp in dopamine activity, dMSN activation, and iMSN inactivation preceding entry into a heroin-paired context, and a decrease in dopamine activity, dMSN inactivation, and iMSN activation preceding exit from a heroin-paired context. Finally, we show that buprenorphine is sufficient to prevent the development of heroin CPP and activation of the NAc post-conditioning. Together, these data support the hypothesis that an imbalance in NAc activity contributes to the development of addiction.

Alternative Vaccination Politics

Background: The timely implementation of the vaccination campaign and sharp rules for vaccine administration can make a difference. The paper investigates the impact of alternative policies based on scientific vaccination priorities inspired by the extended statistics on Covid-19 fatalities.Methods: In the case of Covid-19 vaccination, a principal role is played by promptly adopting a reverse-order of age approach (to target first the elderly) coupled to covering the high priority categories but postponing the low priority ones. We implemented an in silico vaccination simulator capable of comparing what happened in reality with what might have happened if alternative vaccination policies had been adopted. The immunization profile and the death distribution curve allowed measuring the distance between reality and alternative policies and finally quantifying the expected number of saved lives.Results: The alternative approach to vaccination was applied to Italy and Lombardy that host 60 and 10 million residents respectively. In about 100 days of vaccination based on (a) a reverse-order of age policy (from 90+ to 80-89 to 70-79 year-olds, etc.), (b) vaccination of priority categories, (c) postponement of non-priority categories and reallocation of such doses to (a) and (b), the saved lives would have been 3969 in Italy (of which 799 in Lombardy). In the same period, Italy suffered 30,911 fatalities (of which 5,613 in Lombardy). Of those fatalities, about 12.8% in Italy and 14.2% in Lombardy might have been avoided if a different approach to vaccination had been applied. Even better results would have been achieved if the elderly vaccination had been anticipated a few days (which started only 53 days after the very beginning of the Italian vaccination campaign) or if the vaccination engine had performed better in terms of daily administered doses while respecting the available delivered doses.Conclusions: A different approach to the vaccination politics based on sharp and straight policies based on scientific quantitative data of Covid-19 mortality as a function of age and comorbidities would have accomplished a better quantitative effect on extinguishing the pandemic and containing the fatalities toll.

Biochemistry, Not Oncogenes, may Demystify and Defeat Cancer

Presence of mutated genes strongly correlates with incidence of cancer. Decades of research, however, has not yielded any specific causative gene or set of genes for the vast majority of cancers. The Cancer Genome Atlas program was supposed to provide clarity but it only gave much more data without any accompanying insight into how the disease begins and progresses. It may be time to notice that epidemiological studies consistently show that the environment, not genes, has the principal role in causing cancer. Since carcinogenic chemicals in our food, drink, air and water are the primary culprit, we need to look at the biochemistry of cancer, with focus on enzymes which carry out any and all transformations in a cell. In particular, attention should be paid to the rate-limiting enzyme in DNA synthesis, ribonucleotide reductase (RnR) which is tightly linked to tumor growth. Beside the circumstantial evidence that cancer is induced at its vulnerable active-site by various carcinogens, there exists experimental proof of its role in initiating retinoblastoma and HPV-related cervical cancers. Blocking the activity of RnR is a certain way to arrest cancer.

Non-Conventional Yeasts as Alternatives in Modern Baking for Improved Performance and Aroma Enhancement

Saccharomyces cerevisiae remains the baker’s yeast of choice in the baking industry. However, its ability to ferment cereal flour sugars and accumulate CO2 as a principal role of yeast in baking is not as unique as previously thought decades ago. The widely conserved fermentative lifestyle among the Saccharomycotina has increased our interest in the search for non-conventional yeast strains to either augment conventional baker’s yeast or develop robust strains to cater for the now diverse consumer-driven markets. A decade of research on alternative baker’s yeasts has shown that non-conventional yeasts are increasingly becoming important due to their wide carbon fermentation ranges, their novel aromatic flavour generation, and their robust stress tolerance. This review presents the credentials of non-conventional yeasts as attractive yeasts for modern baking. The evolution of the fermentative trait and tolerance to baking-associated stresses as two important attributes of baker’s yeast are discussed besides their contribution to aroma enhancement. The review further discusses the approaches to obtain new strains suitable for baking applications.