Search Results (196)

Background: Published studies have documented the association between sunshine duration and depression symptoms; however, the evidence regarding the long-term effects and potential mechanisms remains insufficient. This study aimed to examine the association between sunshine duration and incident depression and to explore potential mediating pathways. Methods: A total of 336,805 participants from the UK Biobank were included in the study. Meteorological exposures were estimated using the bilinear interpolation approach and time-weighted method. The association between sunshine duration and incident depression was examined through the time-dependent Cox proportional hazard model and generalized propensity score model. Vitamin D, calcium, immune biomarkers, an aggregated inflammation score (INFLA-score), and sleep pattern were selected as the potential mediators. Causal mediation analysis was employed to elucidate underlying mediating effects. Results: With a median follow-up of 13 years, 13,862 cases of incident depression were identified. Sunshine duration demonstrated a negative association with the incident depression. The effects were stronger among the elderly, alcohol consumers, individuals who spent less time outdoors, and those who were less physically active. Vitamin D, calcium, INFLA, neutrophils, and monocytes emerged as the top five contributors of immune biomarkers to the natural indirect effect. The combined mediating effect of top five biomarkers and sleep pattern accounted for 30% of the total effect of sunshine duration on the incident depression. Conclusion: Our study suggests that longer sunshine duration might mitigate depression through vitamin D-related metabolism, inflammation, and sleep pattern. It may serve as an effective natural antidepressant, particularly for the elderly, alcohol consumers, less outdoor spenders, and those who were less physically active. Full article

Background/Objectives: Single-domain immunoglobulins are small protein modules with specific affinities. Among them, the variable domains of heavy chains of heavy-chain-only antibodies (VHH) as the antigen-binding fragment of heavy-chain-only antibodies (also termed nanobodies) have been widely investigated for their applicability, e.g., therapeutics and immunodiagnostics. However, despite their advantageous biochemical and biophysical characteristics, protein aggregation throughout recombinant synthesis is a serious drawback in the development of nanobodies with application perspectives. Therefore, we aimed to develop a computational method to predict the aggregation propensity of VHH antibodies for the selection of promising candidates in early discovery. Methods: We employed a deep learning-based structure prediction for VHHs and derived from it likely biophysical and biochemical properties of the framework region 2 with relevance for aggregation. A total of 106 nanobody variants were produced by recombinant expression and characterized for their aggregation behavior using size exclusion chromatography (SEC). Results: Quantitative characteristics of framework region 2 patches were combined into a function that defines an aggregation score (AS) predicting the aggregation propensities of VHH variants. AS was evaluated for its capability to forecast recombinant VHH aggregation by experimentally studying VHH Fc-fusion proteins for their aggregation. We observed a clear correlation between the calculated aggregation score and the actual aggregation propensities of biochemically characterized VHHs Fc-fusion proteins. Moreover, we implemented an easily accessible pipeline of software modules to design nanobodies with desired solubility properties. Conclusions: AI-based prediction of VHH structures, followed by analysis of framework region 2 properties, can be used to predict the aggregation propensities of VHHs, providing a convenient and efficient tool for selecting stable recombinant nanobodies. Full article

This study explores the structural transitions and aggregation behaviour of recombinant β- and γ-synucleins from five vertebrate species—Cyprinus carpio, Danio rerio, Xenopus laevis, Anolis carolinensis, and Homo sapiens—using thioflavin T fluorescence and circular dichroism spectroscopy, with and without copper ions. Although synucleins are well-conserved proteins among vertebrates, species-specific differences in amino acid composition and predicted secondary structures were observed, particularly within β-strand-forming regions. During a six-day incubation, human β-synuclein exhibited a time-dependent increase in β-sheet-rich structures, while non-mammalian β-synucleins showed limited variation. In contrast, γ-synucleins from all species displayed greater aggregation propensity, with variations in kinetics and magnitude. The presence of copper reduced the rate of aggregation in human β-synuclein, likely due to high-affinity metal-binding sites, whereas γ-synuclein aggregation was only mildly affected. Notably, copper enhanced late-phase aggregation in A. carolinensis β-synuclein. These findings suggest that sequence divergence among synuclein isoforms may underlie species-specific aggregation mechanisms and metal sensitivity. The differential aggregation behaviour observed across taxa may reflect evolutionary adaptations in synuclein function and folding propensity, with implications for understanding the molecular basis of synucleinopathies and their potential modulation by metal ions. Full article

Thermo-tolerance is a virulence factor responsible for the emergence of new fungal pathogens, including Candidozyma auris (formerly classified as Candida auris, C. auris). It has been shown that in C. auris the thermo-tolerance, as well as other virulence traits, such as the ability to aggregate, to form pseudo-hyphae, or to produce melanin are strain-specific features. Here, we investigated the impact of different temperatures (25 °C, 37 °C and 42 °C) on the phenotypic and virulence profile of C. auris strain CDC B11903. The results show a positive correlation between the resistance to antifungals and increasing temperature from 25 °C to 37 °C, while no differences were observed between 37 °C and 42 °C, except for Anidulafungin. Furthermore, C. auris growth was impaired at 25 °C as compared to 37 °C and 42 °C. Except for the haemolytic activity, which increased with rising temperatures, phospholipase, lipase and biofilm production were found at all tested temperatures. Moreover, the ability to produce melanin was observed only at 37 °C and 42 °C. The capacity to grow as pseudo-hyphae or in clusters and to adhere to both biotic and abiotic surfaces were observed at all the temperatures tested, with increased propensity of C. auris to adhere to abiotic surfaces with rising temperatures. The results underline the thermo-tolerance of C. auris strain B11903 and its increased virulence profile at human body temperature both in physiological (37 °C) and febrile state (42 °C). Full article

Background/Objectives: Albumin supplementation is widely used for hypoalbuminemia treatment in patients with critical illness, especially those with cirrhosis. However, studies have demonstrated that routine albumin administration is not always advantageous. We examined how albumin supplementation affects survival outcomes in patients with sepsis with hypoalbuminemia. Methods: This study was conducted by researchers in Taiwan using data from the TriNetX research platform, covering the period from 1 April 2014 to 30 April 2024. This platform aggregates real-world data from healthcare organizations worldwide. From this dataset, 1,147,433 patients who developed sepsis and hypoalbuminemia with albumin levels <3.5 g/dL were identified. The study population was stratified into two groups on the basis of whether they received albumin infusion or not. To compare outcomes, hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated between propensity-score-matched patients who did and did not receive albumin supplementation. Subgroup analysis by albumin levels was conducted. Results: Albumin infusion was linked to increased risks of 30-day mortality (HR [95% CI] = 1.800 [1.774–1.827], p < 0.05), shock (HR [95% CI] = 1.436 [1.409–1.465], p < 0.05), septic shock (HR [95% CI] = 1.384 [1.355–1.415], p < 0.05), hypovolemic shock (HR [95% CI] = 1.496 [1.391–1.608], p < 0.05), cardiogenic shock (HR [95% CI] = 1.553 [1.473–1.637], p < 0.05), heart failure (HR [95% CI] = 1.098 [1.080–1.116], p < 0.05), and pulmonary edema (HR [95% CI] = 1.479 [1.438–1.520], p < 0.05). The subgroup analysis by albumin levels revealed a trend of increased mortality risk with albumin supplementation in patients with high baseline albumin levels. Conclusions: Patients with sepsis with hypoalbuminemia who received albumin supplementation exhibited high 30-day mortality rates and increased risks of shock, heart failure, and pulmonary edema compared with those who did not. These findings indicate that routine albumin administration may be linked with unfavorable outcomes in these patients. Full article

Parkinson’s disease and related synucleinopathies, including dementia with Lewy bodies and multiple system atrophy, are characterised by the pathological aggregation of the α-synuclein (aSyn) protein in neuronal and glial cells, leading to cellular dysfunction and neurodegeneration. This review synthesizes knowledge of aSyn biology, including its structure, aggregation mechanisms, cellular interactions, and systemic influences. We highlight the structural diversity of aSyn aggregates, ranging from oligomers to fibrils, their strain-like properties, and their prion-like propagation. While the role of prion-like mechanisms in disease progression remains a topic of ongoing debate, these processes may contribute to the clinical heterogeneity of synucleinopathies. Dysregulation of protein clearance pathways, including chaperone-mediated autophagy and the ubiquitin–proteasome system, exacerbates aSyn accumulation, while post-translational modifications influence its toxicity and aggregation propensity. Emerging evidence suggests that immune responses and alterations in the gut microbiome are key modulators of aSyn pathology, linking peripheral processes—particularly those of intestinal origin—to central neurodegeneration. Advances in biomarker development, such as cerebrospinal fluid assays, post-translationally modified aSyn, and real-time quaking-induced conversion technology, hold promise for early diagnosis and disease monitoring. Furthermore, positron emission tomography imaging and conformation-specific antibodies offer innovative tools for visualising and targeting aSyn pathology in vivo. Despite significant progress, challenges remain in accurately modelling human synucleinopathies, as existing animal and cellular models capture only specific aspects of the disease. This review underscores the need for more reliable aSyn biomarkers to facilitate the development of effective treatments. Achieving this goal requires an interdisciplinary approach integrating genetic, epigenetic, and environmental insights. Full article

Nanomaterials (NMs) have gained tremendous attention in various applications in the modern era. The most significant challenge associated with NMs is their strong propensity to aggregate. The chemical surface modification of NMs has garnered notable attention in managing NM dispersion and aggregation. Among the modification approaches, the silane modification of NMs has generated great interest among researchers as a versatile approach to tailoring the surface characteristics of NMs. This review comprehensively examined the recent advancements in silane modification techniques with a focus on triboelectric nanogenerator (TENG) applications. It provides an overview of silane chemistry and its interaction with diverse NMs, elucidating the underlying mechanisms governing the successful surface functionalization process. This review emphasized the silane modification, such as improved mechanical properties of composites, enhanced electrical and thermal conductivity, functional coatings, water treatment, textile industries, catalysis, membrane applications, and biomedical applications, of various NMs. In particular, the role of silane-modified NMs in advancing energy harvesting technologies was highlighted, showcasing their potential to enhance the performance and stability of next-generation devices. Full article

This study introduces a new metro train demand model that simultaneously captures both aggregate ridership from automated fare collection (AFC) data and disaggregate consideration propensities, using individual survey data from Chennai, India. This joint framework produces more accurate aggregate demand estimates than traditional OLS (R² improves from 0.67 to 0.75), as it is able to capture the complex and non-linear relationship between disaggregate consideration probability, reflecting potential demand, and aggregate footfall, reflecting realized demand. It is observed that increasing the consideration probability enhances the footfall overall. However, some locations exhibit an opposing trend between consideration and footfall (low consideration but high footfall, or vice versa). Also, the sets of influential factors vary across these two dimensions. For instance, individual-level variables (income and out-of-vehicle travel time) and multi-modal connectivity features (presence of an airport and multimodal hubs near the metro) play a key role in footfall. In contrast, consideration probability is primarily influenced by access time, cost, and egress distance. Furthermore, factors influencing consideration probability (walkability, train service quality, and first–last–mile connectivity) vary across segments (based on vehicle unavailability, exclusive vehicle availability, and limited vehicle availability). Evidence of selection bias among metro riders, non-normality, and intra-person variability effects in footfall is observed. From a policy perspective, neglecting the disaggregate consideration effects on realized aggregate demand, i.e., footfall models, can overestimate the role of metro costs and out-of-vehicle travel time. In addition, the ridership levels of the metro are overestimated at higher metro fare levels. The new model illustrates that applying location-specific and dimension-specific policy interventions can be more effective than uniform area-wide policies for enhancing the user base and realized ridership. Full article

Amyloid beta (Aβ42 and Aβ40) aggregation, along with neurofibrillary tangles, is one of the major neurotoxic events responsible for the onset of Alzheimer’s disease. Many potent peptide-based inhibitors mainly focusing on central hydrophobic core Aβ16–20 (KLVFF) have been reported in recent years. Herein, we report pentapeptides 1–4, based on the β-turn-inducing fragment Aβ19–23 (FFAED). The synthesis of peptides 1–4 was carried out using Fmoc/tBu-based solid-phase peptide synthesis technique, and it was found that pentapeptide 3 potently inhibit the aggregation propensity of Aβ42, when incubated with it at 37 °C for 48 h. The aggregation inhibition study was conducted using thioflavin T-based fluorescence assay and circular dichroism spectroscopy, and supported by transmission electron microscope imaging. The conformational change on the aggregation of Aβ42 and aggregation inhibition by peptides 1–4 was further evaluated using ¹H–¹⁵N HSQC NMR spectroscopy. The results demonstrated that the most potent analog, peptide 3, effectively disrupts the aggregation process. This study is the first to demonstrate that an Aβ19–23 fragment mimic can disrupt the aggregation propensity of Aβ42. Full article

Microplastics (MPs), ubiquitous environmental pollutants, pose substantial threats to aquatic ecosystems and organisms, including the model species Daphnia magna. This study examined the effects of polyethylene (PE) and polystyrene (PS) MPs on D. magna, focusing on their ingestion, epigenetic alterations, and transcriptional responses. Exposure experiments revealed a concentration-dependent accumulation of MPs, with PS particles showing higher ingestion rates due to their higher density and propensity for aggregation. Epigenetic analyses demonstrated that exposure to PE MPs significantly reduced the global DNA methylation (5-mC) of Daphnia magna, suggesting hypomethylation as a potential stress response. Conversely, the DNA hydroxymethylation (5-hmC) of Daphnia magna displayed variability under PS exposure. Transcriptional analysis identified a marked downregulation of Vitellogenin 1 (v1) and upregulation of Ecdysone Receptor B (ecr-b), highlighting the occurrence of stress-related and adaptive molecular responses. These findings enhance our understanding of the molecular and epigenetic effects of MPs on aquatic organisms, offering critical insights for the development of effective environmental management and conservation strategies in the face of escalating MP pollution. Full article

Background: Critical studies have unwaveringly established the importance of peculiar single-nucleotide polymorphisms (SNPs) in apolipoproteins (Apos) genes as genetic risk factors for dyslipidemias and their related comorbidities. In this study, we employed in silico approaches to analyze mutations in Apos. Methods: A comprehensive set of computational tools was utilized. The tools for predictions derived from sequence analysis were: SIFT, PolyPhen-2, FATHMM and SNPs&GO; The tools for structure analysis were: mCSM, DynaMut2, MAESTROweb, and PremPS; for prediction of pathogenic potential were: MutPred2, and PhD-SNP; for profiling of aggregation propensity were: Camsol, and Aggrescan3D 2.0, and lastly, for residual frustration analysis, the Frustratometer was used. These approaches assess variant effects on protein structure, stability, and function. Results: We identified seventeen SNPs in total, twelve for ApoB, one for ApoC2, one for ApoC3, and three for ApoE, representing 70%, 6%, 6% and 18%, respectively. The pathogenity of ApoE, was highlighted in two SNPs the rs769452 with amino acid replacement L46P, and rs769455 with amino acid replacement R163C. The aggregation/solubility analysis revealed that the L46P leads to a decrease in ApoE aggregation. The R163C, showed a decrease in solubility in one of two tools used, resulting in destabilizing effects altering its solubility. Conclusions: The two mutations in ApoE studied with the in silico methodologies identified clinically significant genetic variants, highlighting the robustness of the integrated approach. The future direction of the research is to create a multiplex panel with the SNPs identified here in APOE and expanding to other proteins to have a panel genetic risk assessment and disease prediction in which ApoE correlates. Full article

Tau is a microtubule-associated protein that undergoes liquid–liquid phase separation (LLPS) to form condensates under physiological conditions, facilitating microtubule stabilization and intracellular transport. LLPS has also been implicated in pathological Tau aggregation, which contributes to tauopathies such as Alzheimer’s disease. While LLPS is known to promote Tau aggregation, the relationship between Tau’s structural states and its phase separation behavior remains poorly defined. Here, we examine how oligomerization modulates Tau LLPS and uncover key distinctions between monomeric, oligomeric, and amyloidogenic Tau species. Using dynamic light scattering and fluorescence microscopy, we monitored oligomer formation over time and assessed oligomeric Tau’s ability to undergo LLPS. We found that Tau monomers readily phase separate and form condensates. As oligomerization progresses, Tau’s propensity to undergo LLPS diminishes, with oligomers still being able to phase separate, albeit with reduced efficiency. Interestingly, oligomeric Tau is recruited into condensates formed with 0-day-aged Tau, with this recruitment depending on the oligomer state of maturation. Early-stage, Thioflavin T (ThT)-negative oligomers co-localize with 0-day-aged Tau condensates, whereas ThT-positive oligomers resist condensate recruitment entirely. This study highlights a dynamic interplay between Tau LLPS and aggregation, providing insight into how Tau’s structural and oligomeric states influence its pathological and functional roles. These findings underscore the need to further explore LLPS as a likely modulator of Tau pathogenesis and distinct pathogenic oligomers as viable therapeutic targets in tauopathies. Full article

Prion diseases are fatal neurodegenerative diseases that can be transmitted by infectious protein particles, PrP^Scs, encoded by the endogenous prion protein gene (PRNP). The origin of prion seeds is unclear, especially in non-human hosts, and this identification is pivotal to preventing the spread of prion diseases from host animals. Recently, an abnormally high amyloid propensity in prion proteins (PrPs) was found in a frog, of which the genetic variations in the PRNP gene have not been investigated. In this study, genetic polymorphisms in the PRNP gene were investigated in 194 Dybowski’s frogs using polymerase chain reaction (PCR) and amplicon sequencing. We carried out in silico analyses to predict functional alterations according to non-synonymous single nucleotide polymorphisms (SNPs) using PolyPhen-2, PANTHER, SIFT, and MutPred2. We used ClustalW2 and MEGA X to compare frog PRNP and PrP sequences with those of prion-related animals. To evaluate the impact of the SNPs on protein aggregation propensity and 3D structure, we utilized AMYCO and ColabFold. We identified 34 novel genetic polymorphisms including 6 non-synonymous SNPs in the frog PRNP gene. The hydrogen bond length varied at codons 143 and 207 according to non-synonymous SNPs, even if the electrostatic potential was not changed. In silico analysis predicted S143N to increase the aggregation propensity, and W6L, C8Y, R211W, and L241F had damaging effects on frog PrPs. The PRNP and PrP sequences of frogs showed low homology with those of prion-related mammals. To the best of our knowledge, this study was the first to discover genetic polymorphisms in the PRNP gene in amphibians. Full article

Alzheimer’s disease (AD) is a complex neurodegenerative disorder characterized by extracellular amyloid plaques, predominantly consisting of amyloid-β (Aβ) peptides. The oligomeric form of Aβ is acknowledged as the most neurotoxic, propelling the pathological progression of AD. Interestingly, besides Aβ, other proteins are co-localized within amyloid plaques. Peptide analogs corresponding to the “aggregation-prone” regions (APRs) of these proteins could exhibit high-affinity binding to Aβ and significant inhibitory potential against the Aβ oligomerization process. The peptide analogs of co-localized protease, Cathepsin B, may act as such potent inhibitors. In silico studies on the complexes of the oligomeric state of Aβ and Cathepsin B peptide analogs were performed utilizing molecular docking and molecular dynamics simulations, revealing that these analogs disrupt the β-sheet-rich core of Aβ oligomers, a critical structural feature of their stability. Of the four peptide analogs evaluated, two demonstrated considerable potential by effectively destabilizing oligomers while maintaining low self-aggregation propensity, i.e., a crucial consideration for therapeutic safety. These findings point out the potential of APR-derived peptide analogs from co-localized proteins as innovative agents against AD, paving the way for further exploration in peptide-based therapeutic development. Full article

Background: Rigorous assessment of antibody developability is crucial for optimizing lead candidates before progressing to clinical studies. Recent advances in predictive tools for protein structures, surface properties, stability, and immunogenicity have streamlined the development of new biologics. However, accurate prediction of the impact of single amino acid substitutions on antibody structures remains challenging, due to the diversity of complementarity-determining regions (CDRs), particularly CDR3s. Methods: In this study, we combined in silico tools with in vitro assessments to engineer improved antibodies against the oxidized isoform of the macrophage migration inhibitory factor (oxMIF), building on the first generation anti-oxMIF antibody imalumab. Results: We identified hydrophobic hotspots conferring increased self-interaction and aggregation propensity on imalumab, which unravels its unusually short half-life in humans. By introducing mutations into the variable regions, we addressed these liabilities. Structural prediction tools and molecular dynamics simulations guided the selection of mutations, which were then experimentally validated. The lead candidate antibody, C0083, demonstrated reduced hydrophobicity and self-interaction due to the restructuring of its heavy chain CDR3 loop. Despite these structural changes, C0083 retained target specificity and binding affinity to oxMIF. Conclusions: Altogether, this study shows that a small number of well-selected mutations was sufficient to substantially improve the biophysicochemical properties of imalumab. Full article