Роль совершенствования бухгалтерского учета в управлении производственными запасами

Целью проведения исследования является обоснование направлений повышения эффективности использования материальных производственных запасов на предприятии в условиях рыночной экономики

Comparing Conventional Chemotherapy to Chronomodulated Chemotherapy for Cancer Treatment: Protocol for a Systematic Review

Background: Chronomodulated chemotherapy aims to achieve maximum drug safety and efficacy by adjusting the time of treatment to an optimal biological time as determined by the circadian clock. Although it is a promising alternative to conventional (non–time-stipulated) chemotherapy in several instances, the lack of scientific consensus and the increased logistical burden of timed administration limit the use of a chronomodulated administration protocol. Objective: With the goal to increase scientific consensus on this subject, we plan to conduct a systematic review of the current literature to compare the drug safety and efficacy of chronomodulated chemotherapy with those of conventional chemotherapy. Methods: This systematic review will comply with the PRISMA (Preferred Reporting Items for the Systematic Reviews and Meta-Analysis) guidelines. In order to identify relevant studies, we conducted a comprehensive search in PubMed and Embase on May 18, 2020. We included clinical studies that compare either the safety or efficacy of chronomodulated chemotherapy with that of conventional chemotherapy. Potential studies will be reviewed and screened by 2 independent reviewers. Quality assessment will be performed using the National Institutes of Health’s Study Quality Assessment Tool (Quality Assessment of Controlled Intervention Studies). Disagreements will be resolved by consulting a third independent reviewer. Results: This protocol has received funding, and the search for studies from databases commenced on May 18, 2020. The systematic review is planned to be completed by October 31, 2020. Conclusions: In this systematic review, we will compare drug safety and drug efficacy for cancer patients who were administered either chronomodulated chemotherapy or conventional chemotherapy. Moreover, we will highlight the outcomes and quality of the selected trials for this review

CRYPTOCHROMES promote daily protein homeostasis.

The daily organisation of most mammalian cellular functions is attributed to circadian regulation of clock-controlled protein expression, driven by daily cycles of CRYPTOCHROME-dependent transcriptional feedback repression. To test this, we used quantitative mass spectrometry to compare wild-type and CRY-deficient fibroblasts under constant conditions. In CRY-deficient cells, we found that temporal variation in protein, phosphopeptide, and K+ abundance was at least as great as wild-type controls. Most strikingly, the extent of temporal variation within either genotype was much smaller than overall differences in proteome composition between WT and CRY-deficient cells. This proteome imbalance in CRY-deficient cells and tissues was associated with increased susceptibility to proteotoxic stress, which impairs circadian robustness, and may contribute to the wide-ranging phenotypes of CRY-deficient mice. Rather than generating large-scale daily variation in proteome composition, we suggest it is plausible that the various transcriptional and post-translational functions of CRY proteins ultimately act to maintain protein and osmotic homeostasis against daily perturbation

Compensatory ion transport buffers daily protein rhythms to regulate osmotic balance and cellular physiology

Abstract: Between 6–20% of the cellular proteome is under circadian control and tunes mammalian cell function with daily environmental cycles. For cell viability, and to maintain volume within narrow limits, the daily variation in osmotic potential exerted by changes in the soluble proteome must be counterbalanced. The mechanisms and consequences of this osmotic compensation have not been investigated before. In cultured cells and in tissue we find that compensation involves electroneutral active transport of Na+, K+, and Cl− through differential activity of SLC12A family cotransporters. In cardiomyocytes ex vivo and in vivo, compensatory ion fluxes confer daily variation in electrical activity. Perturbation of soluble protein abundance has commensurate effects on ion composition and cellular function across the circadian cycle. Thus, circadian regulation of the proteome impacts ion homeostasis with substantial consequences for the physiology of electrically active cells such as cardiomyocytes

Daily magnesium fluxes regulate cellular timekeeping and energy balance

Circadian clocks are fundamental to the biology of most eukaryotes, coordinating behaviour and physiology to resonate with the environmental cycle of day and night through complex networks of clock-controlled genes1, 2, 3. A fundamental knowledge gap exists, however, between circadian gene expression cycles and the biochemical mechanisms that ultimately facilitate circadian regulation of cell biology4, 5. Here we report circadian rhythms in the intracellular concentration of magnesium ions, [Mg2+]i, which act as a cell-autonomous timekeeping component to determine key clock properties both in a human cell line and in a unicellular alga that diverged from each other more than 1 billion years ago6. Given the essential role of Mg2+ as a cofactor for ATP, a functional consequence of [Mg2+]i oscillations is dynamic regulation of cellular energy expenditure over the daily cycle. Mechanistically, we find that these rhythms provide bilateral feedback linking rhythmic metabolism to clock-controlled gene expression. The global regulation of nucleotide triphosphate turnover by intracellular Mg2+ availability has potential to impact upon many of the cell’s more than 600 MgATP-dependent enzymes7 and every cellular system where MgNTP hydrolysis becomes rate limiting. Indeed, we find that circadian control of translation by mTOR8 is regulated through [Mg2+]i oscillations. It will now be important to identify which additional biological processes are subject to this form of regulation in tissues of multicellular organisms such as plants and humans, in the context of health and disease

In-depth characterization of firefly luciferase as a reporter of circadian gene expression in mammalian cells

Firefly luciferase (Fluc) is frequently used to report circadian gene expression rhythms in mammalian cells and tissues. During longitudinal assays it is generally assumed that enzymatic substrates are in saturating excess, such that total bioluminescence is directly proportional to Fluc protein level. To test this assumption, we compared the enzyme kinetics of purified luciferase with its activity in mammalian cells. We found that Fluc activity in solution has a lower Michaelis constant (Km) for luciferin, lower temperature dependence, and lower catalytic half-life than Fluc in cells. In consequence, extracellular luciferin concentration significantly affects the apparent circadian amplitude and phase of the widely used PER2::LUC reporter in cultured fibroblasts, but not in SCN, and we suggest that this arises from differences in plasma membrane luciferin transporter activity. We found that at very high concentrations (>1 mM), luciferin lengthens circadian period, in both fibroblasts and organotypic SCN slices. We conclude that the amplitude and phase of circadian gene expression inferred from bioluminescence recordings should be treated with some caution, and we suggest that optimal luciferin concentration should be determined empirically for each luciferase reporter and cell type

Evolutionary acquisition of cysteines determines FOXO paralog-specific redox signaling

Reduction-oxidation (redox) signaling, the translation of an oxidative intracellular environment into a cellular response, is mediated by the reversible oxidation of specific cysteine thiols. The latter can result in disulfide formation between protein hetero- or homodimers that alter protein function until the local cellular redox environment has returned to the basal state. We have previously shown that this mechanism promotes the nuclear localization and activity of the Forkhead Box O4 (FOXO4) transcription factor. Aims: In this study, we sought to investigate whether redox signaling differentially controls the human FOXO3 and FOXO4 paralogs. Results: We present evidence that FOXO3 and FOXO4 have acquired paralog-specific cysteines throughout vertebrate evolution. Using a proteome-wide screen, we identified previously unknown redox-dependent FOXO3 interaction partners. The nuclear import receptors Importin-7 (IPO7) and Importin-8 (IPO8) form a disulfide-dependent heterodimer with FOXO3, which is required for its reactive oxygen species-induced nuclear translocation. FOXO4 does not interact with IPO7 or IPO8. Innovation and Conclusion: IPO7 and IPO8 control the nuclear import of FOXO3, but not FOXO4, in a redox-sensitive and disulfide-dependent manner. Our findings suggest that evolutionary acquisition of cysteines has contributed to regulatory divergence of FOXO paralogs, and that phylogenetic analysis can aid in the identification of cysteines involved in redox signaling. Antioxid. Redox Signal. 22, 15-28