Sequential Accumulation Research Articles

Multi-target 3D single-molecule super resolution imaging throughout mammalian cells with a single-objective tilted light sheet.

Single-molecule based super-resolution fluorescence microscopy offers an approach to sub-diffraction-limited imaging of biological samples. While these approaches have proved significant to understanding subcellular structures, numerous super-resolution systems suffer from drawbacks such as decreased localization precision due to high background fluorescence, lack of control of the extracellular environment, decreased multi-target accuracy due to chromatic offsets in multicolor imaging, and the inability to image structures in three dimensions (3D). Light sheet fluorescence microscopy, which involves illuminating the sample with a thin sheet of light, offers a gentle illumination scheme that greatly reduces photobleaching, photodamage, and out of focus background fluorescence, thereby improving the localization precision. Here, we present a single-objective tilted light sheet super-resolution setup with five added innovations: (i) a microfluidic chip with reflective sidewalls and transparent top, (ii) sequential DNA Point Accumulation for Imaging in Nanoscale Topography (DNA-PAINT) known as Exchange-PAINT, (iii) deep learning for high density single emitter localization, (iv) double helix point spread functions for 3D imaging, and (iv) galvanometric dithering of the illumination beam to reduce scattering artifacts and provide homogenous sample illumination. By utilizing light sheet illumination in conjunction with Exchange-PAINT and deep learning, this setup allows for the use of high concentrations of imager strands given that background fluorescence is drastically reduced and sparse emitters are no longer necessary for accurate localization. Furthermore, sequential washes of imager strands are enabled through the use of microfluidics, which allows for accurate, multi-target reconstructions that are not subject to chromatic offsets. Thus, we demonstrate a setup that offers improved localization precision, extracellular environment control, multi-target information, and 3D imaging that can easily be implemented for fast, accurate, and precise multi-target super-resolution whole cell imaging.

Geochemical Indicators for Paleolimnological Studies of the Anthropogenic Influence on the Environment of the Russian Federation: A Review

Lake sediments are a reliable source of information about the past, including data of the origin of water bodies and their changes. Russia has more than 2 million lakes, so paleolimnological studies are relevant here. This review deals with the most significant studies of sequential accumulation of pollutants, including heavy metals in recent lake sediments in Russia. The key areas are northwestern regions of Russia (Murmansk Region, the Republic of Karelia, Arkhangelsk Region), the Urals (Chelyabinsk Region, the Republic of Bashkortostan), and Siberia. The review presents the data of pollutants accumulation, the sedimentation rate in lakes in the anthropogenic period, and the key sources of pollution of the environment in each of the mentioned regions. The article is divided into three parts (sections): industrial areas, urbanized areas, and background (pristine) areas so that readers might better understand the specifics of particular pollution and its impact on lake ecosystems. The impact of metallurgical plants, mining companies, boiler rooms, coal and mazut thermal power plants, transport, and other anthropogenic sources influencing geochemical characteristics of lakes located nearby or at a distance to these sources of pollution are considered. For instance, the direct influence of factories and transport was noted in the study of lake sediments in industrial regions and cities. In the background territories, the influence of long-range transport of pollutants was mainly noted. It was found that sedimentation rates are significantly lower in pristine areas, especially in the Frigid zone, compared to urbanized areas and industrial territories. In addition, the excess concentrations of heavy metals over the background are higher in the sediments of lakes that are directly affected by the source of pollution. At the end of the article, further prospects of the development of paleolimnological studies in Russia are discussed in the context of the continuing anthropogenic impact on the environment.

Exploring the sequential accumulation of metabolic syndrome components in adults

The metabolic syndrome (MetS) is diagnosed upon the manifestation of ≥ 3 out of 5 specific components, regardless of their combination. The sequence through which these components accumulate may serve to identify underlying pathophysiological mechanisms and improve MetS treatment. We aimed to explore whether there is a more frequent sequence of accumulation of components in adults. The cross-sectional data of the National Health Survey of Chile 2016–2017 was analyzed. Subjects aged 18 to < 65 years, with body mass index ≥ 18.5 kg/m2, having all MetS components measured, and not under drug treatment were included (n = 1944, 60% women). MetS components were operationalized based on harmonized criteria: elevated waist circumference (≥ 91 cm for men, ≥ 83 cm for women), reduced high-density lipoprotein cholesterol (HDL-C; < 40 mg/dL for men, < 50 mg/dL for women), elevated triglycerides (≥ 150 mg/dL), elevated blood pressure (≥ 130 mmHg for systolic, or ≥ 85 mmHg for diastolic), and elevated glycemia (≥ 100 mg/dL). Subjects were grouped according to the number of components. Then, the prevalence of the observed combinations was determined. In subjects with one component, the most prevalent was waist circumference (56.7%). In subjects with two, the most prevalent combination was waist circumference and HDL-C (50.8%), while in subjects with three components was waist circumference, HDL-C, and triglycerides (54.0%). Finally, in subjects with four, the most prevalent combination was waist circumference, HDL-C, triglycerides, and blood pressure (40.8%). This pattern suggests that the most frequent accumulation sequence starts with abdominal obesity, followed by dyslipidemia, elevated blood pressure, and ultimately, dysglycemia. The factors that determine the sequence remain to be determined.

Farnesoid X receptor regulates lung macrophage activation and injury following nitrogen mustard exposure

Nitrogen mustard (NM) is a cytotoxic vesicant known to cause acute lung injury which progresses to fibrosis; this is associated with a sequential accumulation of pro- and anti-inflammatory macrophages in the lung which have been implicated in NM toxicity. Farnesoid X receptor (FXR) is a nuclear receptor involved in regulating lipid homeostasis and inflammation. In these studies, we analyzed the role of FXR in inflammatory macrophage activation, lung injury and oxidative stress following NM exposure. Wild-type (WT) and FXR−/− mice were treated intratracheally with PBS (control) or NM (0.08 mg/kg). Bronchoalveolar lavage fluid (BAL) and lung tissue were collected 3, 14 and 28 d later. NM caused progressive histopathologic alterations in the lung including inflammatory cell infiltration and alveolar wall thickening and increases in protein and cells in BAL; oxidative stress was also noted, as reflected by upregulation of heme oxygenase-1. These changes were more prominent in male FXR−/− mice. Flow cytometric analysis revealed that loss of FXR resulted in increases in proinflammatory macrophages at 3 d post NM; this correlated with upregulation of COX-2 and ARL11, markers of macrophage activation. Markers of anti-inflammatory macrophage activation, CD163 and STAT6, were also upregulated after NM; this response was exacerbated in FXR−/− mice at 14 d post-NM. These findings demonstrate that FXR plays a role in limiting macrophage inflammatory responses important in lung injury and oxidative stress. Maintaining or enhancing FXR function may represent a useful strategy in the development of countermeasures to treat mustard lung toxicity.

Sequential accumulation of dynein and its regulatory proteins at the spindle region in the Caenorhabditis elegans embryo

Cytoplasmic dynein is responsible for various cellular processes during the cell cycle. The mechanism by which its activity is regulated spatially and temporarily inside the cell remains elusive. There are various regulatory proteins of dynein, including dynactin, NDEL1/NUD-2, and LIS1. Characterizing the spatiotemporal localization of regulatory proteins in vivo will aid understanding of the cellular regulation of dynein. Here, we focused on spindle formation in the Caenorhabditis elegans early embryo, wherein dynein and its regulatory proteins translocated from the cytoplasm to the spindle region upon nuclear envelope breakdown (NEBD). We found that (i) a limited set of dynein regulatory proteins accumulated in the spindle region, (ii) the spatial localization patterns were distinct among the regulators, and (iii) the regulatory proteins did not accumulate in the spindle region simultaneously but sequentially. Furthermore, the accumulation of NUD-2 was unique among the regulators. NUD-2 started to accumulate before NEBD (pre-NEBD accumulation), and exhibited the highest enrichment compared to the cytoplasmic concentration. Using a protein injection approach, we revealed that the C-terminal helix of NUD-2 was responsible for pre-NEBD accumulation. These findings suggest a fine temporal control of the subcellular localization of regulatory proteins.

Discovery of fused benzimidazole-imidazole autophagic flux inhibitors for treatment of triple-negative breast cancer

Triple-negative breast cancer (TNBC) with the absence of estrogen receptor (ER), progesterone receptor (PR) and HER2 ptotein, is the highly aggressive subtype of breast cancer that exhibits poor prognosis and high tumor recurrence. It is vital to develop effective agents regulating the core molecular pathway of TNBC. Through a medium throughput screening and iterative medicinal chemistry optimization, we identified compound 7h as an autophagic flux inhibitor, which showed potent activities against human TNBC (MDA-MB-231 and MDA-MB-468) cell lines with IC50 values of 8.3 μM, and 6.0 μM, respectively, which are comparable to the potency of 5-FU and Cisplatin, the first line therapies for TNBC. Extensive investigation of mechanisms of action indicated that 7h inhibits autophagic flux and sequential accumulation of p62, leading to DNA damage and disrepair in TNBC cells. Importantly, nuclear p62 accumulation induced by compound 7h results in the inhibition of RNF168-mediated chromatin ubiquitination and the degradation of HR-related proteins in regulating the DNA damage response (DDR) process. In in vivo studies, compound 7h completely suppressed tumor growth in the MDA-MB-231 xenograft model at a dose of 15 mg/kg/q.d. Our findings indicate that compound 7h is an autophagic flux inhibitor and induced the degradation of HR-related proteins. Compound 7h could be potentially developed as an anti-cancer therapeutics for TNBC.

MSTCGAN: Multiscale Time Conditional Generative Adversarial Network for Long-Term Satellite Image Sequence Prediction

Satellite image sequence prediction is a crucial and challenging task. Previous studies leverage optical flow methods or existing deep learning methods on spatial-temporal sequence models for the task. However, they suffer from either oversimplified model assumptions or blurry predictions and sequential error accumulation issue, for a long-term forecast requirement. In this paper, we propose a novel Multi-Scale Time Conditional Generative Adversarial Network (MSTCGAN). To address the sequential error accumulation issue, MSTCGAN adopts a parallel prediction framework to produce the future image sequences by a one-hot time condition input. In addition, a powerful multi-scale generator is designed with the multi-head axial attention, which helps to carefully preserve the fine-grained details for appearance consistency. Moreover, we develop a temporal discriminator to address the blurry issue and maintain the motion consistency in prediction. Extensive experiments have been conducted on FengYun-4A satellite data set, and the results demonstrate the effectiveness and superiority of the proposed method over state-of-the-art approaches.

Оценка фациальной принадлежности локальных нефтегазоносных объектов по геофизическим данным

In the established practice of geological exploration for oil and gas conclusions about the facies belonging of the rocks of oil and gas basins and individual exploration areas were made mainly on the basis of the study of core material. Recently for this purpose the results of seismic exploration and well logging have been used. Geophysical methods despite their obvious progress are indirect and intermittent core sampling and incomplete coring make facies analysis difficult. Тhe study of cuttings during the well logging process makes it possible to fill this gap through direct continuous observations along the well section. The use of the whole complex of geophysical methods allows one to mutually compensate for the limitations and disadvantages of each of them and more fully and reliably assess the genetic characteristics and reservoir potential of productive deposits. Sequential accumulation, comparison and analysis of heterogeneous geophysical data make it possible to continuously refine apriori facies models and forecast oil and gas content which ultimately allows to optimize the directions and volumes of drilling.

Association of HER1 and HER2 Gene Variants in the Predisposition of Colorectal Cancer.

Background Colorectal cancer (CRC) is a major health concern worldwide. A series of sequential accumulation of genetic and epigenetic changes are responsible for the initiation and progression of diseases via the normal > adenoma > carcinoma sequence. Genetic variants in crucial cancer-causing genes are known to mediate the risk of cancer. Objective In this case-control study, we examined single nucleotide polymorphism (SNP) in HER1 (rs763317 and rs3752651) and HER2 (rs1136201 and rs1058808) genes to assess their role in the susceptibility of CRC in a Saudi population. Methods TaqMan allelic discrimination assay was utilized to identify the genotypes in 163 normal and 143 CRC patients. Results In the overall analysis, the rs3752651 and rs1136201 were significantly associated with the risk of CRC. Although none of the examined SNPs had any impact on the age at which CRC was diagnosed, interestingly, three SNPs showed a significant association based on gender. The rs3752651 conferred significant protection only in men, whereas rs1136201 diminished the risk and rs1058808 considerably increased the susceptibility of CRC only in women. Conclusions Our result suggests that these SNPs in HER1 and HER2 after validation in larger cohorts of different ethnicities may be utilized as genetic screening markers for predicting colorectal cancer predisposition.

Trade Integration, Global Value Chains, and Capital Accumulation

Motivated by increasing trade and fragmentation of production across countries, accompanied by income convergence by many emerging economies, we build a dynamic two-country model featuring sequential, multi-stage production and capital accumulation. As trade costs decline over time, global-value-chain (GVC) trade expands across countries, particularly more in the faster-growing country, consistent with the empirical pattern. Via Heckscher–Ohlin forces, GVC trade can generate back-and-forth feedback between comparative advantage and capital accumulation (growth). Moreover, GVC trade increases both steady-state and dynamic gains from trade.

Myelodysplastic Syndromes in the Postgenomic Era and Future Perspectives for Precision Medicine.

Simple SummaryWith demographic ageing, improved cancer survivorship and increased diagnostic sensitivity, incident cases of patients with Myelodysplastic Syndromes (MDS) are continuously rising, leading to a relevant impact on health care resources. Disease heterogeneity and various comorbidities are challenges for the management of the generally elderly patients. Therefore, experienced physicians and multidisciplinary teams should be involved in the establishment of the correct diagnosis, risk-assessment and personalized treatment plan. Next-generation sequencing allows for early detection of clonal hematopoiesis and monitoring of clonal evolution, but also poses new challenges for its appropriate use. At present, allogeneic hematopoietic stem cell transplantation remains the only curative treatment option for a minority of fit MDS patients. All others receive palliative treatment and will eventually progress, having an unmet need for novel therapies. Targeting compounds are in prospect for precision medicine, however, abrogation of clonal evolution to acute myeloid leukemia remains actually out of reach.Myelodysplastic syndromes (MDS) represent a heterogeneous group of clonal disorders caused by sequential accumulation of somatic driver mutations in hematopoietic stem and progenitor cells (HSPCs). MDS is characterized by ineffective hematopoiesis with cytopenia, dysplasia, inflammation, and a variable risk of transformation into secondary acute myeloid leukemia. The advent of next-generation sequencing has revolutionized our understanding of the genetic basis of the disease. Nevertheless, the biology of clonal evolution remains poorly understood, and the stochastic genetic drift with sequential accumulation of genetic hits in HSPCs is individual, highly dynamic and hardly predictable. These continuously moving genetic targets pose substantial challenges for the implementation of precision medicine, which aims to maximize efficacy with minimal toxicity of treatments. In the current postgenomic era, allogeneic hematopoietic stem cell transplantation remains the only curative option for younger and fit MDS patients. For all unfit patients, regeneration of HSPCs stays out of reach and all available therapies remain palliative, which will eventually lead to refractoriness and progression. In this review, we summarize the recent advances in our understanding of MDS pathophysiology and its impact on diagnosis, risk-assessment and disease monitoring. Moreover, we present ongoing clinical trials with targeting compounds and highlight future perspectives for precision medicine.

Characterization of Kinase Activity By Phosphoproteomics in Myeloid Cell Lines for Identification of Driving Oncogenic Pathways

Introduction: Myelodysplastic syndromes (MDS) are heterogeneous disorders caused by sequential accumulation of genetic lesions in haematopoietic stem cells (HSC). MDS are characterized by dysplasia, ineffective haematopoiesis and a propensity to evolve towards acute myeloid leukemia (AML). Based on the recent advances in next generation sequencing, our understanding of the genetic background of myeloid neoplasms has dramatically increased. However, clonal heterogeneity, genetic interactions, and clonal evolution remain enigmatic phenomena of oncogenesis and important investigational challenges to be addressed in the post-genomic era.Aim and objectives: The aim of this project was to build a bioinformatic pipeline to integrate phosphoproteomic data with genetic information in order to characterize targettable kinase-activities of involved oncogenic pathways. Our objective was to establish a network analysis of the kinase-substrate relationship in myeloid cell lines first, before moving into primary cells. Here, we present data on the ongoing phosphoproteome characterization and the inferred kinase-activity from five myeloid cell lines.Methods: The five myeloid cell lines K562 (erythroid), NB4 (promyelocytic), THP1 (monocytic), OCI-AML3 (myelomonocytic) and MOLM13 (monocytic) were used. These cell lines contain distinct oncogenes, such as BCR-ABL1, PML-RARalpha, MLL-MLLT3, mutated NPM1 and FLT3-ITD, respectively. Cytogenetic analysis and next generation sequencing, using a myeloid driver gene panel of Ion Torrent, were performed for genetic characterization (Table 1). Phosphoproteomes were enriched using Titanium-dioxide (TiO2) and samples were analyzed in triplicates by reversed-phase nano liquid chromatography coupled to tandem-mass spectrometry (nanoLC-MS2). Raw data was analyzed using MaxQuant software and further processed with R . For kinase-activity enrichment analysis (KAEA), we integrated all substrate-kinase datasets from five databases 1) PhosphoSitePlus, 2) Human Protein Reference Database, 3) Regulatory Network in Protein Phosphorylation, 4) The Signaling Network Open Resource and 5) phosphor.ELM . The SetRank R-package was employed for KAEA with p-value and FDR cutoffs set at 0.05.Results: We identified 15'698, 14'087, 13'969, 13'993 and 14'201 unique phosphopeptides corresponding to 3'536, 3'363, 3'411, 3'410 and 3'403 unique phosphoproteins, respectively.KAEA identified 77 different kinases across the five cell lines (Table 2). In the heat-map of the KAEA, phenotypically related cell lines clustered together and unique kinase-activity patterns emerged for each cell line (Figure 1). Two cell lines are driven by oncogenic kinases; K562 by BCR-ABL1 and MOLM13 by FLT3-ITD. An ABL1-kinase signal was detectable from 2 different databases in K562 as well as additional downstream kinases of ABL1, including mTOR and MAPK. We could not enrich for the FLT3-kinase in MOLM-13, due to lack of representation in the currently available substrate-kinase databases. However, our pipeline was able to identify the activity of downstream kinases of FLT3, including AKT1/PKB and MAPK1.Conclusion: Our bioinformatic pipeline was able to detect unique phosphoproteins and enrich for kinase-activities in five distinct myeloid cell lines. Moreover, it reproduced an expected pattern of kinase-activities for two relevant driving oncogenic kinases. These promising results remain still limited by insufficient quantification and incompleteness of available databases. We expect to further improve on quantification and annotation by using heavy labeled cell lines (SILAC) as well as kinase-motif analysis, respectively. This may allow us to perform unsupervised characterization of involved oncogenic pathways and to proceed into the analysis of primary cells. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Scalable recombinase-based gene expression cascades

Temporal modulation of the expression of multiple genes underlies complex complex biological phenomena. However, there are few scalable and generalizable gene circuit architectures for the programming of sequential genetic perturbations. Here, we describe a modular recombinase-based gene circuit architecture, comprising tandem gene perturbation cassettes (GPCs), that enables the sequential expression of multiple genes in a defined temporal order by alternating treatment with just two orthogonal ligands. We use tandem GPCs to sequentially express single-guide RNAs to encode transcriptional cascades that trigger the sequential accumulation of mutations. We build an all-in-one gene circuit that sequentially edits genomic loci, synchronizes cells at a specific stage within a gene expression cascade, and deletes itself for safety. Tandem GPCs offer a multi-tiered cellular programming tool for modeling multi-stage genetic changes, such as tumorigenesis and cellular differentiation.

ERASOR: Egocentric Ratio of Pseudo Occupancy-Based Dynamic Object Removal for Static 3D Point Cloud Map Building

Scan data of urban environments often include representations of dynamic objects, such as vehicles, pedestrians, and so forth. However, when it comes to constructing a 3D point cloud map with sequential accumulations of the scan data, the dynamic objects often leave unwanted traces in the map. These traces of dynamic objects act as obstacles and thus impede mobile vehicles from achieving good localization and navigation performances. To tackle the problem, this paper presents a novel static map building method called ERASOR, Egocentric RAtio of pSeudo Occupancy-based dynamic object Removal, which is fast and robust to motion ambiguity. Our approach directs its attention to the nature of most dynamic objects in urban environments being inevitably in contact with the ground. Accordingly, we propose the novel concept called pseudo occupancy to express the occupancy of unit space and then discriminate spaces of varying occupancy. Finally, Region-wise Ground Plane Fitting (R-GPF) is adopted to distinguish static points from dynamic points within the candidate bins that potentially contain dynamic points. As experimentally verified on SemanticKITTI, our proposed method yields promising performance against state-of-the-art methods overcoming the limitations of existing ray tracing-based and visibility-based methods.

Hydrothermal alteration and hydrocarbon accumulations in ultra-deep carbonate reservoirs along a strike-slip fault system, Tarim Basin, NW China

In recent years, petroleum exploration has extended from shallow to deep reservoirs in the globle petroliferous basins. In contrast to conventional carbonate reservoirs, the fractures and hydrotherm related karst reservoirs could mainly be developed in deep strata along the tectonic deformation and fault zone. The seismic imaging and tectonic analysis have been combined to identify the scale and features of the deep fault system in the Tarim Basin, NW China. It was found that the tectonic collision and movement generated a prevalent strike-slip fault system, which was conjugated and extended from paleo-uplift to the inside of the Manjar Sag (source kitchen) in the Tarim Basin. The micrograph of cores and images of well logging demonstrated that deep reservoirs are dominated by porosities, fractures, and hydrothermal minerals (e.g., fluorite, pyroxenite). Burial dissolution and thermohydrology along strike-slip fault have greatly contributed to the formation of deep carbonate reservoirs, meanwhile controled the accumulation and hydrocarbon properties in the deep carbonates reservoirs of Tarim Basin. The analysis of adamantane, dibenzothiophene, and carbon isotopes indicated that oil-cracking, thermochemical sulfate reduction (TSR), and gas-washing fractionation could be the main factors to control the sequential accumulation of various hydrocarbons around Manjar Sag. The formation and hydrocarbon accumulation of the deep carbonate reservoirs along this strike-slip fault system could provide important details regarding deep petroleum geological processes from both scientific and practical aspects. These findings could be applied to future studies and the exploration of deep potential marine reserves worldwide.

Geochemical characteristics of fluorine- and chlorine-bearing biotite from Tusham Ring Complex, NW India: Constraints on halogen distribution and geodynamic evolution

The present study is carried out to understand the factors controlling halogens present in biotites, role of halogens in metallogeny in context to the magmatic evolution of Tusham Ring Complex (TRC), NW Indian Shield. The investigated rocks are identified with hypersolvus, high-K calc-alkaline, peraluminous, ferroan-enriched and typical A-type granitoids affinity. They are enriched in SiO2, Na2O + K2O, REEs (except Eu), LILE + HFSE, elevated in Fe/Mg, Ga/Al, Th/U, A/CNK ratio and depleted in CaO, MgO, Sr, Cr, Ni, P, Ti, V and Eu abundances. The sequential accumulation of incompatible trace elements (LILE, HFSE, REEs and others) in studied rocks overlaps almost entirely the range of rare metal granitoids and high heat-producing granitoids. The elemental geochemistry in conjunction with high abundances of F (0.80–7.11 wt%) and Cl (0.44–1.56 wt%) in biotite mineral collectively attribute to hydrothermal fluid activity and the subsequent mineralization around TRC region. Our new results suggest that the acidic magmatism that occurred in the TRC is considered as a part of the plume-related Neoproterozoic Malani Igneous Suite (MIS) anorogenic magmatism.

Mutation load at a mimicry supergene sheds new light on the evolution of inversion polymorphisms.

Chromosomal inversions are ubiquitous in genomes and often coordinate complex phenotypes, such as the covariation of behavior and morphology in many birds, fishes, insects or mammals1-11. However, why and how inversions become associated with polymorphic traits remains obscure. Here we show that despite a strong selective advantage when they form, inversions accumulate recessive deleterious mutations that generate frequency-dependent selection and promote their maintenance at intermediate frequency. Combining genomics and in vivo fitness analyses in a model butterfly for wing-pattern polymorphism, Heliconius numata, we reveal that three ecologically advantageous inversions have built up a heavy mutational load from the sequential accumulation of deleterious mutations and transposable elements. Inversions associate with sharply reduced viability when homozygous, which prevents them from replacing ancestral chromosome arrangements. Our results suggest that other complex polymorphisms, rather than representing adaptations to competing ecological optima, could evolve because chromosomal rearrangements are intrinsically prone to carrying recessive harmful mutations.

КЛАССИФИКАЦИЯ ФАКТИЧЕСКИХ СОСТАВОВ В ЗАВИСИМОСТИ ОТ ПОРЯДКА НАКОПЛЕНИЯ ЭЛЕМЕНТОВ

This article analyzes the order of accumulation of elements of the actual composition as a classification criterion for their division into types. Depending on this, the following compositions are distinguished: 1) with the sequential accumulation of their elements; 2) with independent accumulation of elements; 3) built using various structural principles. A logical explanation of the different order of construction of legal facts using the theory of absolute and relative legal relations is given. The relevance of this issue for the modern level of the theory of law is indicated. The conclusion is formulated that relative subjective rights are not, as it were, self-sufficient. They are not able to serve as a means of satisfying interest indefinitely. This right exists only for a limited time and is aimed at achieving such a legal state in which the interest will be ensured through one’s own active behavior. As a result, the temporary order of development of actual circumstances in some situations may have legal significance, and in others — be completely indifferent to future legal consequences.

IN-VITRO SCREENING OF THEAFLAVIN AND GINKGETIN ON A549 LUNG CANCER CELL LINE

Cancer is a complex, multi-gene, multi-step disease occurring as a result of a sequential accumulation of genetic and epigenetic changes. Death due to cancer rank second among all cause of death globally. Dysregulation of signaling pathway e.g. HGF/c-MET which were otherwise activated during embryonic development contributes to malignant transformation and metastasis in later phase of life. Phytochemicals due to their safety, low toxicity, and general availability are either taken as supplement or through dietary sources for cancer chemoprevention or supportive agent during the treatment of cancer. The present study therefore aim to screen in-silico inspired c-MET antagonist Theaflavin &amp; Ginkgetin in-vitro on against A549 cell line along with their antiangiogenesis effect on chick embryo model.

The Molecular Determinants of Thermoadaptation:Methanococcalesas a Case Study

Previous reports have shown that environmental temperature impacts proteome evolution in Bacteria and Archaea. However, it is unknown whether thermoadaptation mainly occurs via the sequential accumulation of substitutions, massive horizontal gene transfers, or both. Measuring the real contribution of amino acid substitution to thermoadaptation is challenging, because of confounding environmental and genetic factors (e.g., pH, salinity, genomic G + C content) that also affect proteome evolution. Here, using Methanococcales, a major archaeal lineage, as a study model, we show that optimal growth temperature is the major factor affecting variations in amino acid frequencies of proteomes. By combining phylogenomic and ancestral sequence reconstruction approaches, we disclose a sequential substitutional scheme in which lysine plays a central role by fine tuning the pool of arginine, serine, threonine, glutamine, and asparagine, whose frequencies are strongly correlated with optimal growth temperature. Finally, we show that colonization to new thermal niches is not associated with high amounts of horizontal gene transfers. Altogether, although the acquisition of a few key proteins through horizontal gene transfer may have favored thermoadaptation in Methanococcales, our findings support sequential amino acid substitutions as the main factor driving thermoadaptation.