Browse Articles

Biomass carbon emissions from nickel mining have significant implications for climate action

Author Correction: Quantifying forest disturbance regimes within caribou (Rangifer tarandus) range in British Columbia

Tipping point-induced abrupt shifts in East Asian hydroclimate since the Last Glacial Maximum

Retraction Note: Quadratic multiple regression model and spectral relaxation approach for carreau nanofluid inclined magnetized dipole along stagnation point geometry

Predicting cell morphological responses to perturbations using generative modeling

Abstract Advancements in high-throughput screenings enable the exploration of rich phenotypic readouts through high-content microscopy, expediting the development of phenotype-based drug discovery. However, analyzing large and complex high-content imaging screenings remains challenging due to incomplete sampling of perturbations and the presence of technical variations between experiments. To tackle these shortcomings, we present IMage Perturbation Autoencoder (IMPA), a generative style-transfer model predicting morphological changes of perturbations across genetic and chemical interventions. We show that IMPA accurately captures morphological and population-level changes of both seen and unseen perturbations on breast cancer and osteosarcoma cells. Additionally, IMPA accounts for batch effects and can model perturbations across various sources of technical variation, further enhancing its robustness in diverse experimental conditions. With the increasing availability of large-scale high-content imaging screens generated by academic and industrial consortia, we envision that IMPA will facilitate the analysis of microscopy data and enable efficient experimental design via in-silico perturbation prediction.

Application of fractal models for determining the relationship between REEs and faults in North Kochakali coal deposit, Central Iran

Lithium loss from pegmatites controlled by country rock temperature

An intelligent attention based deep convoluted learning (IADCL) model for smart healthcare security

Structural basis of THC analog activity at the Cannabinoid 1 receptor

Abstract Tetrahydrocannabinol (THC) is the principal psychoactive compound derived from the cannabis plant Cannabis sativa and approved for emetic conditions, appetite stimulation and sleep apnea relief. THC’s psychoactive actions are mediated primarily by the cannabinoid receptor CB 1 . Here, we determine the cryo-EM structure of HU210, a THC analog and widely used tool compound, bound to CB 1 and its primary transducer, G i1 . We leverage this structure for docking and 1000 ns molecular dynamics simulations of THC and 10 structural analogs delineating their spatiotemporal interactions at the molecular level. Furthermore, we pharmacologically profile their recruitment of G i and β-arrestins and reversibility of binding from an active complex. By combining detailed CB 1 structural information with molecular models and signaling data we uncover the differential spatiotemporal interactions these ligands make to receptors governing potency, efficacy, bias and kinetics. This may help explain the actions of abused substances, advance fundamental receptor activation studies and design better medicines.

Promotion of beta cell proliferation through DYRK kinase inhibition using the marine natural product breitfussin C

AbstractPro-inflammatory cytokines, like interleukin-1 beta and interferon gamma, are known to activate signalling pathways causing pancreatic beta cell death and dysfunction, contributing to the onset of diabetes. Targeting cytokine signalling pathways offers a potential strategy to slow or even halt disease progression, reducing reliance on exogenous insulin and improving glucose regulation. This study explores the protective and proliferative effects of breitfussin C (BfC), a natural compound isolated from the Arctic marine hydrozoan Thuiaria breitfussi, on pancreatic beta cells exposed to pro-inflammatory cytokines. Using the beta cell line RIN-M5F, we assessed the protective effects of BfC through a MTS assay for cell viability, caspase 3/7 activity for apoptosis, and EdU incorporation and cell cycle distribution for proliferation. Additionally, we investigated BfC’s inhibitory effects on the DYRK family of kinases using kinase activity and binding assays, western blotting, and docking simulations. Our findings reveal that BfC treatment effectively increases beta cell proliferation and counteracts cytokine-induced decrease in proliferation. The proliferative effect is associated with inhibition of DYRK kinases and a subsequent decrease in the cell cycle inhibitor p27KIP. These results suggest that BfC mediates beta cell-protective effect by promoting proliferation through DYRK inhibition, highlighting its potential as a molecular starting point for the development of a therapeutic agent against diabetes.

Advanced remote focus control in multicore meta-fibers through 3D nanoprinted phase-only holograms

AbstractIn this study, we present an unexplored approach for remote focus manipulation using 3D nanoprinted holograms integrated on the end face of multi-core single-mode fibers. This innovative method enables precise focus control within a monolithic metafiber device by allowing light coupled into any of the 37 cores to be precisely focused at predefined locations. Our approach demonstrates significant advances over conventional lenses and offers unique functionalities through computationally designed holograms. This research marks the first successful use of multi-core fibers for remote focus control via 3D nanoprinting, achieving crosstalk-free operation at visible wavelengths. Key findings include strong agreement between design, simulation, and experimental results, highlighting the potential of this technology to improve applications in fields such as biological optics, laser micromachining, telecommunications, and laser surgery. This work opens new avenues for the development of advanced optical systems with superior focus control capabilities.

Prognostic significance of albumin corrected anion gap in patients with acute pancreatitis: a novel perspective

Premature birth changes wiring constraints in neonatal structural brain networks

Abstract Structural brain organization in infancy is associated with later cognitive, behavioral, and educational outcomes. Due to practical limitations, such as technological advancements and data availability of fetal MRI, there is still much we do not know about the early emergence of topological organization. We combine the developing Human Connectome Project’s large infant dataset with generative network modeling to simulate the emergence of network organization over early development. Preterm infants had reduced connectivity, shorter connection lengths, and lower network efficiency compared to term-born infants. The models were able to recapitulate the organizational differences between term and preterm networks and revealed that preterm infant networks are better simulated under tighter wiring constraints than term infants. Tighter constraints for preterm models resulted in shorter connection lengths while preserving vital, long-range rich club connections. These simulations suggest that preterm birth is associated with a renegotiation of the cost-value wiring trade-off that may drive the emergence of different network organization.

Lightweight multidimensional feature enhancement algorithm LPS-YOLO for UAV remote sensing target detection

Structural basis of RNA polymerase complexes in African swine fever virus

The effect of mortality salience and early-life maternal care on neuroendocrine, autonomic, and psychological stress responses

AbstractAdverse early-life experiences alter the regulation of major stress systems such as the hypothalamic-pituitary-adrenal (HPA) axis. Low early-life maternal care (MC) has repeatedly been related to blunted cortisol stress responses. Likewise, an acutely increased awareness of mortality (mortality salience [MS]) also has been shown to blunt cortisol responses. In this study we investigated the effects of early-life MC and a potential interaction with MS on HPA axis responsivity, as well as autonomic and subjective stress responses. Seventy-three women (Mage=21.56, SDage=2.85) with self-reported low (n = 30) or high (n = 43) early-life MC, underwent the Trier Social Stress Test for groups. Before, they were asked to briefly contemplate either death (mortality condition, n = 38) or sleep (control condition, n = 35). Salivary cortisol and alpha amylase, heart rate variability and subjective stress levels were assessed repeatedly. Multilevel mixed models confirmed an effect of MC on stress system regulation, indicated by blunted cortisol responses and overall reduced heart rate variability in low versus high MC individuals. Moreover, we found an interaction between MS and MC concerning subjective stress and autonomic measures. Specifically, low MC individuals in the control compared to the mortality condition showed both overall higher subjective stress levels, and less increase in heart rate variability following stress. These findings demonstrate the enduring impact of low early-life MC and the potential role of acute mortality primes on the regulation of stress systems in healthy women.

Reconstitution of human DNA licensing and the structural and functional analysis of key intermediates

Abstract Human DNA licensing initiates replication fork assembly and DNA replication. This reaction promotes the loading of the hMCM2-7 complex on DNA, which represents the core of the replicative helicase that unwinds DNA during S-phase. Here, we report the reconstitution of human DNA licensing using purified proteins. We showed that the in vitro reaction is specific and results in the assembly of high-salt resistant hMCM2-7 double-hexamers. With ATPγS, an hORC1-5-hCDC6-hCDT1-hMCM2-7 (hOCCM) assembles independent of hORC6, but hORC6 enhances double-hexamer formation. We determined the hOCCM structure, which showed that hORC-hCDC6 recruits hMCM2-7 via five hMCM winged-helix domains. The structure highlights how hORC1 activates the hCDC6 ATPase and uncovered an unexpected role for hCDC6 ATPase in complex disassembly. We identified that hCDC6 binding to hORC1-5 stabilises hORC2-DNA interactions and supports hMCM3-dependent recruitment of hMCM2-7. Finally, the structure allowed us to locate cancer-associated mutations at the hCDC6-hMCM3 interface, which showed specific helicase loading defects.

Electrical conductivity in the mantle transition zone beneath eastern Central Asian Orogenic Belt revealed by geomagnetic signals

KLF5 loss sensitizes cells to ATR inhibition and is synthetic lethal with ARID1A deficiency

AbstractATR plays key roles in cellular responses to DNA damage and replication stress, a pervasive feature of cancer cells. ATR inhibitors (ATRi) are in clinical development for treating various cancers, including those with high replication stress, such as is elicited by ARID1A deficiency, but the cellular mechanisms that determine ATRi efficacy in such backgrounds are unclear. Here, we have conducted unbiased genome-scale CRISPR screens in ARID1A-deficient and proficient cells treated with ATRi. We found that loss of transcription factor KLF5 has severe negative impact on fitness of ARID1A-deficient cells while hypersensitising ARID1A-proficient cells to ATRi. KLF5 loss induced replication stress, DNA damage, increased DNA-RNA hybrid formation, and genomic instability upon ATR inhibition. Mechanistically, we show that KLF5 protects cells from replication stress, at least in part through regulating BRD4 recruitment to chromatin. Overall, our work identifies KLF5 as a potential target for eradicating ARID1A-deficient cancers.

Attention-based deep learning for accurate cell image analysis