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Cancer therapy is facing increasingly significant challenges, marked by a wide range of techniques and research efforts centered around somatic mutations, precision oncology, and the vast amount of big data. Despite this abundance of information, the quest to cure cancer often seems more elusive, with the “war on cancer” yet to deliver a definitive victory. A particularly pressing issue is the development of tumor treatment resistance, highlighting the urgent need for innovative approaches. Evolutionary, Quantum Biology and System Biology offer a promising framework for advancing experimental cancer research. By integrating theoretical studies, translational methods, and flexible multidisciplinary clinical research, there’s potential to enhance current treatment strategies and improve outcomes for cancer patients. Establishing stronger links between evolutionary, quantum, entropy and chaos principles and oncology could lead to more effective treatments that leverage an understanding of the tumor’s evolutionary dynamics, paving the way for novel methods to control and mitigate cancer. Achieving these objectives necessitates a commitment to multidisciplinary and interprofessional collaboration at the heart of both research and clinical endeavors in oncology. This entails dismantling silos between disciplines, encouraging open communication and data sharing, and integrating diverse viewpoints and expertise from the outset of research projects. Being receptive to new scientific discoveries and responsive to how patients react to treatments is also crucial. Such strategies are key to keeping the field of oncology at the forefront of effective cancer management, ensuring patients receive the most personalized and effective care. Ultimately, this approach aims to push the boundaries of cancer understanding, treating it as a manageable chronic condition, aiming to extend life expectancy and enhance patient quality of life.

BackgroundChildren with special health care needs including Down Syndrome, Autism Spectrum Disorder and Down Syndrome experience difficulties in receiving dental treatment. Silver Diamine Fluoride (SDF) and Silver Fluoride (SF) are a minimally invasive treatments options to arrest dental caries without sedation; local or general anaesthesia (GA).AimEvaluation of Brazilian's parents' acceptance of the use of SF in CSHCN.MethodsAfter receiving education on SF, 100 Parents of CSHCN completed a questionnaire concerning their acceptance of SF, in different dental situation.ResultMajority of parents (74,5%) agreed to the use of SF for their children. SF was more acceptable on posterior teeth (74,5%) when compared to its use on anterior teeth (43,1%). Parents accepted to use SF in order: to reduce infection and pain (82,4%); to avoid dental injection (72,5%) and treatment under GA (84,3%). The Majority of parents accepted the properties of SF (82,4%) and Silver (80,4%).ConclusionSilver Fluoride was accepted as a treatment option for caries, by Brazilian parents of CSHCN. SF should be considered as a treatment option for caries limited to dentine for CSHCN, taking into consideration the individual needs and opinions with regard to aesthetics and exposure to fluoride and silver.

In all domains of life, Hsp70 chaperones preserve protein homeostasis by promoting protein folding and degradation and preventing protein aggregation. We now report that the Hsp70 from the bacterial pathogen Salmonella enterica serovar Typhimurium-termed DnaK-independently reduces protein synthesis in vitro and in S. Typhimurium facing cytoplasmic Mg2+ starvation, a condition encountered during infection. This reduction reflects a 3-fold increase in ribosome association with DnaK and a 30-fold decrease in ribosome association with trigger factor, the chaperone normally associated with translating ribosomes. Surprisingly, this reduction does not involve J-domain cochaperones, unlike previously known functions of DnaK. Removing the 74 C-terminal amino acids of the 638-residue long DnaK impeded DnaK association with ribosomes and reduction of protein synthesis, rendering S. Typhimurium defective in protein homeostasis during cytoplasmic Mg2+ starvation. DnaK-dependent reduction in protein synthesis is critical for survival against Mg2+ starvation because inhibiting protein synthesis in a dnaK-independent manner overcame the 10,000-fold loss in viability resulting from DnaK truncation. Our results indicate that DnaK protects bacteria from infection-relevant stresses by coordinating protein synthesis with protein folding capacity.

Abstract Background Environmental tobacco smoke (ETS) exposure in children can cause delayed lung development and lifelong cardiovascular damage. The aim of this study was to measure ETS exposure in children in Israel in 2020–2021 using urinary cotinine (UC) measurements and to assess correlates of ETS exposure, including parental smoking. Methods In the framework of the National Human Biomonitoring Program, spot urine samples and questionnaire data were collected from 166 children aged 4–12 years, during the years 2020–2021. We collected urine samples in 233 adults, 69 of whom were parents of children included in the study. Parents of participating children were asked about parental smoking, child’s exposure to ETS and smoking policy at home. Cotinine and creatinine were measured in urine. Creatinine-adjusted and unadjusted urine cotinine (UC) geometric means were calculated. Associations between potential correlates and UC concentrations were analyzed in univariate and multivariate analyses. For 69 child-parent pairs, correlation between child and parental UC was analyzed. Results Based on urinary cotinine measurement, 65.2% of children of smokers are exposed to ETS, compared to 20.7% of children in non-smoking families. Greater numbers of smokers living in the home (beta = 1.27, p

Wildfires significantly influence the environmental distribution of various elements through their fire-induced input and mobilization, yet little is known about their effects on the forest floor in Siberian forests. The present study evaluated the effects of spring wildfires of various severities on the levels of major and minor (Ca, Al, Fe, S, Mg, K, Na, Mn, P, Ti, Ba, and Sr) trace and ultra-trace (B, Co, Cr, Cu, Ni, Se, V, Zn, Pb, As, La, Sn, Sc, Sb, Be, Bi, Hg, Li, Mo, and Cd) elements in the forest floors of Siberian forests. The forest floor (Oi layer) samples were collected immediately following wildfires in Scots pine (Pinus sylvestris L.), larch (Larix sibirica Ledeb.), spruce (Picea obovata Ledeb.), and birch (Betula pendula Roth) forests. Total concentrations of elements were determined using inductively coupled plasma–optical emission spectroscopy. All fires resulted in a decrease in organic matter content and an increase in mineral material content and pH values in the forest floor. The concentrations of most elements studied in a burned layer of forest floor were statistically significantly higher than in unburned precursors. Sb and Sn showed no statistically significant changes. The forest floor in the birch forest showed a higher increase in mineral material content after the fire and higher levels of most elements studied than the burned coniferous forest floors. Ca was a predominant element in both unburned and burned samples in all forests studied. Our study highlighted the role of wildfires in Siberia in enhancing the levels of geochemical elements in forest floor and the effect of forest type and fire severity on ash characteristics. The increased concentrations of elements represent a potential source of surface water contamination with toxic and eutrophying elements if wildfire ash is transported with overland flow.

IntroductionProviding conventional, restorative dental care to children with special healthcare needs (CSHCN) often requires sedation using general anesthesia. Saliva consistency, diet, and oral hygiene practice are different for CSHCN, and limited evidence is available on the efficacy of silver fluoride (SF) for the management of carious lesions for this vulnerable population.MethodsParents of CSHCN were educated about silver fluoride as a treatment option for caries. In total, 550 carious lesions from 100 participants were identified and scored according to the Nyvad Caries criteria. A total of 100 lesions with Nyvad scores 1, 2, and 3 were treated with a single application of silver fluoride and observed postoperatively at 1, 3, and 6 weeks.ResultThe results indicate statistically significant (p

BackgroundConducting oral treatment early in the disease course, is encouraged for better health outcomes. Obtaining informed consent is an essential part of medical practice, protecting the legal rights of patients and guiding the ethical practice of medicine. In practice, consent means different things in different contexts. Silver Diamine Fluoride (SDF) and Silver Fluoride (SF) is becoming popular and cost effective methods to manage carious lesions, however, cause black discolouration of lesions treated. Obtaining informed consent and assent is crucial for any dental treatment—and has specific relevance with SDF/ SF treatments.MethodsThe aim of this paper is to describe informed consent regulations for dental care in a selection of countries, focusing on children and patients with special health care needs. An online survey was shared with a convenience sample of dental professionals from 13 countries. The information was explored and the processes of consent were compared.ResultsFindings suggest that there are variations in terms of informed consent for medical practice. In Tanzania, South Africa, India, Kenya, Malaysia and Brazil age is the determining factor for competence and the ability to give self-consent. In other countries, other factors are considered alongside age. For example, in Singapore, the United Kingdom, and the United States the principle of Gillick Competence is applied. Many countries' laws and regulations do not specify when a dentist may overrule general consent to act in the “best interest” of the patient.ConclusionIt is recommended that it is clarified globally when a dentist may act in the “best interest” of the patient, and that guidance is produced to indicate what constitutes a dental emergency. The insights gathered provide insights on international practice of obtaining informed consent and to identify areas for change, to more efficient and ethical treatment for children and patients with special needs. A larger follow up study is recommended to include more or all countries.

Abstract Background Childhood overweight/obesity has been associated with an elevated risk of insulin resistance and cardiometabolic disorders. Waist-to-height ratio (WHtR) may be a simple screening tool to quickly identify children at elevated risk for cardiometabolic disorders. The primary objective of the present study was to create sex-specific tertile cut points of WHtR and assess its association with Insulin resistance and elevated liver enzyme concentrations in children, factors using cross-sectional data from the randomized, controlled Family Weight Management Study. Methods Baseline data from 360 children (7–12 years, mean Body Mass Index (BMI) ≥ 85th percentile for age and sex) were used to calculate WHtR tertiles by sex, male: ≤ 0.55 (T1), > 0.55- ≤ 0.59 (T2), > 0.59 (T3); female: ≤ 0.56 (T1), > 0.56- ≤ 0.6 (T2), > 0.6 (T3). The Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) was used to categorize participants as insulin-resistant (HOMA-IR ≥ 2.6) and insulin-sensitive (HOMA-IR 26 µkat/L males, > 22 µkat/L females). We examined differences in baseline cardiometabolic risk factors by WHtR tertiles and sex-specific multivariable logistic regression models to predict HOMA-IR and elevation of liver enzymes. Results Study participants had a mean WHtR of 0.59 ([SD: 0.06]). Irrespective of sex, children in WHtR T3 had higher BMIz scores, blood pressure, triglycerides, 2-h glucose, fasting 2-h insulin, and lower high-density lipoprotein cholesterol (HDL-C) concentrations than those in T2 and T1. After adjusting for covariates, the odds of elevated HOMA-IR (> 2.6) were over five-fold higher among males in T3 versus T1 [OR, 95%CI: 5.83, 2.34–14.52] and T2 [OR, 95%CI: 4.81, 1.94–11.92] and females in T3 [OR, 95%CI: 5.06, 2.10–12.20] versus T1. The odds of elevated ALT values (≥ 30) were 2.9 [95%CI: 1.01–8.41] fold higher among females in T3 compared to T1. Conclusion In public health settings, WHtR may be a practical screening tool in pediatric populations to identify children at risk of metabolic syndrome.

Abstract Background Prostate cancer remains one of the deadliest neoplasms in developed countries. Identification of new molecular markers that predict the onset and progression of the disease could improve its clinical management. Low miR-145-5p expression is consistently found in primary tumors and metastases, but the regulatory mechanisms governing its functions remain largely unknown. Methods Bioinformatics analysis was conducted to identify [1] a set of novel potential competing endogenous lncRNAs for sponging of miRNA-145-5p in prostate cancer and [2] miR-145-5p and other EMT-related miRNAs response elements in lnc-ZNF30-3. Quantification of miR-145-5p, lnc-ZNF30-3, and TWIST1 expression levels in tumor tissues in RNA sequencing datasets of our and TCGA PRAD cohorts revealed a correlation with clinical outcome of prostate cancer patients. Biochemical and cell biology approaches, such as RNA pull-down, western blot, immunostaining, and wound healing assays were used for evaluation of the impact of TWIST1/miR-145/ lnc-ZNF30-3 interactions in prostate cancer cells altered in miRNA and lncRNA expression. Results We identified a few potential lncRNA sponges of miR-145-5p, including lnc-ZNF30-3. It contains five response elements for miR-145-5p, but also other miRNAs targeting EMT transcription factors. Lnc-ZNF30-3 is significantly upregulated in prostate cancer cell lines and tumor tissues, and its high expression is correlated with poor patient prognosis. We demonstrated that lnc-ZNF30-3 is associated with AGO2 and specifically interacts with the miR-145-5p seed region. Knockdown of lnc-ZNF30-3 results in decreased migration of prostate cancer cells and downregulation of EMT drivers such as TWIST1 and ZEB1 at both the RNA and protein levels. These phenotypic and molecular features of lnc-ZNF30-3-depleted cells are partially rescued by miR-145-5p inhibition. Conclusions Collectively, our results point to lnc-ZNF30-3 as a novel competing endogenous lncRNA for miR-145-5p and other miRNAs that target TWIST1 as well as other EMT transcription factors. Prostate cancer patients with high lncRNA expression in primary tumors show lower survival rate suggesting that lnc-ZNF30-3 may contribute to prostate cancer progression and metastasis.

Motile cells can use and switch between different modes of migration. Here, we use traction force microscopy and fluorescent labeling of actin and myosin to quantify and correlate traction force patterns and cytoskeletal distributions in Dictyostelium discoideum cells that move and switch between keratocyte-like fan-shaped, oscillatory, and amoeboid modes. We find that the wave dynamics of the cytoskeletal components critically determine the traction force pattern, cell morphology, and migration mode. Furthermore, we find that fan-shaped cells can exhibit two different propulsion mechanisms, each with a distinct traction force pattern. Finally, the traction force patterns can be recapitulated using a computational model, which uses the experimentally determined spatiotemporal distributions of actin and myosin forces and a viscous cytoskeletal network. Our results suggest that cell motion can be generated by friction between the flow of this network and the substrate.

Conversion of integrins from low to high affinity states, termed activation, is important in biological processes, including immunity, hemostasis, angiogenesis, and embryonic development. Integrin activation is regulated by large-scale conformational transitions from closed, low affinity states to open, high affinity states. Although it has been suggested that substrate stiffness shifts the conformational equilibrium of integrin and governs its unbinding, here, we address the role of integrin conformational activation in cellular mechanosensing. Comparison of wild-type versus activating mutants of integrin αVβ3 show that activating mutants shift cell spreading, focal adhesion kinase activation, traction stress, and force on talin toward high stiffness values at lower stiffness. Although all activated integrin mutants showed equivalent binding affinity for soluble ligands, the β3 S243E mutant showed the strongest shift in mechanical responses. To understand this behavior, we used coarse-grained computational models derived from molecular level information. The models predicted that wild-type integrin αVβ3 displaces under force and that activating mutations shift the required force toward lower values, with S243E showing the strongest effect. Cellular stiffness sensing thus correlates with computed effects of force on integrin conformation. Together, these data identify a role for force-induced integrin conformational deformation in cellular mechanosensing.

Long-term series of annual and seasonal water flow and major ions in the Pechora River were analyzed. Long-term phases of increased and decreased water flow were identified, ranging in duration from 11 to 49 years, and the major characteristics of these phases were determined. Changes in the sequence and boundaries of contrast phases in the annual and snowmelt spring–summer flood runoff were found to coincide. The difference between the mean seasonal water runoff during the phases of increased and decreased flow varied from 12 to 41%. The ion flow values of contrast phases typically differed by 9 to 36%, which is less than for water flow. This is due to the inverse dependence between ion concentrations and water discharge. Such peculiar negative feedback stabilizes the rates of chemical denudation in the river catchments to some extent and, thus, the discharge of major ions into seas, even during significant variations in water.

Resumo: Este estudo objetiva identificar o tipo de apoio recebido por cuidadoras familiares de pessoas idosas na pandemia de COVID-19, assim como os fatores socioeconômicos de saúde e relativos ao cuidado associados. Utilizou-se dados do estudo CUIDA-COVID, questionário online realizado entre agosto e novembro de 2020 (n = 4.820). Foram construídos três modelos múltiplos, tendo como desfecho: apoio contratado, apoio familiar e ausência de apoio. As variáveis independentes relacionadas a aspectos socioeconômicos, de saúde e cuidado foram convertidas em categorias dicotômicas. O apoio familiar foi o mais comum (48,6%), seguido pelo ausência de apoio (38,3%) e apoio contratado (13,1%). Não foram observadas associações significativas entre raça/cor, situação de pobreza, problema crônico de coluna e estado de ânimo negativo com nenhum dos tipos de apoio. Foram fatores fortemente associados (RPajustada > 2,0) ao apoio contratado: a não diminuição acentuada da renda na pandemia; a não dedicação ao cuidado em tempo integral; a autoavaliação da saúde boa/excelente; e o alto grau de dependência da pessoa idosa. Para o apoio familiar, as principais associações foram: o não aumento acentuado do esforço dedicado ao cuidado na pandemia; a não dedicação ao cuidado em tempo integral; e a diminuição acentuada da renda na pandemia. Foram as características associadas ao ausência de apoio: viver com o idoso; dedicar-se ao cuidado em tempo integral; residir em domicílios com uma ou duas pessoas; e relatar um aumento acentuado do esforço dedicado ao cuidado na pandemia. No geral, as cuidadoras com apoio contratado tiveram as melhores condições socioeconômicas, de cuidado e saúde. A desassistência foi relacionada a piores condições de saúde e cuidado, enquanto o apoio familiar às piores condições socioeconômicas.

ABSTRACTThe mammalian gut microbiota is a critical human health determinant with therapeutic potential for remediation of many diseases. The host diet is a key factor governing the gut microbiota composition by altering nutrient availability and supporting the expansion of distinct microbial populations. Diets rich in simple sugars modify the abundance of microbial subsets, enriching for microbiotas that elicit pathogenic outcomes. We previously demonstrated that diets rich in fructose and glucose can reduce the fitness and abundance of a human gut symbiont, Bacteroides thetaiotaomicron, by silencing the production of a critical intestinal colonization protein, called Roc, via its mRNA leader through an unknown mechanism. We have now determined that dietary sugars silence Roc by reducing the activity of BT4338, a master regulator of carbohydrate utilization. Here, we demonstrate that BT4338 is required for Roc synthesis, and that BT4338 activity is silenced by glucose or fructose. We show that the consequences of glucose and fructose on orthologous transcription factors are conserved across human intestinal Bacteroides species. This work identifies a molecular pathway by which a common dietary additive alters microbial gene expression in the gut that could be harnessed to modulate targeted microbial populations for future therapeutic interventions.

Objective: To analyze the existing state legislation, including not only the ordinary laws, but also their infralegal regulation and the state legislation on Hospital Dentistry. Material and Methods: A survey was carried out in the databases of the Legislative Assemblies of the Brazilian States and the Federal District, as well as the Regional and Federal Councils of Dentistry in Brazil. Subsequently, a survey was carried out in the databases of the Ministry of Health, State Dental Councils and Federal Dental Council in Brazil. Results: Only 8 Brazilian states have legislation in force regarding hospital dentistry, which represents 29.63% of the federative units. Among the Brazilian regions, the Midwest presented the highest prevalence of the laws found (37.50%), followed by the North (25%) and the other regions with the same coverage (12.50%). Also, an orientation and an ordinance from the Ministry of Health, six resolutions from the Federal Council of Dentistry, and a technical note from the National Health Surveillance Agency were found. Conclusion: Several States do not have rules on the subject, making it imperative to create a federal rule that not only imposes the presence of the dentist, but also regulates the proportion of the team, workload, and availability.

Providing dental care for children with neurological special health care needs, including Down syndrome, Cerebral palsy and Autism spectrum disorders, is challenging. They often require repeat exposure to sedation or general anaesthesia for routine dental care. 51 parents of children with special needs completed a questionnaire regarding the acceptance of Silver Fluoride as a treatment option.BackgroundSilver Diamine Fluoride has become popular as a minimally invasive treatment option for providing oral health care to young or uncooperative children. Silver Fluoride (SF) is a newer development with similar but improved properties. The aim was to determine the acceptance of SDF/SF as treatment option for Children with Special Health Care Needs (CSHCN), including Down Syndrome, Autism Spectrum Disorder and Cerebral Palsy.Methods51 Parents of CSHCN completed a questionnaire on the overall acceptance of SF; aesthetic concerns related to the location of application; the use of SDF as an alternative to general anesthesia; and the composition of SF.ResultsThe use of SF on posterior teeth were more acceptable (70.59%) as opposed to its application to anterior teeth (50.98%). Parents generally agreed/ strongly agreed to the use of SF to reduce infection and pain (82%); to avoid treatment under GA (26.70%); and to avoid an injection (78%). 64% of parents indicated their agreement in using SF because it has a reduced cost when compared to a conventional restoration. Majority of parents were in agreement to use SF even if it contains Fluoride (84%) and Silver (78%).ConclusionThe use of SF, as treatment option for caries, was well accepted by South African parents of CSHCN. Shared decision making should be applied when considering SF as treatment option for CSHCN.

During actin-based cell migration, the actin cytoskeleton in the lamellipodium both generates and responds to force, which has functional consequences for the ability of the cell to extend protrusions. However, the material properties of the lamellipodial actin network and its response to stress on the timescale of motility are incompletely understood. Here, we describe a dynamic wrinkling phenotype in the lamellipodium of fish keratocytes, in which the actin sheet buckles upward away from the ventral membrane of the cell, forming a periodic pattern of wrinkles perpendicular to the cell's leading edge. Cells maintain an approximately constant wrinkle wavelength over time despite new wrinkle formation and the lateral movement of wrinkles in the cell frame of reference, suggesting that cells have a preferred or characteristic wrinkle wavelength. Generation of wrinkles is dependent upon myosin contractility, and their wavelength scales directly with the density of the actin network and inversely with cell adhesion. These results are consistent with a simple physical model for wrinkling in an elastic sheet under compression and suggest that the lamellipodial cytoskeleton behaves as an elastic material on the timescale of cell migration despite rapid actin turnover.

Abstract Anti-neoplastic effect of DNA cross-linking agents such as cisplatin, mitomycin C, and psoralen is attributed to their ability to induce DNA interstrand cross-links (ICLs), which block replication, transcription, and linear repair pathways by preventing DNA strand separation and trigger apoptosis. It is generally agreed that the Fanconi anemia (FA) pathway orchestrates the removal of ICLs by the combined actions of various DNA repair pathways. Recently, attention has been focused on the ability of the NEIL3-initiated base excision repair pathway to resolve psoralen- and abasic site-induced ICLs in an FA-independent manner. Intriguingly, overexpression of NEIL3 is associated with chemo-resistance and poor prognosis in many solid tumors. Here, using loss- and gain-of-function approaches, we demonstrate that NEIL3 confers resistance to cisplatin and participates in the removal of cisplatin–DNA adducts. Proteomic studies reveal that the NEIL3 protein interacts with the 26S proteasome in a cisplatin-dependent manner. NEIL3 mediates proteasomal degradation of WRNIP1, a protein involved in the early step of ICL repair. We propose that NEIL3 participates in the repair of ICL-stalled replication fork by recruitment of the proteasome to ensure a timely transition from lesion recognition to repair via the degradation of early-step vanguard proteins.

Lake Baikal is the largest freshwater lake in the world, accounting for about 20% of the world’s fresh surface water. The lake’s outflow to the ocean occurs only via the Angara River, which has several hydroelectric power plants (HPPs) along its watercourse. The first such HPP, Irkutsk HPP, was built in 1956 and is located 60 km from the Angara River’s source. After two years, the backwater from this HPP expanded to the lake shores and began raising the Baikal Lake level. Currently, there is a dynamic balance between the new lake level, the lake inflow from its tributaries, and the Angara River discharge through the Irkutsk HPP. However, both the Angara River discharge and the Baikal Lake level were distorted by the HPP construction. Thus, to understand the changes to the lake basin over the past century, we first needed to estimate naturalized lake levels that would be if no HPP was ever built. This was an important task that allowed (a) the actual impact of global changes on the regional hydrological processes to be estimated and (b) better management of the HPP itself to be provided through future changes. With these objectives in mind, we accumulated multi-year data on the observed levels of Lake Baikal, and components of its water budget (discharge of main tributaries and the Angara River, precipitation, and evaporation). Thereafter, we assessed the temporal patterns and degree of coupling of multi-year and intra-annual changes in the lake’s monthly, seasonal, and annual characteristics. The reconstruction of the average monthly levels of Lake Baikal and the Angara River water discharge after the construction of the Irkutsk HPP was based on the relationship of the fluctuations with the components of the Lake water budget before regulation. As a result, 123-year time series of “conditionally natural” levels of Lake Baikal and the Angara River discharge were reconstructed and statistically analyzed. Our results indicated high inertia in the fluctuations in the lake level. Additionally, we found a century-long tendency of increases in the lake level of about 15 cm per 100 years, and we quantified the low-frequency changes in Lake Baikal’s water levels, the discharge of the Angara River, and the main lake tributaries. An assessment of the impact of the Irkutsk HPP on the multi-year and intra-annual changes in the Lake Baikal water level and the Angara River discharge showed that the restrictions on the discharge through the HPP and the legislative limitations of the Lake Baikal level regime have considerably limited the fluctuations in the lake level. These fluctuations can lead to regulation violations and adverse regimes during low-water or high-water periods.