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In this scientific paper, the authors address the issue of mobility and the spread of COVID-19, as well as the impact of the COVID-19 pandemic and changes in the mobility of the population of the Czech Republic and Slovakia in 2020. The goal of the study is to determine whether the increase in the number of positive cases of COVID-19 and the associated increase in deaths influences changes in various categories of population mobility at the regional level in selected countries. The aim of the work is to empirically assess the impact of the first year of the pandemic on the mobility of the population. To achieve this, data on population mobility obtained from Google Statistics, together with information on the increase in the number of positive cases and the number of deaths caused by COVID-19 from both countries, were combined. The paper interprets and evaluates the results achieved, providing a picture of the course of the pandemic in the territories of the Czech Republic and Slovakia.

The effects of the COVID-19-related crisis in society can be seen not only in long-distance passenger transport but also in the urban transportation services in the territory. During the pandemic, the travelling public tended to choose private motor vehicles, bicycles, or walking as their mode of transport to work or other activities. This fact was also the subject of our research based on the analysis of data on public passenger rail transport in the individual regions of the Slovak Republic and based on data analysis performed, also in urban transport in the city of Žilina. Mobility in the city was investigated and analysed based on detailed monitoring of the use of the means of transport on a specific trolleybus line No. 67, where a hybrid trolleybus Škoda 26TrA Solaris was deployed. It was found out that the impact of the pandemic and the adoption of restrictive measures to prevent the spread of the disease significantly affected this trolleybus line, where, depending on the extent of the measures taken, the occupancy of the trolleybus fluctuated by up to 60 % in specific months compared to the standard period of use of this means of transport.

Research background: The aim of the scientific contribution is to analyze the current position of the Russian economy in the context of other countries. The article consists of a deduction of the current position of the Russian Federation and the subsequent proposal to continue the fight against the COVID-19 crisis. Purpose of the article: Using the analysis of available sources of scientific research, the analysis of the current position of the Russian economy in the context of other countries. The paper offers basic recommended goals for further progress in the time of a pandemic. Methods: The coronavirus pandemic has turned the world into a new reality. It showed the weaknesses and strengths of states, their constitutional structures, economic and social models. The post-pandemic world will be different, significantly different from the current one. And this pandemic will not be an exception, but will become one of a series of past and future world problems. And the world must be prepared to meet them. It is necessary to learn how to manage the development of large-scale systems at various levels from internal regions, states and to the world economic and political system as a whole. States must learn how to manage in a critical situation so as not to expose their peoples to significant disasters, much less extinction. They should establish mechanisms to predict and combat undesirable hazards. Using the scientific method of analysis of available resources, the authors analyzed the current position of the Russian Federation in relation to selected economies of the world. By synthesizing the knowledge and subsequent deduction, the authors propose further recommendations and steps in the time of the COVID-19 crisis. Findings & Value added: The pandemic that led the world to a crisis of health and survival, economy and trust has shown how much the world needs to be improved. At the same time, it clearly showed what strategic directions Russia needs to move in order to save its people, its territory, and strengthen itself in the top three world economic leaders. And if the strategies are clear, and the tasks are defined, then the matter remains only for their implementation.

Research background: The article deals with the study of the dependencies of selected supplementary charges in rail freight transport. In the environment of a globalized society, it is very important that railway undertakings maintain their competitiveness in an open market. The article is part of a case study that deals with the development of pricing. The research was primarily focused on the structure and development of the price of supplementary charges in the years 2004 – 2020 at Železničná Spoločnosť Cargo Slovakia, j. s. c. Purpose of the article: Based on two selected supplementary charges, and the hypothesis of whether or not the development of their price is dependent will be verified by means of regression analysis. The aim of the research is to point out of the disproportionate increase in the prices of supplementary charge, which form a significant part of the calculation of the price for transportation. And for most customers it is a priority for the price of transport. Methods: The article will use a simple regression analysis according to the relationships depending on the type of dependence used (linear, polynomial, ...) Findings & Value added: The results of the research can help to better set the structure of supplementary charges. The goal of the company should be a satisfied customer and a dominant market share.

The article investigates the relationship of flows of various types (transport, cargo, information, financial, energy, legal and others) between themselves and elements in the delivery system of foreign trade cargo. A hierarchical scheme of points of interaction of various types of flows is proposed. It is note that optimization of flow control will create more favorable conditions for rhythmic work and coordination of transportation with other modes of transport, and a correctly calculate supply of goods to ports and border crossings will provide an opportunity for the economical use of rolling stock. The solution to this problem at a new level has become possible due to the widespread introduction of digital information technologies. A model of the topology of their interaction has been develop with the definition of an integral quality indicator of a particular route or delivery option. An algorithm for assessing the interdependence of various types of elements, flows, legal ties and the degree of complexity of the structure of the system for the delivery of foreign trade goods.

Traffic flows associated with the movement of passengers and goods, characterized by traffic intensity, speed, direction and other factors are closely interrelated. The planned traffic intensity of these flows is de-termined by calculating the carrying capacity of the elements of the transport system or links in the delivery chains. The article provides a comprehensive analysis of the throughput capacity of a railway line, rail-way station, railway stations and landside areas, airports, and highways. Calculated dependencies, used to determine the carrying capacity of transport infrastructure facilities, have been carry out. It is shown that the throughput (capacity) of infrastructure facilities is focused, most of all, on the volume of cargo transportation in various industries. The factors that must be take into account when determining the conditions for further de-velopment and increasing the capacity of transport infrastructure elements are noted. All calculation methods are reduced to determining the maxi-mum permissible volume of cargo transportation (in passenger traffic, - passengers) that can be passed (processed) by an infrastructure object per unit (for a certain period) of time in the considered road transport and weather and climatic conditions.

The article includes the proposal of new methodology assessment of functional performance of material flows as a tool for management decision-making in the selection of suitable suppliers of logistical services in railway transport. This selection is based on evaluation of key indicators and determination of their weights. The evaluation of the indicators and determination of their weights is realised by mathematic methods.

The voltage-gated sodium channel Na v 1.7 is a genetically validated target for the treatment of pain with gain-of-function mutations in man eliciting a variety of painful disorders and loss-of-function mutations affording insensitivity to pain. Unfortunately, drugs thought to garner efficacy via Na v 1 inhibition have undesirable side effect profiles due to their lack of selectivity over channel isoforms. Herein we report the discovery of a novel series of orally bioavailable arylsulfonamide Na v 1.7 inhibitors with high levels of selectivity over Na v 1.5, the Na v isoform responsible for cardiovascular side effects, through judicious use of parallel medicinal chemistry and physicochemical property optimization. This effort produced inhibitors such as compound 5 with excellent potency, selectivity, behavioral efficacy in a rodent pain model, and efficacy in a mouse itch model suggestive of target modulation., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The progressive aggregation of Amyloid-β (Aβ) in the brain is a major trait of Alzheimer's Disease (AD). Aβ is produced as a result of proteolytic processing of the β-amyloid precursor protein (APP). Processing of APP is mediated by multiple enzymes, resulting in the production of distinct peptide products: the non-amyloidogenic peptide sAPPα and the amyloidogenic peptides sAPPβ, Aβ40, and Aβ42. Using a pathway-based approach, we analyzed a large-scale siRNA screen that measured the production of different APP proteolytic products. Our analysis identified many of the biological processes/pathways that are known to regulate APP processing and have been implicated in AD pathogenesis, as well as revealing novel regulatory mechanisms. Furthermore, we also demonstrate that some of these processes differentially regulate APP processing, with some mechanisms favouring production of certain peptide species over others. For example, synaptic transmission having a bias towards regulating Aβ40 production over Aβ42 as well as processes involved in insulin and pancreatic biology having a bias for sAPPβ production over sAPPα. In addition, some of the pathways identified as regulators of APP processing contain genes (CLU, BIN1, CR1, PICALM, TREM2, SORL1, MEF2C, DSG2, EPH1A) recently implicated with AD through genome wide association studies (GWAS) and associated meta-analysis. In addition, we provide supporting evidence and a deeper mechanistic understanding of the role of diabetes in AD. The identification of these processes/pathways, their differential impact on APP processing, and their relationships to each other, provide a comprehensive systems biology view of the "regulatory landscape" of APP.

Elevated plasma homocysteine, a risk factor for Alzheimer's disease, could result from increased production from methionine or by inefficient clearance by folate- and B-vitamin-dependent pathways. Understanding the relative contributions of these processes to pathogenesis is important for therapeutic strategies designed to lower homocysteine. To assess these alternatives, we elevated plasma homocysteine by feeding mutant amyloid precursor protein (APP)-expressing mice diets with either high methionine (HM) or deficient in B-vitamins and folate (B Def). Mutant APP mice fed HM demonstrated increased brain beta amyloid. Interestingly, this increase was not observed in mutant APP mice fed B Def diet, nor was it observed in C57Bl6 or YAC-APP mice fed HM. Furthermore, HM, but not B Def, produced a prolonged increase in brain homocysteine only in mutant APP mice but not wild-type mice. These changes were time-dependent over 10 weeks. Further, by 10 weeks HM increased brain cholesterol and phosphorylated tau in mutant APP mice. Transcriptional profiling experiments revealed robust differences in RNA expression between C57Bl6 and mutant APP mice. The HM diet in C57Bl6 mice transiently induced a transcriptional profile similar to mutant APP cortex, peaking at 2 weeks , following a time course comparable to brain homocysteine changes. Together, these data suggest a link between APP and methionine metabolism.

The availability of genome-wide RNAi libraries has enabled researchers to rapidly assess the functions of thousands of genes; however the fact that these screens are run in living biological systems add complications above and beyond that normally seen in high-throughput screening (HTS). Specifically, error due to variance in both measurement and biology are large in such screens, leading to the conclusion that the majority of "hits" are expected to be false positives. Here, we outline basic guidelines for screen development that will help the researcher to control these forms of variance. By running a large number of positive and negative control genes, error of measurement can be accurately estimated and false negatives reduced. Likewise, by using a complex readout for the screen, which is not easily mimicked by other biological pathways and phenomena, false positives, can be minimized. By controlling variance in these ways, the researcher can maximize the utility of genome-wide RNAi screening.

Rare familial forms of Alzheimer's disease (AD) are thought to be caused by elevated proteolytic production of the Abeta42 peptide from the beta-amyloid-precursor protein (APP). Although the pathogenesis of the more common late-onset AD (LOAD) is not understood, BACE1, the protease that cleaves APP to generate the N terminus of Abeta42, is more active in patients with LOAD, suggesting that increased amyloid production processing might also contribute to the sporadic disease. Using high-throughput siRNA screening technology, we assessed 15,200 genes for their role in Abeta42 secretion and identified leucine-rich repeat transmembrane 3 (LRRTM3) as a neuronal gene that promotes APP processing by BACE1. siRNAs targeting LRRTM3 inhibit the secretion of Abeta40, Abeta42, and sAPPbeta, the N-terminal APP fragment produced by BACE1 cleavage, from cultured cells and primary neurons by up to 60%, whereas overexpression increases Abeta secretion. LRRTM3 is expressed nearly exclusively in the nervous system, including regions affected during AD, such as the dentate gyrus. Furthermore, LRRTM3 maps to a region of chromosome 10 linked to both LOAD and elevated plasma Abeta42, and is structurally similar to a family of neuronal receptors that includes the NOGO receptor, an inhibitor of neuronal regeneration and APP processing. Thus, LRRTM3 is a functional and positional candidate gene for AD, and, given its receptor-like structure and restricted expression, a potential therapeutic target.

Numerous lines of evidence indicate that the initial photoresponse of the circadian clock in Drosophila melanogaster is the light-induced degradation of TIMELESS (TIM). This posttranslational mechanism is in sharp contrast to the well-characterized pacemakers in mammals and Neurospora, where light evokes rapid changes in the transcriptional profiles of 1 or more clock genes. The authors show that light has novel effects on D. melanogaster circadian pacemakers, acutely stimulating the expression of tim at cold but not warm temperatures. This photoinduction occurs in flies defective for the classic visual phototransduction pathway or the circadian-relevant photoreceptor CRYPTOCHROME (CRY). Cold-specific stimulation of tim RNA abundance is regulated at the transcriptional level, and although numerous lines of evidence indicate that period (per) and tim expression are activated by the same mechanism, light has no measurable acute effect on per mRNA abundance. Moreover, light-induced increases in the levels of tim RNA are abolished or greatly reduced in the absence of functional CLOCK (CLK) or CYCLE (CYC) but not PER or TIM. These findings add to a growing number of examples where molecular and behavioral photoresponses in Drosophila are differentially influenced by "positive" (e.g., CLK and CYC) and "negative" (e.g., PER and TIM) core clock elements. The acute effects of light on tim expression are temporally gated, essentially restricted to the daily rising phase in tim mRNA levels. Because the start of the daily upswing in tim expression begins several hours after dawn in long photoperiods (day length), this gating mechanism likely ensures that sunrise does not prematurely stimulate tim expression during unseasonally cold spring/summer days. The results suggest that the photic stimulation of tim expression at low temperatures is part of a seasonal adaptive response that helps advance the phase of the clock on cold days, enabling flies to exhibit preferential daytime activity despite the (usually) earlier onset of dusk. Taken together with prior findings, the ability of temperature and photoperiod to adjust trajectories in the rising phases of 1 or more clock RNAs constitutes a major mechanism contributing to seasonal adaptation of clock function.

The daily timing of circadian ( congruent with 24-h) controlled activity in many animals exhibits seasonal adjustments, responding to changes in photoperiod (day length) and temperature. In Drosophila melanogaster, splicing of an intron in the 3' untranslated region of the period (per) mRNA is enhanced at cold temperatures, leading to more rapid daily increases in per transcript levels and earlier "evening" activity. Here we show that daily fluctuations in the splicing of this intron (herein referred to as dmpi8) are regulated by the clock in a manner that depends on the photoperiod (day length) and temperature. Shortening the photoperiod enhances dmpi8 splicing and advances its cycle, whereas the amplitude of the clock-regulated daytime decline in splicing increases as temperatures rise. This suggests that at elevated temperatures the clock has a more pronounced role in maintaining low splicing during the day, a mechanism that likely minimizes the deleterious effects of daytime heat on the flies by favoring nocturnal activity during warm days. Light also has acute inhibitory effects, rapidly decreasing the proportion of dmpi8-spliced per transcript, a response that does not require a functional clock. Our results identify a novel nonphotic role for phospholipase C (no-receptor-potential-A [norpA]) in the temperature regulation of dmpi8 splicing.

Circadian (approximately 24-h) rhythms are governed by endogenous biochemical oscillators (clocks) that in a wide variety of organisms can be phase shifted (i.e., delayed or advanced) by brief exposure to light and changes in temperature. However, how changes in temperature reset circadian timekeeping mechanisms is not known. To begin to address this issue, we measured the effects of short-duration heat pulses on the protein and mRNA products from the Drosophila circadian clock genes period (per) and timeless (tim). Heat pulses at all times in a daily cycle elicited dramatic and rapid decreases in the levels of PER and TIM proteins. PER is sensitive to heat but not light, indicating that individual clock components can markedly differ in sensitivity to environmental stimuli. A similar resetting mechanism involving delays in the per-tim transcriptional-translational feedback loop likely underlies the observation that when heat and light signals are administered in the early night, they both evoke phase delays in behavioral rhythms. However, whereas previous studies showed that the light-induced degradation of TIM in the late night is accompanied by stable phase advances in the temporal regulation of the PER and TIM biochemical rhythms, the heat-induced degradation of PER and TIM at these times in a daily cycle results in little, if any, long-term perturbation in the cycles of these clock proteins. Rather, the initial heat-induced degradation of PER and TIM in the late night is followed by a transient and rapid increase in the speed of the PER-TIM temporal program. The net effect of these heat-induced changes results in an oscillatory mechanism with a steady-state phase similar to that of the unperturbed control situation. These findings can account for the lack of apparent steady-state shifts in Drosophila behavioral rhythms by heat pulses applied in the late night and strongly suggest that stimulus-induced changes in the speed of circadian clocks can contribute to phase-shifting responses.