Evolutionary Challenges to Humanity Caused by Uncontrolled Carbon Emissions: The Stockholm Paradigm

This review paper discusses the Stockholm Paradigm (SP) as a theoretical framework and practical computational instrument for studying and assessing the risk of emerging infectious diseases (EIDs) as a result of climate change. The SP resolves the long-standing parasite paradox and explains how carbon emissions in the atmosphere increase parasites’ generalization and intensify host switches from animals to humans. The SP argues that the growing rate of novel EID occurrence caused by mutated zoonotic pathogens is related to the following factors brought together as a unified issue of humanity: (a) carbon emissions and consequent climate change; (b) resettlement/migration of people with hyper-urbanization; (c) overpopulation; and (d) human-induced distortion of the biosphere. The SP demonstrates that, in an evolutionary way, humans now play a role migratory birds once played in spreading parasite pathogens between the three Earth megabiotopes (northern coniferous forest belt; tropical/equatorial rainforest areas; and hot/cold deserts), i.e., the role of “super-spreaders” of parasitic viruses, bacteria, fungi and protozoa. This makes humans extremely vulnerable to the EID threat. The SP sees the +1.0–+1.2 °C limit as the optimal target for the slow, yet feasible curbing of the EID hazard to public health (150–200 years). Reaching merely the +2.0 °C level will obviously be an EID catastrophe, as it may cause two or three pandemics each year. We think it useful and advisable to include the SP-based research in the scientific repository of the Intergovernmental Panel on Climate Change, since EID appearance and spread are indirect but extremely dangerous consequences of climate change

Public Policy Measures to Increase Anti-SARS-CoV-2 Vaccination Rate in Russia

The total vaccination rate remains relatively low in Russia as of March 2022 (around 55%, with around 20% in some regions). In the paper, we study the reasons for it. We communicate the results of our survey aimed at detecting reasons for the relatively low anti-SARS-CoV-2 vaccination rate in Russia (47.1% as of mid-January 2022) and suggest potential measures to increase the level of confidence in the Russian vaccination campaign. A total of 14,310 users exhibited interest to participate in the research (16.84% of the total number of invitations sent in the Russian social network VKontakte). After the sample set repair, only 5822 (40.68% of those who agreed to participate) responses were suitable for the research, and they composed the final set. The age range of the respondents was 16–51 years old (y.o.) with a mean of 29.1 ± 10.6 y.o. The proportion of the female gender in responses was 44.23%. A total of 2454 persons (42.15%) expressed their hesitant, cautious, or negative attitude towards vaccine uptake. Of the 2454 persons with cautious attitude towards vaccination, only 928 (37.82%) were concerned about the quality of the Russian vaccines. A total of 1323 individuals (53.91%) supported one or more conspiracy beliefs. A total of 5064 (86.98% of the whole set) showed cautious or negative attitude towards the planned introduction of a nationwide system of vaccination certification/verification based on QR codes. The main social factors that hinder the Russian vaccination campaign are: vexation over the lack of desire of officials to receive feedback from the general population regarding vaccination, wide support for conspiracy beliefs, and controversy over the QR code-based digital system. To elevate the vaccination rate in Russia, the following steps may be taken: social encouragement of those who support vaccination, increase in transparency of the vaccination campaign, acceptance of both digital and paper vaccination certificates, increase in participation of society in vaccination-related discussions, public disclosure of vaccine composition, and avoidance of excessive digitalization of data in the vaccination campaign

Using Alternative Sources of Energy for Decarbonization: A Piece of Cake, but How to Cook This Cake?

Few analytical or research works claim that the negative impact of improper use of ASEs may be comparable with that of hydrocarbons and sometimes even greater. It has become a common view that “green” energy (ASE) is clean, safe and environmentally friendly (eco-friendly) in contrast with “black” energy (hydrocarbons). We analyzed 144 works on systemic and/or comparative research of the modern and prospective ASE: biofuels, hydrogen, hydropower, nuclear power, wind power, solar power, geothermal power, oceanic thermal power, tidal power, wind wave power and nuclear fusion power. We performed our analysis within the Spaceship Earth paradigm. We conclude that there is no perfect ASE that is always eco-friendly. All ASEs may be dangerous to the planet considered as a closed and isolated unit (“spaceship”) if they are used in an inconsistent manner. This is not in the least a reason to deny them as prospective sources of energy. Using all ASEs in different proportions in various regions of the planet, where their harm to the planet and humanity can be minimized and, on the contrary, their efficiency maximized, would give humanity the opportunity to decarbonize the Earth, and make the energy transition in the most effective way

Combined Effect of Bortezomib and Menadione Sodium Bisulfite on Proteasomes of Tumor Cells: The Dramatic Decrease of Bortezomib Toxicity in a Preclinical Trial

Tumor growth is associated with elevated proteasome expression and activity. This makes proteasomes a promising target for antitumor drugs. Current antitumor drugs such as bortezomib that inhibit proteasome activity have significant side effects. The purpose of the present study was to develop effective low-toxic antitumor compositions with combined effects on proteasomes. For compositions, we used bortezomib in amounts four and ten times lower than its clinical dose, and chose menadione sodium bisulfite (MSB) as the second component. MSB is known to promote oxidation of NADH, generate superoxide radicals, and as a result damage proteasome function in cells that ensure the relevance of MSB use for the composition development. The proteasome pool was investigated by the original native gel electrophoresis method, proteasome chymotrypsin-like activity—by Suc-LLVY-AMC-hydrolysis. For the compositions, we detected 10 and 20 μM MSB doses showing stronger proteasome-suppressing and cytotoxic in cellulo effects on malignant cells than on normal ones. MSB indirectly suppressed 26S-proteasome activity in cellulo, but not in vitro. At the same time, MSB together with bortezomib displayed synergetic action on the activity of all proteasome forms in vitro as well as synergetic antitumor effects in cellulo. These findings determine the properties of the developed compositions in vivo: antitumor efficiency, higher (against hepatocellular carcinoma and mammary adenocarcinoma) or comparable to bortezomib (against Lewis lung carcinoma), and drastically reduced toxicity (LD50) relative to bortezomib. Thus, the developed compositions represent a novel generation of bortezomib-based anticancer drugs combining high efficiency, low general toxicity, and a potentially expanded range of target tumors

A nuclear localization signal within HIV-1 matrix protein that governs infection of non-dividing cells

Permissiveness of the host cell to productive infection by onco-retroviruses is cell-cycle dependent(1), and nuclear localization of viral nucleoprotein preintegration complexes will occur only after cells have passed through mitosis(2). In contrast, establishment of an integrated provirus after infection by the lentivirus HIV-1 is independent of host cell proliferation(3–5). The ability of HIV-1 to replicate in non-dividing cells is partly accounted for by the karyophilic properties of the viral preintegration complex which, after virus infection, is actively transported to the host cell nucleus. Here we report that the gag matrix protein of HIV-1 contains a nuclear localization sequence which, when conjugated to a heterologous protein, directs its nuclear import. In addition, HIV-1 mutants containing amino-acid substitutions in this nuclear localization signal integrate and replicate within dividing but not growth-arrested cells, and thus display a phenotype more representative of an onco-retrovirus

Proteasome functioning in breast cancer: connection with clinical-pathological factors.

Breast cancer is one of four oncology diseases that are most widespread in the world. Moreover, breast cancer is one of leading causes of cancer-related deaths in female population within economically developed regions of the world. So far, detection of new mechanisms of breast cancer development is very important for discovery of novel areas in which therapy approaches may be elaborated. The objective of the present study is to investigate involvement of proteasomes, which cleave up to 90% of cellular proteins and regulate numerous cellular processes, in mechanisms of breast cancer development. Proteasome characteristics in 106 patient breast carcinomas and adjacent tissues, as well as relationships of detected proteasome parameters with clinical-pathological factors, were investigated. Proteasome chymotrypsin-like activity was evaluated by hydrolysis of fluorogenic peptide Suc-LLVY-AMC. The expression of proteasome subunits was studied by Western-blotting and immunohistochemistry. The wide range of chymotrypsin-like activity in tumors was detected. Activity in tumors was higher if compared to adjacent tissues in 76 from 106 patients. Multiple analysis of generalized linear models discovered that in estrogen α-receptor absence, tumor growth was connected with the enhanced expression of proteasome immune subunit LMP2 and proteasome activator PA700 in tumor (at 95% confidence interval). Besides, by this analysis we detected some phenomena in adjacent tissue, which are important for tumor growth and progression of lymph node metastasis in estrogen α-receptor absence. These phenomena are related to the enhanced expression of activator PA700 and immune subunit LMP7. Thus, breast cancer development is connected with functioning of immune proteasome forms and activator PA700 in patients without estrogen α-receptors in tumor cells. These results could indicate a field for search of new therapy approaches for this category of patients, which has the worst prognosis of health recovery

Proteasomes in Patient Rectal Cancer and Different Intestine Locations: Where Does Proteasome Pool Change?

A special problem in the surgery of rectal cancer is connected with a need for appropriate removal of intestine parts, along with the tumor, including the fragment close to the sphincter. To determine the length of fragments to remove, it is necessary to reveal areas without changes in molecule functioning, specific for tumor. The purpose of the present study was to investigate functioning the proteasomes, the main actors in protein hydrolysis, in patient rectal adenocarcinoma and different intestine locations. Chymotrypsin-like and caspase-like activities, open to complex influence of different factors, were analyzed in 43–54 samples by Suc-LLVY-AMC- and Z-LLE-AMC-hydrolysis correspondingly. Both activities may be arranged by the decrease in the location row: cancer→adjacent tissue→proximal (8–20 cm from tumor) and distal (2 and 4 cm from tumor) sides. These activities did not differ noticeably in proximal and distal locations. Similar patterns were detected for the activities and expression of immune subunits LMP2 and LMP7 and expression of 19S and PA28αβ activators. The largest changes in tumor were related to proteasome subtype containing LMP2 and PA28αβ that was demonstrated by native electrophoresis. Thus, the results indicate a significance of subtype LMP2-PA28αβ for tumor and absence of changes in proteasome pool in distal fragments of 2–4 cm from tumor

Statistical indicators for revealed dependence of the proteasome parameters in breast samples on simultaneous effect of clinical-pathological factors.^1.

1<p>Multiple GLM (generalized linear models) analysis was applied;</p>2<p>F (DF), F-test value for indicated pair of interacting signs (Degrees of Freedom);</p>3<p><i>p</i>, statistical significance of observed effects.</p><p>Statistical indicators for revealed dependence of the proteasome parameters in breast samples on simultaneous effect of clinical-pathological factors.^1.</p

Expression of proteasome immune subunits and Rpt6 subunit in breast samples at different disease stages.

<p>Western-blotting was performed with the use of mouse mAbs to proteasome subunits LMP2, LMP7 and Rpt6; β-actin was detected as the inner control with the use of mouse mAbs to this protein. TT, tumor tissue. AT, adjacent tissue.</p

Expression of immune subunits LMP2 and LMP7 in cytokeratin 18 containing cells of IDC sample.

<p>(Panels A) Mouse mAbs to cytokeratin 18, rabbit pAbs to LMP2. (Panels B) Mouse mAbs to cytokeratin 18, rabbit pAbs to LMP7. IDC, invasive ductal carcinoma. Scale bar, 100 µm.</p