Browse Articles

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.

Localized statistics decoding for quantum low-density parity-check codes

Abstract Quantum low-density parity-check codes are a promising candidate for fault-tolerant quantum computing with considerably reduced overhead compared to the surface code. However, the lack of a practical decoding algorithm remains a barrier to their implementation. In this work, we introduce localized statistics decoding, a reliability-guided inversion decoder that is highly parallelizable and applicable to arbitrary quantum low-density parity-check codes. Our approach employs a parallel matrix factorization strategy, which we call on-the-fly elimination, to identify, validate, and solve local decoding regions on the decoding graph. Through numerical simulations, we show that localized statistics decoding matches the performance of state-of-the-art decoders while reducing the runtime complexity for operation in the sub-threshold regime. Importantly, our decoder is more amenable to implementation on specialized hardware, positioning it as a promising candidate for decoding real-time syndromes from experiments.

Diabetes mellitus exacerbates cardiovascular remodeling in elderly Chinese by affecting aortic diameter and pulsatile load

Deep learning detection of retinal detachment: Optical coherence tomography staging and estimation of duration of macular detachment

Objective To test the applicability of deep learning models for detecting and staging rhegmatogenous retinal detachment (RRD) based on morphological features using two- and three-dimensional optical coherence tomography (OCT) scans. Design Retrospective study using deep learning-based image classification analysis of 2D and 3D OCT scans combined with clinical baseline data. Subjects Adult patients presenting to the University Medical Center Hamburg-Eppendorf in Germany. Methods A total of 252 eyes with RRD and 770 control eyes were included. All OCT scans and clinical baseline data were reviewed and graded. Binary and multiclass classification approaches were applied. Main outcome measures Area under the curve (AUC) and precision-recall area under the curve (PR AUC) for detection, stage classification and duration estimation of RRD. Results We employed both statistical and deep learning-based approaches using 2D and 3D OCT data. We evaluated an automated 3D OCT classification model in a multiclass analysis to distinguish RRD scans by macula status from a non-RRD group with macula-on cases (PR AUC = 0.66 ± 0.12, AUC = 0.96 ± 0.01) vs. macula-off cases (PR AUC = 0.86 ± 0.07, 0.98 ± 0.01) against non-RRD cases (PR AUC = 1.00, AUC = 1.00) Furthermore, the 3D model was able to classify the duration of macula-off status (< 3 days) with a PR AUC of 0.68 ± 0.2 and a AUC of 0.97 ± 0.2 when compared to a mixed group including longer macular-off, macular-on and non RRD cases. Lastly, manually graded RRD Stages were correlated with best corrected visual acuity (BCVA), as well as macula-off Duration and classified via a 2D model. A 2D model used for RRD stage classification achieved its best performance for stage 4, with a PR AUC of 0.56 ± 0.11 and an AUC of 0.94 ± 0.02. Conclusion The machine learning models demonstrated strong performance in classifying RRD stages, macula status and duration based on OCT imaging. These findings highlight the potential of deep learning methods to support clinical decision-making and surgical planning in RRD management.

Hottest year in recorded history compounds global biodiversity risks

As climate change accelerates, effectively monitoring and managing the growing impacts on biodiversity is an urgent priority. Here, we identify the exposure of species to unprecedented heat to evaluate the potential impact of 2024—the hottest year on record—across >33,000 vertebrate species worldwide. One in six (5,368) species were exposed to unprecedented temperatures across >25% of their range—68% more species than in 2023. Most (81%) species exposed in 2023 were also exposed in 2024, potentially compounding risks. For the first time, widespread species were exposed to extreme temperatures across >10% of their ranges. We propose using these exposure estimates to inform monitoring and mitigation efforts to avoid the worst impacts of climate change.

Fully biocompatible, thermally drawn fiber supercapacitors for long-term bio-implantation

Optimization model for predicting quantum theoretic characteristics of hexagonal systems using temperature dependent graph theoretic estimators

CUB domain-containing protein 1 signaling dysregulates gemcitabine metabolism contributing to therapeutic resistance in T24 cells

Gemcitabine is commonly used in the standard first-line treatment of urothelial carcinoma (UC); however, the emergence of drug resistance significantly limits its clinical benefit. The present study aims to investigate the role of CUB domain-containing protein 1 (CDCP1) in mediating resistance to gemcitabine in UC cells. Gemcitabine-resistant T24 (T24-GR) cells exhibited downregulation of human equilibrative nucleoside transporter 1 and upregulation of cytidine deaminase, key regulators of gemcitabine metabolism, as well as increased CDCP1 expression. Notably, silencing CDCP1 reversed these resistance-associated expression patterns. Mechanistically, T24-GR cells displayed elevated expression of CDCP1 and increased phosphorylation of c-Src and PKCδ, indicating activation of downstream survival signaling. Overexpression of CDCP1 in T24-CD cells activated similar pathways and modulated regulators of gemcitabine metabolism. In contrast, CRISPR/Cas9-mediated knockout of CDCP1 in T24-CDKO cells suppressed c-Src/PKCδ signaling and increased sensitivity to gemcitabine-induced cytotoxicity. Using flow cytometry, we observed that treatment with gemcitabine induced apoptosis in parental T24 cells, as indicated by an increase in the sub-G1 population. In contrast, T24-GR and T24-CD cells showed minimal sub-G1 accumulation, suggesting resistance to gemcitabine-induced apoptosis. Western blot analysis revealed decreased levels of cleaved caspase-3 and cleaved poly(ADP-ribose) polymerase in T24-GR and T24-CD cells following gemcitabine exposure, whereas these markers were upregulated in parental T24 and T24-CDKO cells. Furthermore, the knockdown of CDCP1 and the utilization of c-Src/PKCδ signaling inhibitors in T24-GR cells led to the restoration of sensitivity to gemcitabine. By suppressing apoptosis and altering drug metabolism pathways, highlighting CDCP1 as a potential therapeutic target for overcoming gemcitabine resistance in UC.

Mid-Devonian ocean oxygenation enabled the expansion of animals into deeper-water habitats

The oxygenation history of Earth’s surface environments has had a profound influence on the ecology and evolution of metazoan life. It was traditionally thought that the Neoproterozoic Oxygenation Event enabled the origin of animals in marine environments, followed by their persistence in aerobic marine habitats ever since. However, recent studies of redox proxies (e.g., Fe, Mo, Ce, I) have suggested that low dissolved oxygen levels persisted in the deep ocean until the Late Devonian, when the first heavily wooded ligniophyte forests raised atmospheric O 2 to modern levels. Here, we present a Paleozoic redox proxy record based on selenium enrichments and isotope ratios in fine-grained siliciclastic sediments. Our data reveal transient oxygenation of bottom waters around the Ediacaran–Cambrian boundary, followed by predominantly anoxic deep-water conditions through the Early Devonian (419 to 393 Ma). In the Middle Devonian (393 to 382 Ma), our data document the onset of permanent deep-ocean oxygenation, coincident with the spread of woody biomass across terrestrial landscapes. This episode is concurrent with the ecological occupation and evolutionary radiation of large active invertebrate and vertebrate organisms in deeper oceanic infaunal and epifaunal habitats, suggesting that the burial of recalcitrant wood from the first forests sequestered organic carbon, increased deep marine oxygen levels, and was ultimately responsible for the “mid-Paleozoic marine revolution.”