Browse Articles

G-quadruplexes as a source of vulnerability in BRCA2 <i>-</i> deficient granule cell progenitors and medulloblastoma

Biallelic pathogenic variants in the essential DNA repair gene BRCA2 cause Fanconi anemia complementation group D1. Patients in this group are highly prone to develop embryonal tumors, most commonly medulloblastoma arising from the cerebellar granule cell progenitors (GCPs). GCPs undergo high proliferation in the postnatal cerebellum under Sonic Hedgehog (SHH) activation, but the type of DNA lesions that require the function of the BRCA2 to prevent tumorigenesis remains unknown. To identify such lesions, we assessed both GCP neurodevelopment and tumor formation using a mouse model with deletion of exons three and four of Brca2 in the central nervous system, coupled with global Trp53 loss. Brca2 Δex3-4 ;Trp53 −/− animals developed SHH subgroup medulloblastomas with complete penetrance. Whole-genome sequencing of the tumors identified structural variants with breakpoints enriched in areas overlapping putative G-quadruplexes (G4s). Brca2 -deficient GCPs exhibited decreased replication speed in the presence of the G4-stabilizer pyridostatin. Pif1 helicase, which resolves G4s during replication, was highly upregulated in tumors, and Pif1 knockout in primary medulloblastoma tumor cells resulted in increased genome instability upon pyridostatin treatment. These data suggest that G4s may represent sites prone to replication stalling in highly proliferative GCPs and without BRCA2, G4s become a source of genome instability. Tumor cells upregulate G4-resolving helicases to facilitate rapid proliferation through G4s highlighting PIF1 helicase as a potential therapeutic target for treatment of BRCA2-deficient medulloblastomas.

Understanding farmer’s knowledge, attitudes, and practices towards adopting livestock interventions for food and nutrition security in Bangladesh using latent class analysis

Citizen science reveals alarming update on the invasion of the Asian mantleslug Meghimatium pictum in Brazil

The Asian mantleslug Meghimatium pictum is an exotic species introduced to Brazil in the late 1990s, but only formally reported in 2011. Since then, it has been deemed an agricultural pest and given the status of an invasive species; furthermore, it has been confirmed as an intermediate host for the nematode Angiostrongylus costaricensis in Brazil. Despite its potential for impacts, no additional studies on the status of its invasion have been conducted since the initial report. In this study, we used the citizen science platform iNaturalist to analyse the current distribution of M. pictum in Brazil, while also using genetic barcode data to understand the relationships between Brazilian and Asian populations and applying a species distribution model to investigate the suitable range for its distribution in Brazil. Our survey has recovered a total of 520 new records of this species in Brazil, confirming its spread to four additional states since its original report. Currently, M. pictum is recorded in the Distrito Federal and the states of Minas Gerais, Espírito Santo, Rio de Janeiro, São Paulo, Paraná, Santa Catarina, and Rio Grande do Sul. Our phylogenetic analysis suggests a close relationship between M. pictum populations in South America and those from Okinawa, Taiwan, and Guangzhou (mainland China), the latter being the most likely point of origin for the South American populations. Our species distribution model supports the idea that, in Brazil, the species is largely restricted to subtropical areas belonging to the Atlantic Forest ecoregion, while also showing suitable areas where the species has not been recorded yet and might become established in the near future. The implications of these findings are discussed, highlighting the recent surge in records and the usefulness of iNaturalist as a tool to monitor invasive species in the country.

Substantial reductions in black carbon from both fossil fuels and biomass burning during China’s Clean Air Action

Black carbon (BC) aerosols exacerbate air pollution and climate warming, but their climatic impacts and sources are poorly constrained by bottom–up emission inventories (EIs). China’s Clean Air Action (CAA), which was launched in 2013, provides an excellent opportunity for investigating interannual variations in source contributions and validate the accuracy of EIs. Here, we present an 11-y (2008–2018) record of the BC concentration and its source-diagnostic radiocarbon ( 14 C) and stable carbon isotope ( 13 C) signatures at a receptor site in the Pearl River Delta (PRD) region, South China. The results revealed that the implementation of the CAA (2014–2018) led to a 41% reduction in the BC concentration compared with that in the preaction period (2008–2013). There is a large and systemic discrepancy over the whole period in the contribution of biomass burning to BC in South China between predictions from technology-based EIs (4 to 9%) and these source-diagnostic dual-isotopic fingerprints of actual ambient aerosols (21 to 32%). Observational constraints by source-diagnostic δ 13 C/Δ 14 C isotope measurements revealed that the reduction in biomass burning contributed 22% to the decrease in BC associated with the CAA, whereas predictions from EIs assigned a much smaller fraction. These results emphasize the need for observation-based source diagnostics of changing BC emission sources. Detailed source apportionment using independent δ 13 C/Δ 14 C isotope methodology is crucial for refining air pollution control strategies and improving the accuracy of models used for assessing the air quality and climate effects of BC in China and elsewhere.

Optically-driven organic nano-step actuator for reconfigurable photonic circuits

Nonlocal complex short pulse equation in $${\mathcal{P}\mathcal{T}}$$-symmetry like symmetry breaking, breather–grammian interactions and soliton solutions

Rupture risk assessment for AComA aneurysms with morphological, hemodynamic and structural mechanical analysis

Introduction The Anterior Communicating Artery complex (AComA) is one of the most common intracranial aneurysms locations. Accurate rupture risk assessment in patients with cerebral aneurysms is essential for optimizing treatment decisions. Computational fluid dynamics has significantly advanced insight into aneurysmal hemodynamics. Many studies concentrate predominantly on blood flow patterns, frequently neglecting the biomechanical properties of the aneurysm wall. Fluid-structure interaction analysis combines hemodynamic behavior with wall mechanics, potentially facilitating a more thorough evaluation of rupture risk assessment. Methods In this study, we employed advanced techniques to investigate several single and composite parameters to predict the rupture risk of AComA aneurysms in a cohort of 150 patients treated at the Kepler University Hospital in Linz, Austria. For this reason, clinical, morphological, hemodynamic, and structural mechanical parameters were assessed. Results A subsequent workflow analysis, consisting of comparative analysis, collinearity analysis, predictive modeling, composite parameter, performance evaluation, and internal threshold validation, revealed the Gaussian curvature GLN (AUC = 0.91) with a sensitivity of 0.93 and specificity of 0.83 as a best-performing single parameter for aneurysm rupture prediction. Composite parameters like WGD (combination of wall shear stress, Gaussian curvature, and wall displacement) achieved an AUC of 0.89, and WG (combination of wall shear stress and Gaussian curvature) an AUC of 0.88. An internal validation with 25 independent ruptured aneurysms was performed, and the previous results were confirmed with very high sensitivity values of 0.92 for GLN. Conclusion Our findings indicate that the investigated morphological, hemodynamic, and structural, mechanical parameters could provide a potential tool for evaluating rupture risk for AComA aneurysms. The single morphological parameter GLN offers, followed by composite parameters WGD and WG, excellent prediction power for the aneurysm rupture state, as confirmed by internal validation. Further studies are warranted to evaluate the prospective clinical application of these parameters.

Quantum relaxometry for detecting biomolecular interactions with single NV centers

The investigation of biomolecular interactions at the single-molecule level has emerged as a pivotal research area in life science, particularly through optical, mechanical, and electrochemical approaches. Spins existing widely in biological systems offer a unique degree of freedom for detecting such interactions. However, most previous studies have been largely confined to ensemble-level detection in the spin degree. Here, we developed a molecular interaction analysis method approaching single-molecule level based on relaxometry using the quantum sensor, nitrogen-vacancy (NV) center in diamond. Experiments utilized an optimized diamond surface functionalized with a polyethylenimine nanogel layer, achieving ∼ 10 nm average protein distance and mitigating interfacial steric hindrance. Then we measured the strong interaction between streptavidin and spin-labeled biotin complexes, as well as the weak interaction between bovine serum albumin and biotin complexes, at both the micrometer scale and nanoscale. For the micrometer-scale measurements using ensemble NV centers, we reexamined the often-neglected fast relaxation component and proposed a relaxation rate evaluation method, substantially enhancing the measurement sensitivity. Furthermore, we achieved nanoscale detection approaching single-molecule level using single NV centers. This methodology holds promise for applications in molecular screening, identification, and kinetic studies at the single-molecule level, offering critical insights into molecular function and activity mechanisms.

Structural insights into proprotein convertase activation facilitate the engineering of highly specific furin inhibitors

Abstract Proprotein convertases (PCs), including furin and PC1/3 among nine mammalian homologues, mediate the maturation of numerous secreted substrates by proteolytic cleavage. Disbalance of PC activity is associated with diseases like cancer, fibrosis, neurodegeneration and infections. Therefore, PCs are promising drug targets for the treatment of many diseases. However, the highly conserved active site of PCs complicates the development of specific inhibitors. Here we investigate the activation mechanism of PCs using X-ray crystallography and biochemical methods. The structure-based optimization of the multibasic secondary cleavage site loop not only prevents the prodomain’s proteolytic cleavage but also increases its inhibition of furin. Combination of cleavage-resistant PC1/3-prodomain variants and a furin-specific nanobody in fusion proteins reveal very potent inhibitors (Ki = 1.2 pM) with a more than 25,000-fold higher specificity for furin compared to the closely related PC-member PCSK5. Such fusion proteins effectively suppress the replication of a furin-dependent H7N7-influenza virus in cell-based assays.

Preclinical safety and feasibility of a bupivacaine-loaded hydrogel for pain relief after spinal surgery

Computational prediction of high-risk non-synonymous SNPs in human ApoE and their structural impact on amyloid-β interaction in Alzheimer’s disease pathogenesis

Apolipoprotein E (ApoE) plays a critical role in Alzheimer’s disease (AD) by regulating amyloid beta (Aβ) clearance through direct interaction. Non-synonymous single nucleotide polymorphisms (nsSNPs) in ApoE alter its structure and impair function, contributing to disease progression. This study aimed to identify functionally damaging nsSNPs in the ApoE gene using in silico tools and to assess their structural and binding effects on Aβ in the context of AD progression. A total of 376 nsSNPs were retrieved from dbSNP, ClinVar, and DisGeNET databases. Eight predictive tools (SIFT, PolyPhen-2, PredictSNP, PhD-SNP, PANTHER, PROVEAN, Meta-SNP, and SNAP2) were employed to identify deleterious variants. Protein stability was assessed using I-Mutant 2.0, MUpro, INPS-MD, iStable, and DynaMut2, while structural effects were evaluated via HOPE, MutPred2, Swiss-PDB Viewer, and Missense3D. Domain localization was determined using InterPro. Molecular docking was performed using PyRx and AutoDock Vina. Molecular dynamic simulation (MDS) evaluate binding stability and dynamics through 100-ns by Schrödinger Maestro, analyzing RMSD, RMSF, Rg, SASA. Out of 376 nsSNPs, 10 were consistently predicted as deleterious by all eight computational tools. Among these, two variants (L107P and L122P) were classified as high-risk and located within the receptor-binding domain of ApoE. The receptor-binding domain mediates the interaction between ApoE and Aβ. Molecular docking revealed binding affinities of −5.5 kcal/mol (WT), −5.6 kcal/mol (L107P), and −6.6 kcal/mol (L122P), indicating stronger Aβ binding by L122P. Stronger binding affinity of L122P mutation may promote Aβ aggregation or hinder clearance, potentially contributing to disease severity. MDS showed L122P had the highest structural stability, with the lowest RMSD, RMSF, Rg values and increased SASA, supporting its enhanced interaction with Aβ. These findings suggest that L122P mutation may enhance Aβ aggregation or hinder its clearance, potentially worsening AD and highlight the structural and functional impact of ApoE variants and the need for experimental validation.

Microvilli’s grip on T cell development

Anthropogenic forcing drives equatorward migration of heatwave locations across continents

MAIA platform for routine clinical testing: an artificial intelligence embryo selection tool developed to assist embryologists

Crush syndrome diagnosis and management in resource-constrained settings: A Delphi study

Background Crush syndrome is an important source of morbidity and mortality in resource-constrained settings including earthquake disaster zones, austere military environments, and countries where motor vehicle collisions and interpersonal violence are prevalent. In South Africa and other countries with high rates of community violence, patients develop crush due to a unique form of trauma called community assault, where individuals suspected of wrongdoing are assaulted by multiple persons as a form of mob justice. The purpose of this study is to generate consensus about crush syndrome definitions and endpoints to inform the development of scoring systems appropriate for community assault and usable in resource-limited settings. Methods This study used in-depth interviews of clinicans from South Africa to determine the challenges associated with crush management in resource-constrained environments. These qualitative findings informed a subsequent Delphi survey process which sought consensus regarding crush definitions, endpoints, and co-variates. Three surveys were administered to an international panel of clinicians with experience managing crush injuries in military, disaster, and civilian clinical environments. There was a pre-established consensus threshold of 75%. Results There were 8 interview participants and 15 Delphi participants. These clinicians recommended maintaining a high index of suspicion for crush syndrome as this diagnosis can easily be overlooked in polytrauma patients, and advised early administration of intravenous fluids titrated to urine output and respiratory status. Crush injury was conceptualized as a localized process of muscle injury from trauma, whereas crush syndrome was viewed as the resulting systemic complications including renal failure and hemodynamic instability. Preferred clinical endpoints included acute kidney injury, renal replacement therapy, and need for respiratory support. Conclusion This study provided context related to crush injury management in resource-constrained environments. Clinical risk prediction models must account for the unique patient populations and data limitations commonly encountered in these settings.

Radiocarbon dating of Jerusalem’s Siloam Dam links climate data and major waterworks

Using well-established microarchaeological sampling methods, we reached a precise radiocarbon date of 800 BC for the Siloam Pool’s monumental water dam in Jerusalem. This date is a critical link connecting several imposing waterworks constructed at that time. Climate data pointing to droughts and flash floods during the last decades of the 9th century BC provide a logical framework for the reasons behind such endeavors. These included the fortification of the city’s primary water source, the Gihon Spring, and the redirection of the water into the city through a channel to an artificial reservoir created by building the Siloam Dam at the end of the Tyropoeon Valley, which blocked the drainage of rain and redirected spring waters.

Self-reinforcement in filled rubber via strain-induced crystallisation

Facile and green synthesis of α-Fe2O3 nanoparticles stabilized with chitosan for phototherapy with 808 nm laser irradiation

Abstract In this research, biocompatible α-Fe2O3 nanoparticles were prepared as an agent for photothermal and photodynamic therapy methods by combining green synthesis and hydrothermal methods. The addition of chitosan bio-polymer played a crucial role in this process, as it not only stabilized the suspension of nanoparticles but also enhanced their biocompatibility. This stability was confirmed by zeta potential analysis Various analyses such as transmission electron microscope, X-ray diffraction, UV–visible spectrum, and Fourier transform infrared spectrum were performed to determine the structural and optical characteristics of the nanocomposite. The average size of the spherical crystals of α-Fe2O3 nanoparticles was estimated at 43 nm using the Williamson–Hall equation. The corresponding band gap value of nanoparticles was estimated at 1.8 eV by drawing a Tauc diagram. Photothermal effects for several different concentrations of an aqueous solution of CS-nanocomposite were measured by an 808 nm laser with a power density of 1 W/cm2, and the concentration of 5 mg/ml was chosen as the optimal concentration for use in photothermal therapy. The value of the photothermal conversion efficiency of this nanocomposite was determined at 7% using Roper’s equation. To investigate the photodynamic properties of nanoparticles, a methylene blue probe was used to detect active oxygen species. Finally, an MTT assay studied the cytotoxicity of nanocomposite on AGS cells before and after laser irradiation. Under laser irradiation, cell viability at concentrations of 250ppm and 500ppm was 88% and 69%, respectively, compared to the control cells, confirming this nanocomposite’s photothermal therapy and photodynamic therapy effects.

SEE+ computerized classroom-based training enhances 7- to 10-year-olds' socio-emotional cognition through observation and inference

Smooth social interactions rely on children’s abilities to decode others’ social signals, which includes what an individual may say or do, and their facial emotional expressions. Failure can lead to exclusion from social groups. Consequently, a number of social and emotional learning (SEL) training programmes have been developed, with some evidence of positive impacts on those skills themselves and on academic achievement. Here, we present and evaluate the efficacy of a novel classroom-based computerized learning activity, called SEE+ (Socio-emotional engagement through observation), in supporting and enhancing 7- to 10-year-olds’ emotion recognition and theory of mind judgements through observation and inference. SEE+ involved observing four virtual characters interacting within social scenarios and inferring their mental states. Participants were recruited from across diverse school settings (rural, urban) in England as part of a large-scale randomised controlled trial (n = 5585; 7.3–11.0 years old, M age = 9.1, SD = 1.0) resulting in a mix of socio-economic and ethnic backgrounds. Mixed model ANOVAs were used to compare performance on socio-emotional tasks between the SEE+ group, an active control group and a teaching-as-usual control group. SEE + was associated with the equivalent of 4–6 months improvement in performance on the socio-emotional assessment tasks. Children showed near transfer effects of the intervention (i.e., when characters present in the computerized learning activity were used in the assessment), while no strong evidence of far transfer effects (i.e., when photographs of unknown children were used in the assessment) was found. Limitations were the use of pen-and-paper assessments with a reduced number of trials, and a possible ceiling effect in the older children in the photograph condition. Our findings point to the relative plasticity of younger children’s socio-emotional cognition and underscore SEE+ as an easy-to-use cost-effective socio-emotional resource for teachers to embed SEL in the school curriculum.

Chants across seven traditions share acoustic traits that enhance subjective relaxation

For over 5,000 y, chanting has been practiced across many Western and Eastern traditions. However, there is hardly any empirical research on 1) whether chants from across the globe share common acoustic properties, 2) whether these acoustic features make them distinct from other human vocalizations, and 3) the extent to which they may positively impact listeners’ well-being. Here, we collected 242 chants belonging to seven distinct traditions and associated with a wide range of language families, and compared them acoustically to a large corpus of song (n = 126) and speech (n = 616) samples from across 14 linguistic and 12 geographical regions. We show that, irrespective of language and geographical origin, chants share distinctive acoustic traits, namely relatively flat and slow-changing intonation and steady, unbroken voicing in a comfortable, rather low pitch range with a prevalence of mid-central vowels. Thus, chants are produced in a relaxed vocal tract configuration with minimal articulation. Additionally, playback experiments involving original chants (with a participant pool of 61 listeners), resynthesized chants (with 114 listeners), and fully synthetic chants (with 80 listeners) demonstrate that these acoustic characteristics enhance listeners’ perceived sensations of relaxation. Specifically, relatively flat and slow-changing intonation, combined with vowel production in a relatively relaxed vocal tract configuration, resulted in higher overall relaxation ratings. Together these results hint at a specific function of chants’ acoustic commonalities: the enhancement of well-being through relaxation.