Hypothetical Mechanism Research Articles

Effect of pre-oxidation on the rate of formation of sulfur-containing aromatic compounds during vacuum gas oil thermal cracking

It was shown that oxidation followed by heat treatment is an effective method for desulfurization of vacuum gas oil. Patterns of changes in the quantitative content of the thiophene series compounds in liquid cracking products of vacuum gas oil and liquid cracking products of pre-oxidized vacuum gas oil are described. A mixture of hydrogen peroxide and formic acid (molar ratio 3:4) was used as the oxidation system. The hypothetical mechanism for the formation of thiophene, benzo- and dibenzothiophene and their homologues from high-molecular weight components of the initial vacuum gas oil and its oxidation products is proposed. Presumably, main path of formation considerate compounds is thermal decomposition of high-molecular weight sulfur-containing components. On the basis of IR spectroscopy and structure-group analysis data, the averaged structures of such components were constructed. The influence of pre-oxidation and its conditions on the value of the rate constants for the formation of thiophene, benzo- and dibenzothiophene and their homologues during thermal cracking of initial and oxidized vacuum gas oils is studied.

The Effects of Bioactive Compounds on PTSD Treatment.

Post-traumatic Stress Disorder (PTSD) is a psychiatric disease that arises in individuals who have experienced a traumatic event such as combat exposure, childhood physical abuse, sexual violence, physical assault, an accident, etc. Being difficult to diagnose and treat, PTSD is actively studied in areas of medicine, psychiatry, biochemistry, and rehabilitation. PTSD is characterized by significant comorbidity and is accompanied by depression and anxiety. Current treatment strategies for PTSD symptoms include psychotherapy and medications. Naturally derived compounds can offer therapeutic benefits for mood disorders without unpleasant side effects. Bioactive compounds found in food exhibit beneficial effects such as antioxidant, anti-inflammatory, and neuroprotective activities. Here, we describe the promising therapeutic benefits of a number of bioactive substances that have been evaluated in a variety of animal models and human experimental studies. Anxiolytic, antidepressant, and antidementia activities of bioactive compounds emphasize their potential for treating PTSD comorbidities. Hypothetical mechanisms of actions are also discussed, providing insights into their potential for human mental health.

Deciphering the Interdomain Coupling in a Gram-Negative Bacterial Membrane Insertase.

YidC is a membrane protein that plays an important role in inserting newly generated proteins into lipid membranes. The Sec-dependent complex is responsible for inserting proteins into the lipid bilayer in bacteria. YidC facilitates the insertion and folding of membrane proteins, both in conjunction with the Sec complex and independently. Additionally, YidC acts as a chaperone during the folding of proteins. Multiple investigations have conclusively shown that Gram-positive bacterial YidC has Sec-independent insertion mechanisms. Through the use of microsecond-level all-atom molecular dynamics (MD) simulations, we have carried out an in-depth investigation of the YidC protein originating from Gram-negative bacteria. This research sheds light on the significance of multiple domains of the YidC structure at a detailed molecular level by utilizing equilibrium MD simulations. Specifically, multiple models of YidC embedded in the lipid bilayer were constructed to characterize the critical role of the C2 loop and the periplasmic domain (PD) present in Gram-negative YidC, which is absent in its Gram-positive counterpart. Based on our results, the C2 loop plays a role in the overall stabilization of the protein, most notably in the transmembrane (TM) region, and it also has an allosteric influence on the PD region. We have found critical inter- and intradomain interactions that contribute to the stability of the protein and its function. Finally, our study provides a hypothetical Sec-independent insertion mechanism for Gram-negative bacterial YidC.

Solar Alpha Particle Radiation Increases Human Mortality – Examples from the Neoplasms Mortality in the Europe and Mediterranean

A dangerous phenomenon for humanity is described. In the joint analysis of data from satellites in orbit around the Earth and from the health statistics source EUROSTAT, it became clear that, by some mechanism, flows of positively charged particles with high energy entering the Earth's orbit increase mortality on the planet's surface. The increase in mortality is in a band of maximum risk in the Northern Hemisphere, parallel to the Equator and bounded by the parallels of 30° and 50° north latitude. Examples are given for the European Union mortality from neoplasms, confirming the described phenomenon. A hypothetical mechanism based on observational evidence has been proposed, according to which this dangerous phenomenon is due to solar alpha particles of high energy sufficient to overcome the atmosphere's resistance and reach the Earth's surface in a limited area of maximum death impact.

Combined manifestation of two geometric visual illusions.

The present study continued to investigate whether the effects of length misperception caused by cross-shaped (formed by two pairs of the oppositely oriented Müller-Lyer wings) contextual distractors can be explained by the combined manifestation of two different (i.e., the Müller-Lyer and filled-space) geometric illusions of extent. In psychophysical experiments, the luminance of one pair of wings was randomly changed, while the luminance of the other pair remained constant. Two different distractor orientations were used-when the wings with constant luminance formed the right side of the cross or the left side, otherwise. To separately evaluate the manifestation of the Müller-Lyer illusion under different luminance conditions, two distracting crosses of the same orientation were attached to the lateral stimulus terminators in the first series of experiments. In the following four series, a single distracting cross (with different orientation) was attached to one of the lateral stimulus terminators and various combinations of the constant and background luminance were used. To interpret the experimental data, we used the basic computational principles of previously developed quantitative models of hypothetical visual mechanisms underlying the emergence of the Müller-Lyer illusion and the filled-space illusion. It was shown that the results of theoretical calculations adequately approximate the experimental curves obtained for all modifications of stimuli, which strongly supports the suggestion that the joint manifestations of these two illusions can be considered among the main factors determining the features of the illusion investigated.

The Association Between Distinct Delusional Ideations and Depressive Symptoms in Alzheimer's Disease: A Re-Analysis of CATIE-AD.

Delusional ideations, one of neuropsychiatric symptoms (NPSs), are frequently shown in the long-term progression of Alzheimer's disease (AD), and comorbid with other NPSs including depression or agitation. Despite various types of delusional ideations, the comorbidity between each delusional ideation and depressive symptoms has not been discussed. The present cross-sectional study is aimed at testing the hypothetical mechanism of comorbid pattern in AD. Among 421 patients with AD, we analyzed the dataset of the Clinical Antipsychotic Trials of Intervention Effectiveness-Alzheimer's Disease to compare age, sex, racial type, Mini-Mental State Examination (MMSE) scores, and Neuropsychiatric Inventory (NPI) depression score of between the presence and absence of each delusional ideation (delusion of persecution, theft, jealousy, abandonment, phantom boarder, Capgras syndrome, misidentification of place, or television sign). Next, with the stratification based on MMSE score of < or > = 15 points, we further explored association between delusional ideation and depressive symptom that was found significances in the primary analysis. Among eight subtypes of delusional ideations, depression score was higher in those with persecution delusion or Capgras syndrome. Moreover, the Capgras syndrome was associated with presence of depression in severer global cognitive impairment status. As comorbid NPSs of delusional ideation in AD, depressive severity is associated with specific delusional subtype: persecution delusion and Capgras syndrome. Capgras syndrome may be attributable to severe cognitive impairment in addition to depressive symptom. The consideration of pathogenetic differences in the distinct delusional ideations may be helpful for clinicians to select the treatment strategy.

A Disease Hidden in Plain Sight: Pathways and Mechanisms of Neurological Complications of Post-acute Sequelae of COVID-19 (NC-PASC).

The global impact of coronavirus disease 2019 (COVID-19) marked by numerous pandemic peaks is attributed to its high variability and infectious nature, transforming it into a persistent global public health concern. With hundreds of millions of cases reported globally, the illness is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Despite its initial classification as an acute respiratory illness, recent evidence indicates that lingering effects on various bodily systems, such as cardiovascular, pulmonary, nervous, gastrointestinal (GI), and musculoskeletal, may endure well beyond the acute phase. These persistent manifestations following COVID-19, commonly known as long COVID, have the potential to affect individuals across the entire range of illness severity, with a tendency to be more prevalent in mild to moderate cases. At present, there are no established criteria for diagnosing long COVID. Nonetheless, it is conceptualized as a multi-organ disorder encompassing a diverse array of clinical manifestations. The most common, persistent, and debilitating symptoms of long COVID may be neurological, known as neurological complications of post-acute sequelae of COVID-19 (NC-PASC). More than one-third of individuals with a prior SARS-CoV-2 infection show involvement of both the central nervous system (CNS) and peripheral nervous system (PNS), as evidenced by an approximately threefold higher incidence of neurological symptoms in observational studies. The persistent neurological symptoms of long COVID encompass fatigue, headache, cognitive decline, "brain fog", dysautonomia, neuropsychiatric issues, loss of smell (anosmia), loss of taste (ageusia), and peripheral nerve problems (peripheral neuropathy). Reported pathogenic mechanisms encompass viral persistence and neuro-invasion by SARS-CoV-2, neuroinflammation, autoimmunity, coagulopathy, and endotheliopathy. Raising awareness of potential complications is crucial for preventing and alleviating the long-term effects of long COVID and enhancing the prognosis for affected patients. This review explores the hypothetical pathophysiological mechanisms and pathways of NC-PASC with a sole aim to increase awareness about this crippling disease.

Can hydrogen prevent stress fractures in athletes?

As a result of the ability of hydrogen rich water to delay muscle fatigue, and considering that tired striated muscles do not sufficiently protect the bone from mechanical stress, the hypothetical mechanism according to which the consumption of the respective drink by athletes could reduce the incidence of stress fractures is discussed. The application of patches with transdermal release of molecular hydrogen in the areas where stress fractures occur frequently could strengthen this preventive action, due to the local anti-inflammatory and regenerative action established experimentally on the senescent bone, to which could be added the stimulation of osteogenesis, the inhibition of bone resorption and the prevention of fractures due to the antioxidant action. The hypothesis can be tested experimentally using the rabbit tibia as a model, or statistical studies can be done on the incidence of stress fractures in athletes who consume hydrogen rich water. Even baths in water saturated with molecular hydrogen can prevent stress fractures, because they reduce the perception of muscle fever, and the plasters could also prevent the complications of this type of fractures.

Hypothetical mechanisms driving physical activity levels in ethnic minority groups living in Europe: a systematically identified evidence-based conceptual systems model

BackgroundIn Europe, physical activity levels tend to be lower in ethnic minority groups than the general population. Interventions and policies based on research examining isolated determinants of physical activity have had limited success in increasing physical activity levels. This study used systems dynamics theory and the capability approach theoretical framework to develop a conceptual model of how individual characteristics, institutional and physical environments and the migration context may interact to promote or hinder physical activity in ethnic minority groups living in Europe.MethodsA systematic update of Langøien et al.’s 2017 review of the determinants of physical activity in ethnic minority groups living in Europe was conducted. Our target population included individuals of all ages who reported a familial migration background from any low- and middle-income countries or belonging to minority indigenous population in Europe. Outcomes pertaining to non-work related physical activity of light, moderate or vigorous intensity performed in any setting were included. Included studies provided an evidence base from which to derive the causal loop diagrams comprising our conceptual model. Sub-system causal loop diagrams were interpreted in co-author review sessions to explicate non-linear system mechanisms, such as reinforcing and balancing feedback loops.ResultsForty-one studies were identified, of which the majority was qualitative. The conceptual model consisted of 4 causal loop diagrams relating to psychosocial constructs; sociocultural constructs; health and health communication and social and material resources, in interaction with environmental/migration context. Four hypothetical mechanisms were identified, e.g. hypothesizing that participation in organised activities leads to increased self-efficacy, thereby enabling further participation.ConclusionsThis study contributes an evidence-based conceptual systems model which elucidates how low levels of physical activity in ethnic minority groups in Europe could be supported by reinforcing and balancing mechanisms involving factors relating to physical and institutional environments, migration context and individuals. A pluralistic approach to literature review, integrating complexity methods such as CLDs into more conventional systematic literature review, supports novel insights into how factors could interact to support persistently low levels of activity, moving beyond the identification of potential relationships between isolated factors to indicating the ways in which these relationships are sustained and could be modified by intervention or policy.

D-Glutamate production by stressed Escherichia coli gives a clue for the hypothetical induction mechanism of the ALS disease

In the search for the origin of Amyotrophic Lateral Sclerosis disease (ALS), we hypothesized earlier (Monselise, 2019) that d-amino acids produced by stressed microbiome may serve as inducers of the disease development. Many examples of d-amino acid accumulation under various stress conditions were demonstrated in prokaryotic and eukaryotic cells. In this work, wild-type Escherichia coli, members of the digestive system, were subjected to carbon and nitrogen starvation stress. Using NMR and LC–MS techniques, we found for the first time that d-glutamate accumulated in the stressed bacteria but not in control cells. These results together with the existing knowledge, allow us to suggest a new insight into the pathway of ALS development: d-glutamate, produced by the stressed microbiome, induces neurobiochemical miscommunication setting on C1q of the complement system. Proving this insight may have great importance in preventive medicine of such MND modern-age diseases as ALS, Alzheimer, and Parkinson.

Space Alpha Particle Fluxes Towards the Earth Increase Human Mortality. Is It Possible an Intervention of Non-Human Intelligence?

In the present work, a dangerous phenomenon for mankind is described, increasing mortality, mainly from the most deadly diseases on the planet – circulatory diseases, in particular ischemic heart diseases. In the joint analysis of data from satellites in orbit around the Earth and from the health statistics sources EUROSTAT and US medical statistics, it became clear that, by some mechanism, flows of positively charged particles with high energy entering the Earth's orbit increase human mortality, mainly from diseases of the circulatory system, but also from diseases of many other organs and systems of the human body. The circulatory disease mortality increase as a result of said alpha radiation is by an average of 5% to 15% in a zone of maximum risk in the Northern Hemisphere, parallel to the equator and bounded by the parallels of 30° and 50° north latitude. A hypothetical mechanism based on observational evidence has been proposed, according to which this dangerous phenomenon is due to solar alpha particles of high energy sufficient to overcome the resistance of the atmosphere and reach the Earth's surface in a limited area of maximum death impact. The impact is most often short-lasting – for minutes, hours, or sometimes a few days. In the area with maximum risk, alpha particles have a detrimental effect on the human body. The area with maximum risk is limited in area and in time by two conditions 1. the path of the particles through the atmosphere to the Earth's surface is as short as possible (during the local culmination of the Sun, local noon) and 2. the direction of the incoming alpha particles coincides with the direction of the vector of geomagnetic induction at the point of maximum risk, where alpha particles are not affected by the deflecting force of the geomagnetic field. Such a coincidence between the culmination of the Sun, which changes during the year, and the direction of the geomagnetic induction vector, which is unchanged for a given point of observation, occurs twice a year for points with a geographical latitude of 30° – 50° N. Examples are given confirming the proposed mechanism of action. In the second part of the study, attention is paid to the nature of alpha particle streams reaching the Earth's orbit. In addition to those emitted by the Sun as a result of natural processes, there are also series of pulses lasting less than 5 minutes, with strict periodicity in the series day or week, with the same moment of registration of the pulses and coincidence of the pulses in the series by magnitude over extended time intervals, sometimes over the lifetime of the series from months to years. The alpha particles from each pulse in the series bombard the Earth's surface always in the same place. There are many such series, differing in time of recording and period, each of which is focused on a certain region of the Earth's surface. Such are, in particular, the series of pulses affecting the territory of the USA, Europe, and Central Asia. There is statistical confirmation in the US health statistics that the series of pulses affecting the country cause an increase in the mortality of ischemic heart disease by up to 5%. The lack of free access to detailed statistics on the cases of death in the other countries affected by the phenomenon does not allow a conclusion of the impact of the series of pulses of alpha particles on the health of their inhabitants. The strange characteristics of the mentioned series of pulses of alpha particles do not exclude the hypothesis that they are artificially generated from a non-human mind. The level of technological development of human civilization does not imply the possibility for it to generate such large-scale processes as the series of pulses of alpha particles, i.e. the highly developed non-human mind that generates them has nothing to do with human civilization. The series of pulses may be navigational signals causing unwitting casualties to humanity, but they may also be a form of murderous contact with a higher civilization that we have long sought, expecting only benefits after its realization, not suspecting that we live in this nightmarish contact indefinitely.

Transcriptomic analysis reveals PC4's participation in thermotolerance of scallop Argopecten irradians irradians by regulating myocardial bioelectric activity

Rising ocean temperatures due to global warming pose a significant threat to the bay scallop aquaculture industry. Understanding the mechanisms of thermotolerance in bay scallops is crucial for developing thermotolerant breeds. Our prior research identified Arg0230340.1, part of the positive cofactor 4 (PC4) family, as a key gene associated with the thermotolerance index Arrhenius break temperature (ABT) in bay scallops. Further validation through RNA interference (RNAi) reinforced PC4's role in thermotolerance, offering a solid basis for investigating thermal response mechanisms in these scallops. In this study, we performed a comparative transcriptomic analysis on the temperature-sensitive hearts of bay scallops after siRNA-mediated RNAi targeting Arg0230340.1, to delve into the detailed molecular mechanism of PC4's participation in thermotolerance regulation. The analysis revealed that silencing Arg0230340.1 significantly reduced the expression of mitochondrial tRNA and rRNA, potentially affecting mitochondrial function and the heart's blood supply capacity. Conversely, the up-regulation of genes involved in energy metabolism, RNA polymerase II (RNAPII)-mediated basal transcription, and aminoacyl-tRNA synthesis pathways points to an intrinsic protective response, providing energy and substrates for damage repair and maintenance of essential functions under stress. GO and KEGG enrichment analyses indicated that the up-regulated genes were primarily associated with energy metabolism and spliceosome pathways, likely contributing to myocardial remodeling post-Arg0230340.1 knockdown. Down-regulated genes were enriched in ion channel pathways, particularly those for Na+, K+, and Ca2+ channels, whose dysfunction could disrupt normal myocardial bioelectric activity. The impaired cardiac performance resulting from RNAi targeting Arg0230340.1 reduced the cardiac workload in scallop hearts, thus affecting myocardial oxygen consumption and thermotolerance. We propose a hypothetical mechanism where PC4 down-regulation impairs cardiac bioelectric activity, leading to decreased thermotolerance in bay scallops, providing theoretical guidance for breeding thermotolerant scallop varieties and developing strategies for sustainable aquaculture in the face of long-term environmental changes.

Modelling the growth of the network value

We investigate the evolution of network effects, specifically focusing on the emerging paradigm of third-generation networks known as group-forming networks (GFNs). In contrast to traditional views where network value adheres to Metcalfe’s quadratic growth or Sarnoff’s linear growth, GFNs, such as social networks and community-centric platforms like Apple, Microsoft, and Google, exhibit a distinct exponential growth pattern in network value as postulated by Reed’s hypothesis.Unlike conventional network science, economic perspectives on network effects do not necessitate precise knowledge of the network topology. Instead, they often align with mean-field models akin to those found in statistical physics. Recent empirical studies challenge earlier assumptions, revealing that many GFNs have undergone exponential or notably superquadratic growth, deviating significantly from established models based solely on user and link counts.This paper introduces a simplified model aimed at capturing the growth dynamics of marketable groups within a network comprising n users. The model explores various hypothetical mechanisms governing the expansion of these groups, and through rigorous analysis and simulation, we uncover compelling evidence that the observed growth in GFNs surpasses traditional quadratic models. Our findings challenge existing notions, suggesting a new framework for understanding the intricacies of network growth dynamics, and providing solid analytical and conceptual foundations for the recent explosive processes of economic and financial value growth of networks that exploit the formation of groups.

Phenotypic switching mechanisms determine the structure of cell migration into extracellular matrix under the ‘go-or-grow’ hypothesis

A fundamental feature of collective cell migration is phenotypic heterogeneity which, for example, influences tumour progression and relapse. While current mathematical models often consider discrete phenotypic structuring of the cell population, in-line with the ‘go-or-grow’ hypothesis (Hatzikirou et al., 2012; Stepien et al., 2018), they regularly overlook the role that the environment may play in determining the cells’ phenotype during migration. Comparing a previously studied volume-filling model for a homogeneous population of generalist cells that can proliferate, move and degrade extracellular matrix (ECM) (Crossley et al., 2023) to a novel model for a heterogeneous population comprising two distinct sub-populations of specialist cells that can either move and degrade ECM or proliferate, this study explores how different hypothetical phenotypic switching mechanisms affect the speed and structure of the invading cell populations. Through a continuum model derived from its individual-based counterpart, insights into the influence of the ECM and the impact of phenotypic switching on migrating cell populations emerge. Notably, specialist cell populations that cannot switch phenotype show reduced invasiveness compared to generalist cell populations, while implementing different forms of switching significantly alters the structure of migrating cell fronts. This key result suggests that the structure of an invading cell population could be used to infer the underlying mechanisms governing phenotypic switching.

Testing the response suppression mechanism of working memory.

Many working memory (WM) paradigms involve recalling multiple items from the same memory set. Participants rarely repeat items they have already recalled, avoiding repetition errors. To prevent these errors, WM models incorporate a response suppression mechanism that removes recalled items from the set of response options. Despite its importance for our understanding of WM, response suppression has received limited direct testing. To address this gap, we used computational models implementing two hypothetical mechanisms of response suppression to derive predictions and tested these predictions experimentally. Participants were asked to recall the same items multiple times during a single trial. If already recalled items are removed from the response set to prevent repetition errors, memory performance should be impaired when the same item is tested again. Contrary to this, we found that memory performance was unimpaired when the same item was tested a second time, and even displayed a recall advantage. Therefore, this study demonstrates the implausibility of response suppression to account for how people avoid repetition errors. We discuss alternative explanations. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Unraveling the degradation of levofloxacin using highly efficient β-cyclodextrin-modified copper ferrite through peroxymonosulfate activation: Mechanistic performance and degradation pathways

In this study, a highly magnetic β-cyclodextrin-modified copper ferrite (CuFe2O4@β-CD) catalyst was developed utilizing a hydrothermal method, which was subsequently utilized to degrade Levofloxacin (LEV) antibiotic in aqueous solution via heterogeneous activation of peroxymonosulfate (PMS). The findings demonstrated that the 98.87 % degradation of LEV was achieved with CuFe2O4@β-CD/PMS, much higher than that of pure CuFe2O4/PMS (87.78 %) within a 24-minute time frame under optimal parameters ([CuFe2O4@β-CD] = 0.4 g/L, [PMS] = 0.4 mM, [LEV] = 25 mg/L, pH = 6), and CuFe2O4@β-CD/PMS was present. The rate constant of CuFe2O4@β-CD/PMS (0.1608 min−1) was much greater than that of the CuFe2O4/PMS system (0.0822 min−1). The increased availability of active sites for PMS activation may be credited to the larger surface area (189.42 m2/g) of the CuFe2O4@β-CD catalyst in comparison to the pristine CuFe2O4 (87.76 m2/g), which facilitated the improved degradation of LEV. Additionally, the impact of various reaction parameters and intervening anions on the degradation of LEV was investigated. The emergence of free radicals (SO4•−, •OH, and 1O2) was corroborated via electron paramagnetic resonance and scavenging experiments. On the basis of recognizing reaction intermediates, a hypothetical degradation mechanism for LEV was developed. PMS activation was caused by the transformation of Cu+/Cu2+ and Fe3+/Fe2+ pairs, which was accomplished via radical and non-radical pathways. Also, CuFe2O4@β-CD demonstrated exceptional stability and retained its catalytic activity after five concurrent cycles. In conclusion, the CuFe2O4@β-CD catalyst demonstrated encouraging potential in the context of purifying LEV-contaminated water.

Baking quality of wheat variety mixtures: Describing the mechanisms for mixture effects

The use of intra-crop diversity (e.g.: variety mixtures) in bread wheat cropping is getting popular in Europe, mostly for agronomic purposes. However, much less is known about the implications on baking quality.In this paper, we formalized and tested a framework based on two hypothetical mechanisms for mixture effects as a result of plant interactions within mixtures: (i) proportion shifts, relating to changes in grain weight proportion of the varieties at harvest and (ii) component alteration, relating to changes in the baking quality of the component varieties. To test this framework, we measured several baking quality indicators on twelve variety mixtures and their component varieties in pure stands. By recording varietal proportions at harvest, we could measure the relative importance of both mechanisms in explaining observed mixture effects.Our results showed that proportion shifts explained a large share of mixture effects on protein baking quality (Zélény sedimentation index and W baking strength) but failed to explain mixture effects on protein content in one year and Hagberg's falling number in both years. Our results also suggest component alteration on protein content resulting from altered nitrogen uptake in mixtures, and possibly on Hagberg's falling number resulting from lodging reduction in mixtures.

Solar Alpha Particle Radiation Increases Human Mortality – an example from the HIV disease mortality in the European Union

A dangerous phenomenon for humanity is described. In the joint analysis of data from satellites in orbit around the Earth and from the health statistics source EUROSTAT, it became clear that, by some mechanism, flows of positively charged particles with high energy entering the Earth's orbit increase mortality on the planet's surface. The increase in mortality is in a zone of maximum risk in the Northern Hemisphere, parallel to the equator and bounded by the parallels of 30° and 50° north latitude. Examples are given for the European Union mortality from HIV disease confirming the described phenomenon. A hypothetical mechanism based on observational evidence has been proposed, according to which this dangerous phenomenon is due to solar alpha particles of high energy sufficient to overcome the atmosphere's resistance and reach the Earth's surface in a limited area of maximum death impact.

Point mutations in Arf1 reveal cooperative effects of the N-terminal extension and myristate for GTPase-activating protein catalytic activity.

The ADP-ribosylation factors (Arfs) constitute a family of small GTPases within the Ras superfamily, with a distinguishing structural feature of a hypervariable N-terminal extension of the G domain modified with myristate. Arf proteins, including Arf1, have roles in membrane trafficking and cytoskeletal dynamics. While screening for Arf1:small molecule co-crystals, we serendipitously solved the crystal structure of the non-myristoylated engineered mutation [L8K]Arf1 in complex with a GDP analogue. Like wild-type (WT) non-myristoylated Arf1•GDP, we observed that [L8K]Arf1 exhibited an N-terminal helix that occludes the hydrophobic cavity that is occupied by the myristoyl group in the GDP-bound state of the native protein. However, the helices were offset from one another due to the L8K mutation, with a significant change in position of the hinge region connecting the N-terminus to the G domain. Hypothesizing that the observed effects on behavior of the N-terminus affects interaction with regulatory proteins, we mutated two hydrophobic residues to examine the role of the N-terminal extension for interaction with guanine nucleotide exchange factors (GEFs) and GTPase Activating Proteins (GAPs. Different than previous studies, all mutations were examined in the context of myristoylated Arf. Mutations had little or no effect on spontaneous or GEF-catalyzed guanine nucleotide exchange but did affect interaction with GAPs. [F13A]myrArf1 was less than 1/2500, 1/1500, and 1/200 efficient as substrate for the GAPs ASAP1, ARAP1 and AGAP1; however, [L8A/F13A]myrArf1 was similar to WT myrArf1. Using molecular dynamics simulations, the effect of the mutations on forming alpha helices adjacent to a membrane surface was examined, yet no differences were detected. The results indicate that lipid modifications of GTPases and consequent anchoring to a membrane influences protein function beyond simple membrane localization. Hypothetical mechanisms are discussed.

Most Chronic Medical Conditions in Women are related to Increased Cellular Permeability and most can be Effectively Treated with Dopaminergic Drugs

Based on a conglomeration of basic science research studies a model of hypothetical mechanisms of how the fetal semi-allograft can develop into a live baby was created. One of the tenets of the model is that it is necessary to remodel some of the typically thick-walled uterine arteries found during the proliferative phase into thin-walled spiral arteries to allow nutrient exchange between mother and fetus through an autoimmune mechanism during the luteal phase. The model suggests that the rise in progesterone inhibits dopamine. One function of dopamine is to diminish cellular permeability allowing irritants to infuse into the endometrium thus evoking an inflammatory reaction. The body must suppress these cellular immune cells from attacking the fetus. Progesterone activates membrane progesterone receptors which produces immunomodulatory proteins e.g., the Progesterone Induced Blocking Factor (PIBF), which negates the killing effect of cellular immunity. One hypothesis suggested that PIBF may be secreted by malignant tumors facilitating these tumors with foreign antigens to escape immunosurveillance and thus metastasize. Progesterone receptor antagonists e.g., mifepristone, which suppresses PIBF, have successfully increased length and quality of life in patients with a large variety of end stage treatment resistant cancers. Excessive permeability of various tissues was hypothesized to be related to possible relative deficiency of dopamine. A large variety of medical conditions have been ameliorated significantly by the use of dopaminergic drugs e.g. dextroamphetamine or cabergoline. The model explains why certain conditions may get worse premenstrually e.g., pelvic pain or headaches by the added suppressive effect of progesterone on dopamine. Though possibly further research may modify this model, based on the present hypothesis, a large number of treatment refractory conditions had very successful improvement based on treating with drug releasing dopamine thus correcting tissue permeability disorders.