Physical immune escape: Weakened mechanical communication leads to escape of metastatic colorectal carcinoma cells from macrophages.

The significance of biochemical cues in the tumor immune microenvironment in affecting cancer metastasis is well established, but the role of physical factors in the microenvironment remains largely unexplored. In this article, we investigated how the mechanical interaction between cancer cells and immune cells, mediated by extracellular matrix (ECM), influences immune escape of cancer cells. We focus on the mechanical regulation of macrophages' targeting ability on two distinct types of colorectal carcinoma (CRC) cells with different metastatic potentials. Our results show that macrophages can effectively target CRC cells with low metastatic potential, due to the strong contraction exhibited by the cancer cells on the ECM, and that cancer cells with high metastatic potential demonstrated weakened contractions on the ECM and can thus evade macrophage attack to achieve immune escape. Our findings regarding the intricate mechanical interactions between immune cells and cancer cells can serve as a crucial reference for further exploration of cancer immunotherapy strategies.

Health risk assessment of heavy metal(loid)s in road dust via dermal exposure pathway from a low latitude plateau provincial capital city: The importance of toxicological verification.

The human health risk assessment through the dermal exposure of metal (loid)s in dust from low latitude and high geological background plateau cities was largely unknown. In this study, the road dust samples were harvested from a typical low-latitude plateau provincial capital city Kunming, Southwest China. The total concentration and dermal bioaccessibility of heavy metal (loid)s in road dust were determined, and their health risks as well as cytotoxicity on human skin keratinocytes were also assessed. The average concentrations of As (28.5 mg/kg), Cd (2.65 mg/kg), Mn (671 mg/kg), and Zn (511 mg/kg) exceeded the soil background values. Arsenic had the highest bioaccessibility after 2 h (3.79%), 8 h (4.24%), and 24 h (16.6%) extraction. The dermal pathway when bioaccessibility is considered has a higher hazard quotient than the conventional method using total metal(loid)s in the dust. In addition, toxicological verification suggested that the dust extracts suppressed the cell viability, increased the reactive oxygen species (ROS) level and DNA damage, and eventually activated the mitochondria-mediated apoptosis pathway, evidenced by the upregulation of Caspase-3/9, Bax, and Bak-1. Cadmium was positively correlated with the mRNA expression of Bax. Taken together, our data indicated that both dermal bioaccessibility and cytotoxicity should be considered for accurate human skin health risk assessment of heavy metal(loid)s in road dust, which may provide new insight for accurate human health risk assessment and environmental management.

How to enhance the polarization intensity of two-dimensional sliding ferroelectricity for hexagonal boron- or nitrogen-based binary compounds?

In recent years, two-dimensional (2D) sliding ferroelectric (SFE) materials have received widespread attention due to their unique ferroelectric mechanism, which exists in van der Waals bilayer and multilayer systems. However, compared to traditional ferroelectric materials, their relatively weak polarization intensity and low energy barrier limit their practical applications. Here, using the first-principles calculations, we focus on hexagonal layered structures formed by group III-V elements and propose a design principle that utilizes bilayer materials composed of elements with significant differences in atomic electronegativity to address this issue. The results show that materials composed of two atoms with significant electronegativity differences can effectively increase the polarization intensity and possess moderate energy barriers. Furthermore, the polarization intensity can be effectively modulated by adjusting interlayer distance. The research findings have important significance for the exploration of other 2D SFE materials with high polarization intensity.

Inhibitor PF-04691502 works as a senolytic to regulate cellular senescence.

Aging is a gradual process of natural change that occurs after reaching sexual maturity. It is also a known risk factor for many chronic diseases. Recent research has shown that senolytics can extend the lifespans and health spans of model organisms, and they have also been demonstrated effective in treating age-related diseases. In this study, we conducted a high-throughput screening of 156 drugs that targeted the PI3K/AKT/mTOR pathway to identify potential senolytic medications. Among these drugs, PF-04691502 was selected for further investigation to understand its molecular mechanism of action. Our findings indicate that PF-04691502, a dual inhibitor of PI3K/AKT and mTOR, specifically eliminates senescent cells. It reduces the expression levels of key markers of cellular senescence, such as SA-ß-Gal, senescence-associated secretory phenotypes (SASPs) and p16INK4a. Additionally, PF-04691502 inhibits the phosphorylation of S6K and AKT, leading to the apoptosis of senescent cells. These results suggest that PF-04691502 holds promise as a new senolytic drug. This paper provides important insights into the potential application of PF-04691502 in the study of cell senescence.

Road dust exposure and human corneal damage in a plateau high geological background provincial capital city: Spatial distribution, sources, bioaccessibility, and cytotoxicity of dust heavy metals.

Ocular surface diseases are common in the plateau city, Kunming China, the continued daily exposure to heavy metals in dust may be an important inducement. In this study, the 150 road dust samples from five functional areas in Kunming were collected. The concentrations, distribution, possible sources, and bioaccessibility of heavy metals were analyzed. The adverse effects of dust extracts on human corneal epithelial cells and the underlying mechanisms were also assessed. The concentrations (mg·kg-1) of As (19.1), Cd (2.67), Cr (90.5), Cu (123), Pb (78.4), and Zn (389) in road dust were higher than the soil background, with commercial and residential areas showing the highest pollution. Their bioaccessibility in artificial tears was As (6.59 %) > Cu (5.11 %) > Ni (1.47 %) > Cr (1.17 %) > Mn (0.84 %) > Cd (0.76 %) > Zn (0.50 %) > Pb (0.31 %). The two main sources of heavy metals included tire and mechanical abrasion (24.5 %) and traffic exhaust (21.6 %). All dust extracts induced cytotoxicity, evidenced by stronger inhibition of cell viability, higher production of ROS, and altered mRNA expression of antioxidant enzymes and cell cycle-related genes, with commercial- areas-2 (CA2)-dust extract showing the greatest oxidative damage and cell cycle arrest. Our data may provide new evidence that dust exposure in high geological background cities could trigger human cornea damage.

Self-efficacy and well-being in the association between caregiver burden and sleep quality among caregivers of elderly patients having multiple chronic conditions in rural China: a serial multiple mediation analysis.

BACKGROUND: Caregivers of elderly patients with multiple chronic conditions have heavy caregiver burden and poor sleep quality, which has an important impact on both caregivers and patients. This study aimed to examine among rural caregivers of elderly patients who have multiple chronic conditions in China, whether self-efficacy and well-being mediate the link between caregiver burden and sleep quality. METHODS: The study recruited 325 caregivers of elderly patients having multiple chronic conditions in rural China. Several measures including the Caregiver Burden Inventory (CBI), Athens Insomnia Scale (AIS), General Self-Efficacy Scale (GSES) and Index of Well-Being (IWB) were utilized to collect data. Structural equation modeling was employed to study the relationships among caregiver burden, sleep quality, self-efficacy, as well as well-being. RESULTS: Significant correlations were found between the measured variables (each p < 0.01). Self-efficacy and well-being acted as mediators in the link between caregiver burden and sleep quality, accounting for 10.94% and 15.63% of the total effect, respectively. In addition, self-efficacy and well-being had a serial multiple mediating effect in the association between caregiver burden and sleep quality, with this mediating pathway, explaining 9.93% of the total effect. CONCLUSIONS: Caregivers of elderly patients having multiple chronic conditions in rural China experienced poor sleep quality due to the caregiver burden. Self-efficacy and well-being had serial mediating roles on the relationship between caregiver burden and sleep quality. Effective interventions should be developed to improve self-efficacy and well-being of caregivers, reduce their caregiver burden and, eventually, improve their sleep quality.

The adaptor protein 14-3-3zeta modulates intestinal immunity and aging in Drosophila.

The proteins that coordinate the complex transcriptional networks of aging have not been completely documented. Protein 14-3-3zeta is an adaptor protein that coordinates signaling and transcription factor networks, but its function in aging is not fully understood. Here, we showed that the protein expression of 14-3-3zeta gradually increased during aging. High levels of 14-3-3zeta led to shortened lifespan and imbalance of intestinal immune homeostasis in Drosophila, but the decrease in 14-3-3zeta protein levels by RNAi was able to significantly promote the longevity and intestinal immune homeostasis of fruit flies. Importantly, we demonstrate that adult-onset administration of TIC10, a compound that reduces the aging-related AKT and extracellular signal-regulated kinase (ERK) signaling pathways, rescues the shortened lifespan of 14-3-3zeta-overexpressing flies. This finding suggests that 14-3-3zeta plays a critical role in regulating the aging process. Our study elucidates the role of 14-3-3zeta in natural aging and provides the rationale for subsequent 14-3-3zeta-based antiaging research.

Sorcin regulate pyroptosis by interacting with NLRP3 inflammasomes to facilitate the progression of hepatocellular carcinoma.

A high recurrence rate and easy metastasis are two prominent clinical features of hepatocellular carcinoma (HCC), which is also the most common cause of cancer-related death. However, the molecular pathogenesis of HCC remains unclear. Soluble resistance-related calcium-binding protein (Sorcin) is highly expressed in a variety of tumor cell lines and multidrug-resistant cell lines and participates in the malignant progression of tumors by regulating apoptosis. Pyroptosis is also a form of programmed cell death that plays a crucial role in exerting tumor suppression function and evoking anti-tumor immune responses. However, there is no consensus that Sorcin promotes HCC progression by regulating pyroptosis. Our study manifested that Sorcin was considerably upregulated, whereas pyroptosis-associated proteins were significantly decreased in HCC tissues and cells. Sorcin silencing attenuated the proliferation, migration, and invasion of HCC cells. Knockdown of Sorcin activates pyroptosis, and overexpression of Sorcin inhibits pyroptosis, yet has no significant effect on apoptosis, ferroptosis, and autophagy in HCC cells. Furthermore, coimmunoprecipitation and immunofluorescence assays revealed that Sorcin interacted with NLRP3 inflammasome to regulate pyroptosis in HCC cells. Then, the NLRP3 inhibitor MCC950 inhibited the activation of Sorcin knockdown-induced pyroptosis and reversed the effect of Sorcin silencing-induced weakening of malignant biological behavior in HCC. Similarly, suppression of Caspase-1 reversed the inhibitory effect of Sorcin knockdown on the malignant progression of HCC via knockdown of Caspase-1 or the inhibitor VX765. Consistent with the in vitro results, the nude mouse experiment showed that Sorcin knockdown inhibited the growth of HCC by activating pyroptosis, while Caspase-1 knockdown partially restored the growth inhibition caused by Sorcin knockdown. Collectively, high Sorcin expression in HCC negatively regulates pyroptosis by interacting with the NLRP3 inflammasome to promote HCC proliferation, migration, and invasion. The results of this study provide a scientific basis for Sorcin as a new biomarker and potential therapeutic target for HCC.

A simple green method for in-situ selective extraction of Li from spent LiFePO4 batteries by synergistic effect of deep-eutectic solvent and ozone.

Efficient and clean extraction lithium (Li) from spent LiFePO4 batteries (LIBs) still remains a challenge. In this paper, a green deep eutectic solvent (DES) based on ethylene glycol (EG) and choline chloride (CC), combined with ozone (O3) from air source, realized highly selective leaching Li from LiFePO4 in situ for the first time. The influence of experimental parameters on Li and Fe leaching efficiencies (ηLi, ηFe) were studied by orthogonal and single-factor tests, and ηLi ≥ 92.2% while ηFe ≤ 1.6% were obtained under the optimal conditions (6 h, 20 g/L, 8EG:1CC, 40 °C). The impurity Fe in the filtrate was completely precipitated as amorphous FePO4·3H2O after heating (150 °C, 0.5 h), achieving a pure Li-solution. The leaching mechanism elucidated that the synergistic effect (acidification, replacement and oxidation reaction) between the DES and O3 determined the phase transition of Li and Fe, promoting the efficient selective extraction of Li and in-situ separation of Fe (FePO4). The average ηLi and ηFe were separately 85.4% and 2.0% after ten cycles of the 8EG:1CC, indicative of its' excellent reusability. Meanwhile, LiCl was recovered from the filtrate. This process avoided the use of strong acid/alkali and discharge of waste water, providing fresh perspectives on the green recovery of spent LiFePO4 batteries.

Effects on the Microstructure Evolution and Properties of Graphene/Copper Composite during Rolling Process.

Rolling treatments have been identified as a promising fabrication and deformation processing technique for graphene/metal composites with high performance. However, it is still a challenge to choose appropriate rolling parameters to achieve high strength, ductility and electrical conductivity of the composite simultaneously. In this study, graphene/Cu composites were prepared with an in situ growth method and rolling treatment. The effects of rolling deformation and temperature on the microstructural evolution of graphene and Cu grains, interface bonding between graphene and the matrix, mechanical and electrical properties were systemically investigated. The cold-rolled composite with 85% deformation displayed a maximum ultimate strength of 548 MPa, a high elongation of 8.8% and a good electrical conductivity of 86.2% IACS. This is attributed to oriented graphene arrangement and matrix grain refinement. Our research provides a comprehensive understanding for the rolling behavior of graphene/Cu composites, and can promote the development of graphene-based composites with high performance.

Three-Dimensional Macroporous rGO-Aerogel-Based Composite Phase-Change Materials with High Thermal Storage Capacity and Enhanced Thermal Conductivity.

Three-dimensional porous network encapsulation strategy is an effective means to obtain composite phase-change materials (PCMs) with high heat storage capacity and enhanced thermal conductivity. Herein, macroporous reduced graphene oxide (rGO) aerogels with adjustable pore size are prepared by the emulsion template method and hydrothermal reduction process. Further, the shape-stabilized rGO-aerogel-based composite PCMs are constructed after the combination of 3D porous rGO supports and paraffin wax (PW) through vacuum melting infiltration. By regulating the pore structure of the rGO aerogel network, the rGO-based composite PCMs achieve excellent energy storage properties with a phase-change enthalpy of 179.94 J/g for the loading amount of 95.61 wt% and an obvious enhancement in thermal conductivity of 0.412 W/m-1·K-1, which is 54.89% higher than pristine PW and enduring thermal cycling stability. The obtained macroporous rGO-aerogel-based composite PCMs with high thermal storage and heat transfer performance effectively broaden the application of PCMs in the field of thermal energy storage.

A novel green deep eutectic solvent for one-step selective separation of valuable metals from spent lithium batteries: Bifunctional effect and mechanism.

This study used a novel green bifunctional deep eutectic solvent (DES) containing ethylene glycol (EG) and tartaric acid (TA) for the efficient and selective recovery of cathode active materials (LiCoO2 and Li3.2Ni2.4Co1.0Mn1.4O8.3) used in lithium-ion batteries through one-step in-situ separation of Li and Co/Ni/Mn. The effects of leaching parameters on the recovery of Li and Co (ηLi and ηCo) from LiCoO2 are discussed, and the optimal reaction conditions are verified, for the first time, using a response surface method. The results demonstrate that under optimal conditions (120 °C, 12 h, EG to TA mole ratio (MEG:TA) of 5:1, and solid to liquid ratio (RS/L) of 20 g/L), the ηLi from LiCoO2 reached 98.34%, and Co was formed as a purple precipitate of cobalt tartrate (CoC4H4O6), which was transformed into a black powder of Co3O4 after calcination. Notably, the ηLi for DES 5 EG:1 TA was maintained at 80% after five cycles, indicating good cyclic stability. When the as-prepared DES was used to leach the spent active material Li3.2Ni2.4Co1.0Mn1.4O8.3, the in-situ selective separation of Li (ηLi = 98.86%) from other valuable elements such as Ni, Mn, and Co, was achieved, indicating the good selective leaching capacity and practical application potential of the DES.

Oridonin Inhibits Mycobacterium marinum Infection-Induced Oxidative Stress In Vitro and In Vivo.

Prior to the COVID-19 pandemic, tuberculosis (TB) was the leading cause of death globally attributable to a single infectious agent, ranking higher than HIV/AIDS. Consequently, TB remains an urgent public health crisis worldwide. Oridonin (7a,20-Epoxy-1a,6b,7,14-tetrahydroxy-Kaur-16-en-15-one Isodonol, C20H28O6, Ori), derived from the Rabdosia Rrubescens plant, is a natural compound that exhibits antioxidant, anti-inflammatory, and antibacterial properties. Our objective was to investigate whether Ori's antioxidant and antibacterial effects could be effective against the infection Mycobacterium marinum (Mm)-infected cells and zebrafish. We observed that Ori treatment significantly impeded Mm infection in lung epithelial cells, while also suppressing inflammatory response and oxidative stress in Mm-infected macrophages. Further investigation revealed that Ori supplementation inhibited the proliferation of Mm in zebrafish, as well as reducing oxidative stress levels in infected zebrafish. Additionally, Ori promoted the expression of NRF2/HO-1/NQO-1 and activated the AKT/AMPK-α1/GSK-3ß signaling pathway, which are both associated with anti-inflammatory and antioxidant effects. In summary, our results demonstrate that Ori exerts inhibitory effects on Mm infection and proliferation in cells and zebrafish, respectively. Additionally, Ori regulates oxidative stress by modulating the NRF2/HO-1/NQO-1 and AKT/AMPK-α1/GSK-3ß signaling pathways.

The influence of claw morphology on gripping efficiency.

This paper considers the effects of claw morphology on the gripping efficiency of arboreal (Varanus varius) and burrowing (Varanus gouldii and Varanus panoptes) lizards. To ensure a purely morphological comparison between the lizards, we circumvent the material effects of claws from different species, by modelling and testing claw replicates of the same material properties. We correlate climbing efficiency to critical morphological features including; claw height (hc), width (wc), length (lc), curvature () and tip angle (γ), which are expressed as ratios to normalise mechanically beneficial claw structures. We find that there is strong correlation between the static grip force Fsg and the claw aspect and the cross-sectional rigidity ratio , and milder correlation (i.e. higher scatter) with the profile rigidity ratio . These correlations are also true for the interlocking grip force Fint over different shaped and sized protuberances, though we note that certain protuberance size-shape couplings are of detriment to the repeatability of Fint. Of the three lizard species, the claws of the arboreal (V. varius) are found to be superior to those of the burrower lizards (V. gouldii and V. panoptes) as a result of the V. varius claws having a smaller aspect, a higher cross-sectional rigidity ratio and a small profile rigidity ratio, which are deemed noteworthy morphological parameters that influence a claw's ability to grip effectively.

HHL1 and SOQ1 synergistically regulate nonphotochemical quenching in Arabidopsis.

Nonphotochemical quenching (NPQ) is an important photoprotective mechanism that quickly dissipates excess light energy as heat. NPQ can be induced in a few seconds to several hours; most studies of this process have focused on the rapid induction of NPQ. Recently, a new, slowly induced form of NPQ, called qH, was found during the discovery of the quenching inhibitor suppressor of quenching 1 (SOQ1). However, the specific mechanism of qH remains unclear. Here, we found that hypersensitive to high light 1 (HHL1)-a damage repair factor of photosystem II-interacts with SOQ1. The enhanced NPQ phenotype of the hhl1 mutant is similar to that of the soq1 mutant, which is not related to energy-dependent quenching or other known NPQ components. Furthermore, the hhl1 soq1 double mutant showed higher NPQ than the single mutants, but its pigment content and composition were similar to those of the wildtype. Overexpressing HHL1 decreased NPQ in hhl1 to below wildtype levels, whereas NPQ in hhl1 plants overexpressing SOQ1 was lower than that in hhl1 but higher than that in the wildtype. Moreover, we found that HHL1 promotes the SOQ1-mediated inhibition of plastidial lipoprotein through its von Willebrand factor type A domain. We propose that HHL1 and SOQ1 synergistically regulate NPQ.

Assessment of chemistry knowledge in large language models that generate code.

In this work, we investigate the question: do code-generating large language models know chemistry? Our results indicate, mostly yes. To evaluate this, we introduce an expandable framework for evaluating chemistry knowledge in these models, through prompting models to solve chemistry problems posed as coding tasks. To do so, we produce a benchmark set of problems, and evaluate these models based on correctness of code by automated testing and evaluation by experts. We find that recent LLMs are able to write correct code across a variety of topics in chemistry and their accuracy can be increased by 30 percentage points via prompt engineering strategies, like putting copyright notices at the top of files. Our dataset and evaluation tools are open source which can be contributed to or built upon by future researchers, and will serve as a community resource for evaluating the performance of new models as they emerge. We also describe some good practices for employing LLMs in chemistry. The general success of these models demonstrates that their impact on chemistry teaching and research is poised to be enormous.

The role of noncoding RNAs in pancreatic birth defects.

Congenital defects in the pancreas can cause severe health issues such as pancreatic cancer and diabetes which require lifelong treatment. Regenerating healthy pancreatic cells to replace malfunctioning cells has been considered a promising cure for pancreatic diseases including birth defects. However, such therapies are currently unavailable in the clinic. The developmental gene regulatory network underlying pancreatic development must be reactivated for in vivo regeneration and recapitulated in vitro for cell replacement therapy. Thus, understanding the mechanisms driving pancreatic development will pave the way for regenerative therapies. Pancreatic progenitor cells are the precursors of all pancreatic cells which use epigenetic changes to control gene expression during differentiation to generate all of the distinct pancreatic cell types. Epigenetic changes involving DNA methylation and histone modifications can be controlled by noncoding RNAs (ncRNAs). Indeed, increasing evidence suggests that ncRNAs are indispensable for proper organogenesis. Here, we summarize recent insight into the role of ncRNAs in the epigenetic regulation of pancreatic development. We further discuss how disruptions in ncRNA biogenesis and expression lead to developmental defects and diseases. This review summarizes in vivo data from animal models and in vitro studies using stem cell differentiation as a model for pancreatic development.

Dual roles for CND1 in maintenance of nuclear and chloroplast genome stability in plants.

The coordination of chloroplast and nuclear genome status is critical for plant cell function. Here, we report that Arabidopsis CHLOROPLAST AND NUCLEUS DUAL-LOCALIZED PROTEIN 1 (CND1) maintains genome stability in the chloroplast and the nucleus. CND1 localizes to both compartments, and complete loss of CND1 results in embryo lethality. Partial loss of CND1 disturbs nuclear cell-cycle progression and photosynthetic activity. CND1 binds to nuclear pre-replication complexes and DNA replication origins and regulates nuclear genome stability. In chloroplasts, CND1 interacts with and facilitates binding of the regulator of chloroplast genome stability WHY1 to chloroplast DNA. The defects in nuclear cell-cycle progression and photosynthesis of cnd1 mutants are respectively rescued by compartment-restricted CND1 localization. Light promotes the association of CND1 with HSP90 and its import into chloroplasts. This study provides a paradigm of the convergence of genome status across organelles to coordinately regulate cell cycle to control plant growth and development.