Search Results (1,910)

Human serum albumin (HSA) is an endogenous inhibitor of angiotensin I-converting enzyme (ACE) and, thus, plays a key role in the renin–angiotensin–aldosterone system (RAAS). However, little is known about the mechanism of interaction between these proteins, and the structure of the HSA–ACE complex has not yet been obtained experimentally. The purpose of the presented work is to apply computer modeling methods to study the interaction of HSA with ACE in order to obtain preliminary details about the mechanism of their interaction. Ten possible HSA–ACE complexes were obtained by the procedure of macromolecular docking. Based on the number of steric and polar contacts between the proteins, three leading complexes were selected, the stabilities of which were then tested by molecular dynamics (MD) simulation. Based on the results of MD simulation, the two most probable conformations of the HSA–ACE complex were selected. The analysis of these conformations revealed that the processes of oxidation of the thiol group of Cys34 of HSA and the binding of albumin to ACE can reciprocally affect each other. Known point mutations in the albumin molecules Glu82Lys, Arg114Gly, Glu505Lys, Glu565Lys and Lys573Glu can also affect the interaction with ACE. According to the result of MD simulation, the known ACE mutations, albeit associated with various diseases, do not affect the HSA–ACE interaction. A comparative analysis was performed of the resulting HSA–ACE complexes with those obtained by AlphaFold 3 as well as with the crystal structure of the HSA and the neonatal Fc receptor (FcRn) complex. It was found that domains DI and DIII of albumin are involved in binding both ACE and FcRn. The obtained results of molecular modeling outline the direction for further study of the mechanisms of HSA–ACE interaction in vitro. Information about these mechanisms will help in the design and improvement of pharmacotherapy aimed at modulation of the physiological activity of ACE. Full article

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potential cure for myelodysplastic neoplasms (MDSs) and other hematologic malignancies. This study investigates post-transplantation genetic evolution and telomere dynamics in hematopoietic cells, with a focus on clonal hematopoiesis (CH). We conducted a longitudinal analysis of 21 MDS patients who underwent allo-HSCT between September 2009 and February 2015. Genetic profiles of hematopoietic cells from both recipients and donors were compared at equivalent pre- and post-transplantation time points. Targeted sequencing identified CH-associated mutations, and real-time quantitative PCR measured telomere length. Furthermore, we compared CH incidence between recipients and age-matched controls from the GENIE cohort from routine health checkups. Post-allo-HSCT, 38% of recipients developed somatic mutations not detected before transplantation, indicating de novo CH originating from donor cells. Compared to age-matched healthy controls, recipients showed a significantly higher incidence of CH, suggesting increased susceptibility to genetic changes post-transplant. Telomere length analysis also revealed accelerated shortening in transplanted cells, highlighting the heightened stress and proliferation demands in the new microenvironment. Our findings reveal a notable incidence of donor-derived CH in allo-HSCT recipients, alongside significant telomere attrition. This suggests the potential influence of the marrow microenvironment on genetic and molecular changes in hematopoietic cells. Full article

Background: Familial hypercholesterolemia (FH) is an autosomal dominant genetic disorder characterized by significantly elevated levels of low-density lipoprotein (LDL) cholesterol, which plays a major role in the progression of atherosclerosis and leads to a heightened risk of premature atherosclerotic cardiovascular disease. Methods: We have carried out an observational study on a group of 17 patients treated at the Outpatient Lipid Clinic from 2019 to 2024. Result: The most frequent mutation observed was found in the LDL receptor (LDLR) gene, which was identified in ten patients (58.8%). Five patients were identified to have a mutation in the apolipoprotein B (APOB) gene, whereas two patients had two points mutations, one in the LDLR, and the other in the APOB gene. The average age of patients with LDLR mutation was 54.8 (12.3); for APOB mutation it was 61.4 (9.3) and for patients with two points mutation it was 61.5 (14.8). The study results showed that at Week 12, individuals with LDLR-defective heterozygotes who were given alirocumab 150 mg every two weeks experienced a 63.0% reduction in LDL cholesterol levels. On the other hand, individuals with APOB heterozygotes experienced a 59% reduction in LDL cholesterol levels. However, in patients with double heterozygous for mutations in LDLR and APOB genes, there was a hyporesponsiveness to alirocumab, and the reduction in LDL-C was only by 23% in two individuals. Conclusions: In patients with a single mutation, there was a greater response to treatment with alirocumab in contrast to patients with double heterozygous mutation, who did not respond to treatment with PCSK9 inhibitors. Full article

Despite the success of AlphaFold2 approaches in predicting single protein structures, these methods showed intrinsic limitations in predicting multiple functional conformations of allosteric proteins and have been challenged to accurately capture the effects of single point mutations that induced significant structural changes. We examined several implementations of AlphaFold2 methods to predict conformational ensembles for state-switching mutants of the ABL kinase. The results revealed that a combination of randomized alanine sequence masking with shallow multiple sequence alignment subsampling can significantly expand the conformational diversity of the predicted structural ensembles and capture shifts in populations of the active and inactive ABL states. Consistent with the NMR experiments, the predicted conformational ensembles for M309L/L320I and M309L/H415P ABL mutants that perturb the regulatory spine networks featured the increased population of the fully closed inactive state. The proposed adaptation of AlphaFold can reproduce the experimentally observed mutation-induced redistributions in the relative populations of the active and inactive ABL states and capture the effects of regulatory mutations on allosteric structural rearrangements of the kinase domain. The ensemble-based network analysis complemented AlphaFold predictions by revealing allosteric hotspots that correspond to state-switching mutational sites which may explain the global effect of regulatory mutations on structural changes between the ABL states. This study suggested that attention-based learning of long-range dependencies between sequence positions in homologous folds and deciphering patterns of allosteric interactions may further augment the predictive abilities of AlphaFold methods for modeling of alternative protein sates, conformational ensembles and mutation-induced structural transformations. Full article

Parkinson’s disease (PD) is the second most prevalent neurodegenerative disease worldwide; therefore, since its initial description, significant progress has been made, yet a mystery remains regarding its pathogenesis and elusive root cause. The widespread distribution of pathological α-synuclein (αSyn) aggregates throughout the body raises inquiries regarding the etiology, which has prompted several hypotheses, with the most prominent one being αSyn-associated proteinopathy. The identification of αSyn protein within Lewy bodies, coupled with genetic evidence linking αSyn locus duplication, triplication, as well as point mutations to familial Parkinson’s disease, has underscored the significance of αSyn in initiating and propagating Lewy body pathology throughout the brain. In monogenic and sporadic PD, the presence of early inflammation and synaptic dysfunction leads to αSyn aggregation and neuronal death through mitochondrial, lysosomal, and endosomal functional impairment. However, much remains to be understood about αSyn pathogenesis, which is heavily grounded in biomarkers and treatment strategies. In this review, we provide emerging new evidence on the current knowledge about αSyn’s pathophysiological impact on PD, and its presumable role as a specific disease biomarker or main target of disease-modifying therapies, highlighting that this understanding today offers the best potential of disease-modifying therapy in the near future. Full article

Cystic fibrosis (CF) is a monogenic syndrome caused by variants in the CF Transmembrane Conductance Regulator (CFTR) gene, affecting various organ and systems, in particular the lung, pancreas, sweat glands, liver, gastrointestinal tract, vas deferens, and vascular system. While for some organs, e.g., the pancreas, a strict genotype-phenotype occurs, others, such as the lung, display a different pathophysiologic outcome in the presence of the same mutational asset, arguing for genetic and environmental modifiers influencing severity and clinical trajectory. CFTR variants trigger a pathophysiological cascade of events responsible for chronic inflammatory responses, many aspects of which, especially related to immunity, are not ascertained yet. Although clock genes expression and function are known modulators of the innate and adaptive immunity, their involvement in CF has been only observed in relation to sleep abnormalities. The aim of this review is to present current evidence on the clock genes role in immune-inflammatory responses at the lung level. While information on this topic is known in other chronic airway diseases (chronic obstructive pulmonary disease and asthma), CF lung disease (CFLD) is lacking in this knowledge. We will present the bidirectional effect between clock genes and inflammatory factors that could possibly be implicated in the CFLD. It must be stressed that besides sleep disturbance and its mechanisms, there are not studies directly addressing the exact nature of clock genes’ involvement in inflammation and immunity in CF, pointing out the directions of new and deepened studies in this monogenic affection. Importantly, clock genes have been found to be druggable by means of genetic tools or pharmacological agents, and this could have therapeutic implications in CFLD. Full article

This study describes the first genome sequence and analysis of Coniella granati, a fungal pathogen with a broad host range, which is responsible for postharvest crown rot, shoot blight, and canker diseases in pomegranates. C. granati is a geographically widespread pathogen which has been reported across Europe, Asia, the Americas, and Africa. Our analysis revealed a 46.8 Mb genome with features characteristic of hemibiotrophic fungi. Approximately one third of its genome was compartmentalised within ‘AT-rich’ regions exhibiting a low GC content (30 to 45%). These regions primarily comprised transposable elements that are repeated at a high frequency and interspersed throughout the genome. Transcriptome-supported gene annotation of the C. granati genome revealed a streamlined proteome, mirroring similar observations in other pathogens with a latent phase. The genome encoded a relatively compact set of 9568 protein-coding genes with a remarkable 95% having assigned functional annotations. Despite this streamlined nature, a set of 40 cysteine-rich candidate secreted effector-like proteins (CSEPs) was predicted as well as a gene cluster involved in the synthesis of a pomegranate-associated toxin. These potential virulence factors were predominantly located near repeat-rich and AT-rich regions, suggesting that the pathogen evades host defences through Repeat-Induced Point mutation (RIP)-mediated pseudogenisation. Furthermore, 23 of these CSEPs exhibited homology to known effector and pathogenicity genes found in other hemibiotrophic pathogens. The study establishes a foundational resource for the study of the genetic makeup of C. granati, paving the way for future research on its pathogenicity mechanisms and the development of targeted control strategies to safeguard pomegranate production. Full article

The aim of the present study was to investigate possible differences in the sensitivity of HNSCC cells to known EMT regulators. Three HNSCC cell lines (UM-SCC-1, -3, -22B) and the HaCaT control keratinocyte cell line were exposed to transforming growth factor beta 1 (TGF-β1), a known EMT master regulator, and the cellular response was evaluated by real-time cell analysis (RTCA), Western blot, quantitative PCR, flow cytometry, immunocytochemistry, and the wound closure (scratch) assay. Targeted sequencing on 50 cancer-related genes was performed using the Cancer Hotspot Panel v2. Mutant, and wild type SMAD4 cDNA was used to generate recombinant SMAD4 constructs for expression in mammalian cell lines. The most extensive response to TGF-β1, such as cell growth and migration, β-actin expression, or E-cadherin (CDH1) downregulation, was seen in cells with a more epithelial phenotype. Lower response correlated with higher basal p-TGFβ RII (Tyr424) levels, pointing to a possible autocrine pre-activation of these cell lines. Targeted sequencing revealed a homozygous SMAD4 mutation in the UM-SCC-22B cell line. Furthermore, PCR cloning of SMAD4 cDNA from the same cell line revealed an additional SMAD4 transcript with a 14 bp insertion mutation, which gives rise to a truncated SMAD4 protein. Overexpression of this mutant SMAD4 protein in the highly epithelial control cell line HaCaT resulted in upregulation of TGF-β1 and vimentin. Consistent with previous reports, the invasive and metastatic potential of HNSCC tumor cells appears associated with the level of autocrine secretion of EMT regulators such as TGF-β1, and it could be influenced by exogenous EMT cytokines such as those derived from immune cells of the tumor microenvironment. Furthermore, mutant SMAD4 appears to be a significant contributor to the mesenchymal transformation of HNSCC cells. Full article

Background/Objectives: Rare diseases are a wide and heterogeneous group of multisystem life-threatening or chronically debilitating clinical conditions with reduced life expectancy and a relevant mortality rate in childhood. Some of these disorders have typical neurological symptoms, presenting from birth to adulthood. Dietary patterns and nutritional compounds play key roles in the onset and progression of neurological disorders, and the impact of alimentary needs must be enlightened especially in rare neurological diseases. This work aims to collect the in vitro, in vivo, and clinical evidence on the effects of diet and of nutrient intake on some rare neurological disorders, including some genetic diseases, and rare brain tumors. Herein, those aspects are critically linked to the genetic, biological, biochemical, and pathophysiological hallmarks typical of each disorder. Methods: By searching the major web-based databases (PubMed, Web of Science Core Collection, DynaMed, and Clinicaltrials.gov), we try to sum up and improve our understanding of the emerging role of nutrition as both first-line therapy and risk factors in rare neurological diseases. Results: In line with the increasing number of consensus opinions suggesting that nutrients should receive the same attention as pharmacological treatments, the results of this work pointed out that a standard dietary recommendation in a specific rare disease is often limited by the heterogeneity of occurrent genetic mutations and by the variability of pathophysiological manifestation. Conclusions: In conclusion, we hope that the knowledge gaps identified here may inspire further research for a better evaluation of molecular mechanisms and long-term effects. Full article

The contradiction between water supply and spring preservation issues is becoming increasingly apparent as Lijiang City develops. An investigation into the dynamic variations in the discharge rate of Heilongtan Spring in Lijiang City and the response law between the water level of the spring and precipitation is crucial for safeguarding the landscape water of Heilongtan Spring. This study employed linear regression analysis, Mann–Kendall (MK) mutation test, wavelet analysis, and vector autoregression (VAR) to examine the fluctuating pattern of the Heilongtan Spring discharge and the response of the Heilongtan Spring water level to precipitation in Lijiang City. Furthermore, the study discussed the influence of human activities on the alteration of Heilongtan Spring. The results indicate that the mean discharge rate of Heilongtan Spring is 0.94 m³/s, with an annual variation of 0.05 m³/s. The time series analysis reveals that the variation pattern of Heilongtan Spring discharge aligns with the precipitation trend in Lijiang City. Nevertheless, there is a distinction between the timing of the Heilongtan Spring discharge station point and the precipitation mutation point in Lijiang City. The significant primary cycle of spring discharge change occurs every 18 months, with a cycle length of 12 months. The vector autoregression (VAR) model demonstrates a lagged relationship between the water level of Heilongtan Spring and the precipitation in Lijiang City. Specifically, the water level of Heilongtan Spring has a four-month lag response to precipitation variability in Lijiang City. The results can provide a beneficial reference for preserving spring water and managing regional water resources. Full article

Alkaptonuria (AKU) is a rare autosomal recessive metabolic disorder caused by mutations in the homogentisate 1,2-dioxygenase (HGD) gene, leading to the accumulation of homogentisic acid (HGA), causing severe inflammatory conditions. Recently, the presence of serum amyloid A (SAA) has been reported in AKU tissues, classifying AKU as novel secondary amyloidosis; AA amyloidosis is characterized by the extracellular tissue deposition of fibrils composed of fragments of SAA. AA amyloidosis may complicate several chronic inflammatory conditions, like rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel disease, chronic infections, neoplasms, etc. Treatments of AA amyloidosis relieve inflammatory disorders by reducing SAA concentrations; however, no definitive therapy is currently available. SAA regulation is a crucial step to improve AA secondary amyloidosis treatments. Here, applying a comprehensive in vitro and in silico approach, we provided evidence that HGA is a disruptor modulator of SAA, able to enhance its polymerization, fibril formation, and aggregation upon SAA/SAP colocalization. In silico studies deeply dissected the SAA misfolding molecular pathway and SAA/HGA binding, suggesting novel molecular insights about it. Our results could represent an important starting point for identifying novel therapeutic strategies in AKU and AA secondary amyloidosis-related diseases. Full article

Zearalenone (ZEN) is a toxic secondary metabolite produced by the Fusarium fungi, which widely contaminates grains, food, and feed, causing health hazards for humans and animals. Therefore, it is essential to find effective ZEN detoxification methods. Enzymatic degradation of ZEN is believed to be an eco-friendly detoxification strategy, specifically thermostable ZEN degradation enzymes are needed in the food and feed industry. In this study, a novel ZEN lactone hydrolase ZHRnZ from Rosellinia necatrix was discovered using bioinformatic and molecular docking technology. The recombinant ZHRnZ showed the best activity at pH 9.0 and 45 °C with more than 90% degradation for ZEN, α-zearalenol (α-ZOL), β-zearalenol (β-ZOL) and α-zearalanol (α-ZAL) after incubation for 15 min. We obtained 10 mutants with improved thermostability by single point mutation technology. Among them, mutants E122Q and E122R showed the best performance, which retained more than 30% of their initial activity at 50 °C for 2 min, and approximately 10% of their initial activity at 60 °C for 1 min. The enzymatic kinetic study showed that the catalytic efficiency of E122R was 1.3 times higher than that of the wild-type (WT). Comprehensive consideration suggests that mutant E122R is a promising hydrolase to detoxify ZEN in food and feed. Full article

The partition behavior of single and double-point mutants of bacteriophage T4 lysozyme (T4 lysozyme) and staphylococcal nuclease A was examined in different aqueous two-phase systems (ATPSs) and studied by Solvent Interaction Analysis (SIA). Additionally, the solvent accessible surface area (SASA) of modeled mutants of both proteins was calculated. The in silico calculations and the in vitro analyses of the staphylococcal nuclease and T4 lysozyme mutants correlate, indicating that the partition analysis in ATPSs provides a valid descriptor (SIA signature) covering various protein features, such as structure, structural dynamics, and conformational stability. Full article

The Qinba Mountain range is a typical climate-sensitive and ecologically fragile region. Monitoring of vegetation dynamics is crucial for ecological protection and achieving sustainable development goals. Various mutation-detection methods, along with slope analysis, hot-spot analysis, and residual analysis, were used to examine changes in the Normalized Difference Vegetation Index (NDVI) during the growing and non-growing seasons over 41 years and to distinguish the relative effects of the drivers. This revealed four key findings. (1) NDVI increased at 0.02 decade⁻¹, with mutation points in 2006 for growing-season NDVI and 2007 for non-growing-season NDVI. (2) The trend in NDVI changed markedly at the mutation point. After the mutation point, NDVI was impacted more by human activity than by climate change. The hot and cold spots of the NDVI trend rate change in location and range in the growing season; in the non-growing season, it shows an obvious north–south distribution. (3) The spatial patterns in the effects of the drivers changed at this point. In the growing season, before this point, climate change and human activity collectively enhanced NDVI in ca. 81.3% of the region; after the mutation point, this value declined to 59.9% of the area, and human activity became the dominant driver in the area formerly dominated by both factors in combination. In the non-growing season, after the mutation point, the areas where both factors promoted vegetation growth decreased by 12.6% and those where climate change alone promoted it decreased by 11.1%, whereas the area affected only by human activity increased by 11.6%. (4) Before this point, human activity contributed >60% to the change in NDVI in the western Qinling region, with climate change contributing >60% in the other areas. After this point, human activity exerted a stronger influence than climate change, contributing >60% to enhancing vegetation growth and >80% reducing it. These findings provide a scientific basis for protecting the Qinba Mountain ecosystem and are essential for achieving sustainable development goals. Full article

This paper introduces an evolutionary algorithm for objective functions defined over clouds of points of varying sizes. Such design variables are modeled as uniform discrete measures with finite support and the crossover and mutation operators of the algorithm are defined using the Wasserstein barycenter. We prove that the Wasserstein-based crossover has a contracting property in the sense that the support of the generated measure is included in the closed convex hull of the union of the two parents’ supports. We introduce boundary mutations to counteract this contraction. Variants of evolutionary operators based on Wasserstein barycenters are studied. We compare the resulting algorithm to a more classical, sequence-based, evolutionary algorithm on a family of test functions that include a wind-farm layout problem. The results show that Wasserstein-based evolutionary operators better capture the underlying geometrical structures of the considered test functions and outperform a reference evolutionary algorithm in the vast majority of the cases. The tests indicate that the mutation operators play a major part in the performances of the algorithms. Full article