Browse Articles

Measurements of stable ruthenium fission products in nuclear reactor fuel samples

Endogenous LRRK2 and PINK1 function in a convergent neuroprotective ciliogenesis pathway in the brain

Mutations in Leucine-rich repeat kinase 2 (LRRK2) and PTEN-induced kinase 1 (PINK1) are associated with familial Parkinson’s disease (PD). LRRK2 phosphorylates Rab guanosine triphosphatase (GTPases) within the Switch II domain while PINK1 directly phosphorylates Parkin and ubiquitin (Ub) and indirectly induces phosphorylation of a subset of Rab GTPases. Herein we have crossed LRRK2 [R1441C] mutant knock-in mice with PINK1 knock-out (KO) mice and report that loss of PINK1 does not impact endogenous LRRK2-mediated Rab phosphorylation nor do we see significant effect of mutant LRRK2 on PINK1-mediated Rab and Ub phosphorylation. In addition, we observe that a pool of the Rab-specific, protein phosphatase family member 1H phosphatase, is transcriptionally up-regulated and recruited to damaged mitochondria, independent of PINK1 or LRRK2 activity. Parallel signaling of LRRK2 and PINK1 pathways is supported by assessment of motor behavioral studies that show no evidence of genetic interaction in crossed mouse lines. Previously we showed loss of cilia in LRRK2 R1441C mice and herein we show that PINK1 KO mice exhibit a ciliogenesis defect in striatal cholinergic interneurons and astrocytes that interferes with Hedgehog induction of glial derived-neurotrophic factor transcription. This is not exacerbated in double-mutant LRRK2 and PINK1 mice. Overall, our analysis indicates that LRRK2 activation and/or loss of PINK1 function along parallel pathways to impair ciliogenesis, suggesting a convergent mechanism toward PD. Our data suggest that reversal of defects downstream of ciliogenesis offers a common therapeutic strategy for LRRK2 or PINK1 PD patients, whereas LRRK2 inhibitors that are currently in clinical trials are unlikely to benefit PINK1 PD patients.

Performance prediction and optimization of a high-efficiency tessellated diamond fractal MIMO antenna for terahertz 6G communication using machine learning approaches

The mediating role of psychological equilibrium in the relationship between dietary variety and self-reported health among older adults in rural China

Growth decline in European beech associated with temperature-driven increase in reproductive allocation

Climate change is impacting forests in complex ways, with indirect effects arising from interactions between tree growth and reproduction often overlooked. Our 43-y study of European beech ( Fagus sylvatica ) showed that rising summer temperatures since 2005 have led to more frequent seed production events. This shift increases reproductive effort but depletes the trees’ stored resources due to insufficient recovery periods between seed crops. Consequently, annual tree ring increments have declined by 28%, dropping from a stable average of 1.60 mm y −1 between 1980 and 2005 to 1.16 mm y −1 thereafter. Importantly, this growth decline occurred without an accompanying trend in summer drought, indicating that altered reproductive patterns—not moisture stress—are driving the reduction. This creates a “perfect storm”: Increased reproductive effort drains resources, viable seed output falls due to the loss of mast-seeding benefits via pollination and lower seed predation, and the ongoing growth decline reduces current carbon uptake and future reproductive potential. These compounding factors threaten the sustainability of Europe’s most widespread forest tree. Our findings unveil a critical yet underrecognized indirect mechanism by which climate change endangers forest ecosystems, emphasizing the need to consider interactions between demographic processes when assessing species vulnerability to climate change.

Three-dimensional ultrastructural analysis of human skin with the arrector pili muscle interacting with the hair follicle epithelium

Abstract This study developed a three-dimensional ultrastructural analysis application using serial block-face scanning electron microscopy (SBF-SEM) to investigate surgically acquired human skin tissues containing the arrector pili muscle. We utilized the en bloc staining, including reduced osmium, thiocarbohydrazide, and lead aspartate, as well as the embedding using a carbon-based conductive resin. Next, we obtained serial images with SBF-SEM. The results revealed dense nerve fiber networks branching from nearby nerve fiber bundles outside the muscle and running among muscle fibers. Additionally, the dense nerve network running through and along arrector pili muscle fibers rarely penetrates the connective tissues between smooth muscle fibers and epithelial cells. Furthermore, in the observation area, no individual smooth muscle fibers formed adhesion structures with the epithelial cells of the hair follicle, ending in the dermal extracellular matrix near the epithelial cells. These results indicate the usefulness of this approach for three-dimensional ultrastructural analyses of human skin tissues comprising follicular units and revealing structural changes in skin tissues, especially the arrector pili muscle and nerve fibers with hair follicular epithelium, in aging and diseased conditions.

Retinoic acid antagonizes estrogen signaling to maintain adult uterine cell fate

Classical tissue recombination experiments demonstrate that cell-fate determination along the anterior–posterior axis of the Müllerian duct occurs prior to postnatal day 7 in mice. However, little is known about how these cell types are maintained in adults. In this study, we provide genetic evidence that a balance between antagonistic retinoic acid (RA) and estrogen signaling activity is required to maintain simple columnar cell fate in adult uterine epithelium. Transdifferentiation of simple columnar uterine epithelium into stratified cervicovaginal-like epithelium was observed in three related mouse genetic models, in which RA signaling was perturbed in the postnatal uterus. Single-cell RNA sequencing analysis identified the transformed epithelial cell populations and revealed extensive immune cell infiltration resulting from loss of RA signaling. Surprisingly, disruption of RA signaling led to dysregulated expression of a substantial number of estrogen target genes, suggesting that these two pathways may functionally oppose each other in determining and maintaining uterine epithelial cell fate. Consistent with this model, neonatal exposure to the strong synthetic estrogen, diethylstilbestrol, downregulated expression of a group of RA target genes and led to epithelial stratification and immune cell infiltration in wild-type uterus. Treating RA receptor triple conditional knockout pups with fulvestrant, an estrogen antagonist, reestablished the balance between the two signaling pathways, and effectively prevented the transformation of mutant simple columnar epithelia to metaplastic stratified epithelia. These findings implicate an essential role for RA signaling in maintaining uterine cytodifferentiation by antagonizing estrogen signaling in the postnatal uterus.

Perceptual space and adjective rating of 2.5D tactile patterns

Abstract The present study investigates the human haptic perception of 2.5D tactile patterns based on adjective ratings and how physical factors, such as the bump diameter of the pattern or material, affect their tactile perception. We designed fifty tactile patterns by varying the pattern’s bump diameter, pattern uniformity, and material and evaluated the effect of the parameters on haptic perception by conducting a couple of human subject experiments. In Experiment 1, the perceived intensities of the tactile patterns were tested for a total of ten properties (adjective pairs). The experimental results indicate significant effects of the factors, the bump diameter, pattern type, and material on the perceived intensities of the 2.5D patterns. In Experiment 2, a cluster sorting of the tactile patterns was conducted, and a haptic perceptual space was constructed with an MDS (multi-dimensional scaling). The results indicate a grouping of the samples by bump diameter and an effect of sample pattern uniformity for larger 2.5D tactile patterns. Overall, the present study showed that bump diameter, pattern type, and material significantly affected the perception of 2.5D tactile patterns based on the adjective ratings, and the 2.5D patterns could be grouped by the pattern’s bump diameter and uniformity.

The actin filament pointed-end depolymerase Srv2/CAP depolymerizes barbed ends, displaces capping protein, and promotes formin processivity

Cellular actin networks exhibit distinct assembly and disassembly dynamics, primarily driven by multicomponent reactions occurring at the two ends of actin filaments. While barbed ends are recognized as the hotspot for polymerization, depolymerization is predominantly associated with pointed ends. Consequently, mechanisms promoting barbed-end depolymerization have received relatively little attention. Here, using microfluidics-assisted three-color single-molecule imaging, we reveal that cyclase-associated protein (CAP), long known for its roles in nucleotide exchange and pointed-end depolymerization, also acts as a processive depolymerase at filament barbed ends. CAP molecules track barbed ends for several minutes, inducing depolymerization rates of up to 60 subunits per second. Importantly, CAP modulates barbed-end dynamics even under cytosol-mimicking assembly promoting conditions. We further show that CAP can colocalize with both formin and capping protein (CP) at barbed ends. CAP enhances formin processivity by 10-fold, allowing CAP–formin complexes to track fast-elongating barbed ends. In contrast, CAP destabilizes CP-bound barbed ends and accelerates dissociation of CP by fourfold. Our findings, combined with CAP’s previously reported activities, firmly establish CAP as a key regulator of cellular actin dynamics.

Association of loneliness with the risk of pain in older Chinese adults

Organismal complexity strongly correlates with the number of protein families and domains

In the pregenomic era, scientists were puzzled by the observation that haploid genome size (the C-value) did not correlate well with organismal complexity. This phenomenon, called the “C-value paradox,” is mostly explained by the fact that protein-coding genes occupy only a small fraction of eukaryotic genomes. When the first genome sequences became available, scientists were even more surprised by the fact that the number of genes (G-value) was also a poor predictor of complexity, which gave rise to the “G-value paradox.” The proposed explanations usually invoke mechanisms that increase the information content of each individual gene (protein–protein interactions, intrinsic disorder, posttranslational modifications, alternative splicing, etc.). Less attention has been paid to mechanisms that increase the amount of genetic material but do not increase (or not to the same extent) the amount of information encoded in the genome, such as gene duplication and domain shuffling. Proteins belonging to the same family and/or sharing the same domains often carry out similar or even redundant functions. We thus hypothesized that an organism’s number of different protein families and domains should be suitable predictors of organismal complexity. In agreement with our hypothesis, we observed that the number of protein families, clans, domains, and motifs increases from simple to progressively more complex organisms. In addition, these metrics correlate with the number of cell types better than and independently of the number of protein-coding genes and several previously proposed predictors of organismal complexity. Our observations have the potential to represent a resolution to the G-value paradox.

Unravelling anti-cancer properties of solanaceous extracts using GC–MS and HPLC

Triethylamine-mediated protonation–deprotonation unlocks dual-drug self assembly to suppress breast cancer progression and metastasis

Carrier-free nanomedicines exhibited significant potential in elevating drug efficacy and safety for tumor management, yet their self assembly typically relied on chemical modifications of drugs or the incorporation of surfactants, thereby compromising the drug’s inherent pharmacological activity. To address this challenge, we proposed a triethylamine (TEA)-mediated protonation–deprotonation strategy that enabled the adjustable-proportion self assembly of dual drugs without chemical modification, achieving nearly 100% drug loading capacity. Molecular dynamic simulations, supported by experiment evidence, elucidated the underlying self-assembly mechanism. Specifically, TEA facilitated the deprotonation of Doxorubicin (Dox) and α-Tocopherol succinate (α-tos), causing Dox to transition from a hydrophilic to a hydrophobic state, while simultaneously increasing the hydrophilicity of α-tos. This allowed for a fine-tuned balance between the hydrophilic and hydrophobic properties of the two compounds, enabling their precise self assembly into a carrier-free nanomedicine (DT) with a tailored drug ratio. The engineered DT demonstrated the ability to accumulate at the tumor sites and release its therapeutic drugs in a controlled manner. The combination of Dox and α-tos synergistically generated reactive oxygen species and modulated the expression of tumor matrix metalloproteinase-9, leading to superior antitumor efficacy without significant metastasis, while maintaining excellent safety profiles. Our findings provided unique perspectives on the design of carrier-free nanomedicine for cancer therapy, thereby laying a solid foundation for its potential clinical translation.

Association between 5-item modified frailty index and clinical outcomes in elderly rectal cancer patients after radical surgery

Structural insights into the role of reduced cysteine residues in SOD1 amyloid filament formation

The formation of superoxide dismutase 1 (SOD1) filaments has been implicated in amyotrophic lateral sclerosis (ALS). Although the disulfide bond formed between Cys57 and Cys146 in the active state has been well studied, the role of the reduced cysteine residues, Cys6 and Cys111, in SOD1 filament formation remains unclear. In this study, we investigated the role of reduced cysteine residues by determining and comparing cryoelectron microscopy (cryo-EM) structures of wild-type (WT) and C6A/C111A SOD1 filaments under thiol-based reducing and metal-depriving conditions, starting with protein samples possessing enzymatic activity. The C6A/C111A mutant SOD1 formed filaments more rapidly than the WT protein. The mutant structure had a unique paired-protofilament arrangement, with a smaller filament core than that of the single-protofilament structure observed in WT SOD1. Although the single-protofilament form developed more slowly, cross-seeding experiments demonstrated the predominance of single-protofilament morphology over paired protofilaments, regardless of the presence of the Cys6 and Cys111 mutations. These findings highlight the importance of the number of amino acid residues within the filament core in determining the energy requirements for assembly. Our study provides insights into ALS pathogenesis by elucidating the initiation and propagation of filament formation, which potentially leads to deleterious amyloid filaments.

Optical hausdorff quantum energy of spherical magnetic particles

Suppressing APOE4-induced neural pathologies by targeting the VHL–HIF axis

The ε4 variant of human apolipoprotein E ( APOE4 ) is a key genetic risk factor for neurodegeneration in Alzheimer’s disease and elevated all-cause mortality in humans. Understanding the factors and mechanisms that can mitigate the harmful effects of APOE4 has significant implications. In this study, we find that inactivating the VHL-1 (Von Hippel–Lindau) protein can suppress mortality, neural and behavioral pathologies caused by transgenic human APOE4 in Caenorhabditis elegans . The protective effects of VHL-1 deletion are recapitulated by stabilized HIF-1 (hypoxia-inducible factor), a transcription factor degraded by VHL-1. HIF-1 activates a genetic program that safeguards against mitochondrial dysfunction, oxidative stress, proteostasis imbalance, and endolysosomal rupture—critical cellular events linked to neural pathologies and mortality. Furthermore, genetic inhibition of Vhl reduces cerebral vascular injury and synaptic lesions in APOE4 mice, suggesting an evolutionarily conserved mechanism. Thus, we identify the VHL–HIF axis as a potent modulator of APOE4 -induced neural pathologies and propose that targeting this pathway in nonproliferative tissues may curb cellular damage, protect against neurodegeneration, and reduce tissue injuries and mortality.

ECG heartbeat classification using progressive moving average transform

Abstract This paper presents the Progressive Moving Average Transform (PMAT), a novel signal transformation method for converting time-domain signals into 2D representations by progressively computing Moving Averages (MAs) with varying window sizes. The approach aims to enhance signal analysis and classification, particularly in the context of heartbeat classification. Our approach integrates PMAT with a 2D-Convolutional Neural Network (CNN) model for the classification of ECG heartbeat signals. The 2D-CNN model is employed to extract meaningful features from the transformed 2D representations and classify them efficiently. To assess the effectiveness of our approach, we conducted extensive simulations utilizing three widely-used databases: the MIT-BIH database and the INCART database, chosen to cover a wide range of heartbeats. Our experiments involved classifying more than 6 heartbeat types grouped into three main classes. Results indicate high accuracy and F1-scores, with 99.09% accuracy and 92.13% F1-score for MIT-BIH, and 98.37% accuracy and 79.37% F1-score for INCART. Notably, the method demonstrates robustness when trained on one database and tested on another, achieving accuracy rates exceeding 95% in both cases. Specifically, the method achieves 96% accuracy when trained on MIT-BIH and tested on the ST-T European database. These findings underscore the effectiveness and stability of the proposed approach in accurately classifying heartbeats across different datasets, suggesting its potential for practical implementation in medical diagnostics and healthcare systems.

A planar-sheet nongraphitic zero-bandgap sp ² carbon phase made by the low-temperature reaction of γ-graphyne

The highest sheet symmetry form of graphyne, with one triple bond between each neighboring hexagon in graphene, irreversibly transforms exothermically at ambient pressure and low temperatures into a nongraphitic, planar-sheet, zero-bandgap phase consisting of intrasheet-bonded sp 2 carbons. The synthesis of this sp 2 carbon phase is demonstrated, and other carbon phases are described for possible future synthesis from graphyne without breaking graphyne bonds. While measurements and theory indicate that the reacting graphyne becomes nonplanar because of sheet wrinkling produced by dimensional mismatch between reacted and nonreacted sheet regions, sheet planarity is regained when the reaction is complete. Although the observed elimination of triple bonds to make parallel planar sp 2 carbon sheets likely requires ordered transformation within each sheet, diffraction data for reacted multisheet stacks indicate that the relative lateral positions of neighboring sheets are disordered, as predicted, since no crystalline diffraction peak (other than for the intersheet spacing) is observed.

Carboxypeptidase B1 in dialyzed chronic kidney disease patients