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.

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.

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.

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.

Efficacy of OFD with EMD for treatment of periodontal defects: A systematic review and meta-analysis.

OBJECTIVES: In order to enhance clinical improvement of periodontal defects, the addition of enamel matrix derivatives (EMD) to open flap debridement (OFD) has been investigated. The aim of this systematic review is to figure out whether such a combination, in comparison to the treatment with OFD alone has some effects on the following outcomes: clinical attachment level gain, probing depth reduction, and gingival recessions increase. METHODS: Electronic databases (PubMed, Embase, Web of Science, and Cochrane) were searched for randomized controlled trials in humans addressing the use of a combination of OFD and EMD versus a control group with OFD alone for the treatment of periodontal defects, with a minimum of 6 months of follow-up; meta-analysis and trial sequential analysis were then performed. RESULTS: From a total of 204 records screened by title and abstract, 13 studies were read full-text and eight out of them included in the meta-analysis. Some significant differences have been demonstrated both for clinical attachment level gain and probing depth reduction between test and control groups. CONCLUSIONS: In the treatment of periodontal defects, the addition of EMD to OFD seems to be beneficial in terms of clinical attachment level gain, probing depth reduction, promoting periodontal regeneration. However, such results should be considered with caution because of the small number of studies included in the meta-analysis and their heterogeneity.

Causal knowledge graph construction and evaluation for clinical decision support of diabetic nephropathy.

BACKGROUND: Many important clinical decisions require causal knowledge (CK) to take action. Although many causal knowledge bases for medicine have been constructed, a comprehensive evaluation based on real-world data and methods for handling potential knowledge noise are still lacking. OBJECTIVE: The objectives of our study are threefold: (1) propose a framework for the construction of a large-scale and high-quality causal knowledge graph (CKG); (2) design the methods for knowledge noise reduction to improve the quality of the CKG; (3) evaluate the knowledge completeness and accuracy of the CKG using real-world data. MATERIAL AND METHODS: We extracted causal triples from three knowledge sources (SemMedDB, UpToDate and Churchill's Pocketbook of Differential Diagnosis) based on rule methods and language models, performed ontological encoding, and then designed semantic modeling between electronic health record (EHR) data and the CKG to complete knowledge instantiation. We proposed two graph pruning strategies (co-occurrence ratio and causality ratio) to reduce the potential noise introduced by SemMedDB. Finally, the evaluation was carried out by taking the diagnostic decision support (DDS) of diabetic nephropathy (DN) as a real-world case. The data originated from a Chinese hospital EHR system from October 2010 to October 2020. The knowledge completeness and accuracy of the CKG were evaluated based on three state-of-the-art embedding methods (R-GCN, MHGRN and MedPath), the annotated clinical text and the expert review, respectively. RESULTS: This graph included 153,289 concepts and 1,719,968 causal triples. A total of 1427 inpatient data were used for evaluation. Better results were achieved by combining three knowledge sources than using only SemMedDB (three models: area under the receiver operating characteristic curve (AUC): p < 0.01, F1: p < 0.01), and the graph covered 93.9 % of the causal relations between diseases and diagnostic evidence recorded in clinical text. Causal relations played a vital role in all relations related to disease progression for DDS of DN (three models: AUC: p > 0.05, F1: p > 0.05), and after pruning, the knowledge accuracy of the CKG was significantly improved (three models: AUC: p < 0.01, F1: p < 0.01; expert review: average accuracy: + 5.5 %). CONCLUSIONS: The results demonstrated that our proposed CKG could completely and accurately capture the abstract CK under the concrete EHR data, and the pruning strategies could improve the knowledge accuracy of our CKG. The CKG has the potential to be applied to the DDS of diseases.

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.

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.

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.

Multiple Responsiveness of Polymer Actuators.

To improve photosensitivity of polymer materials, an effective protocol is to increase the content of photosensitive moieties. However, most of photosensitive units are toxic. The high content is not acceptable for real-world applications. Therefore, achieving photosensitive polymers with low content of photosensitive moieties but maintaining their photosensitivity remains a challenge. Herein, a protocol is reported to address this challenge by combining photosensitive monomers with hygroscopic monomers, where the synergistic action of two types of functional moieties can improve the photosensitivity of polymer network. Upon exposure to light irradiation, the polymer can be driven by not only the structural isomerization of photosensitive units, but also the photothermal effects. This synergistic effect results in the polymer-based soft actuators capable of showing rapid response to light even at the extremely-low content of photosensitive moieties of 2.6 mol.%. Importantly, the combination of hygroscopic and photosensitive moieties provides polymer with multiple responsiveness including acidochromism, humidity responsiveness, photohardening, shape memory, photochromism, and in situ swelling, making it useful in sensing systems, information transmission, and artificial muscles.

Flavonoids-Natural Gifts to Promote Health and Longevity.

The aging of mammals is accompanied by the progressive atrophy of tissues and organs and the accumulation of random damage to macromolecular DNA, protein, and lipids. Flavonoids have excellent antioxidant, anti-inflammatory, and neuroprotective effects. Recent studies have shown that flavonoids can delay aging and prolong a healthy lifespan by eliminating senescent cells, inhibiting senescence-related secretion phenotypes (SASPs), and maintaining metabolic homeostasis. However, only a few systematic studies have described flavonoids in clinical treatment for anti-aging, which needs to be explored further. This review first highlights the association between aging and macromolecular damage. Then, we discuss advances in the role of flavonoid molecules in prolonging the health span and lifespan of organisms. This study may provide crucial information for drug design and developmental and clinical applications based on flavonoids.

Organophosphorus Flame Retardant TCPP Induces Cellular Senescence in Normal Human Skin Keratinocytes: Implication for Skin Aging.

Tris (1-chloro-2-propyl) phosphate (TCPP) is one of the most frequently detected organophosphorus flames in the environment. Continuous daily exposure to TCPP may harm human skin. However, little is known about the adverse effects of TCPP on human skin. In this study, we first evaluated the detrimental effects and tried to uncover the underlying mechanisms of TCPP on human skin keratinocytes (HaCaT) after 24 h exposure. We found that TCPP caused a concentration-dependent decrease in HaCaT cell viability after exposure to 1.56-400 µg/mL for 24 h, with an IC50 of 275 µg/mL. TCPP also promoted the generation of intracellular reactive oxygen species (ROS) and triggered DNA damage, evidenced by an increase of phosphorylated histone H2A.X (γH2A.X) in the nucleus. Furthermore, the cell cycle was arrested at the G1 phase at 100 µg/mL by upregulation of the mRNA expression of p53 and p21 and downregulation of cyclin D1 and CDK4 expression. Additionally, both the senescence-associated-ß-galactosidase activity and related proinflammatory cytokine IL-1ß and IL-6 were elevated, indicating that TCPP exposure caused cellular senescence may be through the p53-dependent DNA damage signal pathway in HaCaT cells. Taken together, our data suggest that flame-retardant exposure may be a key precipitating factor for human skin aging.

Novel mutations of TCTN3/LTBP2 with cellular function changes in congenital heart disease associated with polydactyly.

Congenital heart disease (CHD) associated with polydactyly involves various genes. We aimed to identify variations from genes related to complex CHD with polydactyly and to investigate the cellular functions related to the mutations. Blood was collected from a complex CHD case with polydactyly, and whole exome sequencing (WES) was performed. The CRISPR/Cas9 system was used to generate human pluripotent stem cell with mutations (hPSCs-Mut) that were differentiated into cardiomyocytes (hPSC-CMs-Mut) and analysed by transcriptomics on day 0, 9 and 13. Two heterozygous mutations, LTBP2 (c.2206G>A, p.Asp736Asn, RefSeq NM_000428.2) and TCTN3 (c.1268G>A, p.Gly423Glu, RefSeq NM_015631.5), were identified via WES but no TBX5 mutations were found. The stable cell lines of hPSCs-LTBP2mu /TCTN3mu were constructed and differentiated into hPSC-CMs-LTBP2mu /TCTN3mu . Compared to the wild type, LTBP2 mutation delayed the development of CMs. The TCTN3 mutation consistently presented lower rate and weaker force of the contraction of CMs. For gene expression pattern of persistent up-regulation, pathways in cardiac development and congenital heart disease were enriched in hPSCs-CM-LTBP2mu , compared with hPSCs-CM-WT. Thus, the heterozygous mutations in TCTN3 and LTBP2 affect contractility (rate and force) of cardiac myocytes and may affect the development of the heart. These findings provide new insights into the pathogenesis of complex CHD with polydactyly.

Early goal-directed and lactate-guided therapy in adult patients with severe sepsis and septic shock: a meta-analysis of randomized controlled trials.

BACKGROUND: The ProCESS, ARISE, and ProMISe trials have failed to show that early goal-directed therapy (EGDT) reduces mortality in patients with severe sepsis and septic shock. Although lactate-guided therapy (LGT) has been shown to result in significantly lower mortality, its use remains controversial. Therefore, we performed a meta-analysis to evaluate EGDT vs. LGT or usual care (UC) in adult patients with severe sepsis and septic shock. METHODS: Relevant randomized controlled trials published from January 1, 2001 to March 30, 2017 were identified in PubMed, EMBASE, Web of Science, and the Cochrane Library. The primary outcome was mortality; secondary outcomes included red cell transfusions, dobutamine use, vasopressor infusion, and mechanical ventilation support within the first 6 h and Acute Physiology and Chronic Health Evaluation II (APACHE II) score. RESULTS: Sixteen studies enrolling 5968 patients with 2956 in EGDT, 2547 in UC, and 465 in LGT were included in this meta-analysis. Compared with UC, EGDT was associated with a lower mortality (10 trials; RR 0.85, 95% CI 0.74-0.97, P = 0.01), and this difference was more pronounced in the subgroup of UC patients with mortality > 30%. In addition, EGDT patients received more red cell transfusions, dobutamine, and vasopressor infusions within the first 6 h. Compared with LGT, EGDT was associated with higher mortality (6 trials; RR 1.42, 95% CI 1.19-1.70, P = 0.0001) with no heterogeneity (P = 0.727, I2 = 0%). CONCLUSION: EGDT seems to reduce mortality in adult patients with severe sepsis and septic shock, and the benefit may primarily be attributed to red cell transfusions, dobutamine administration, and vasopressor infusions within the first 6 h. However, LGT may result in a greater mortality benefit than EGDT.

Low-Cost and Scaled-Up Production of Fluorine-Free, Substrate-Independent, Large-Area Superhydrophobic Coatings Based on Hydroxyapatite Nanowire Bundles.

To date, the scaled-up production and large-area applications of superhydrophobic coatings are limited because of complicated procedures, environmentally harmful fluorinated compounds, restrictive substrates, expensive equipment, and raw materials usually involved in the fabrication process. Herein, the facile, low-cost, and green production of superhydrophobic coatings based on hydroxyapatite nanowire bundles (HNBs) is reported. Hydrophobic HNBs are synthesised by using a one-step solvothermal method with oleic acid as the structure-directing and hydrophobic agent. During the reaction process, highly hydrophobic C-H groups of oleic acid molecules can be attached in situ to the surface of HNBs through the chelate interaction between Ca2+ ions and carboxylic groups. This facile synthetic method allows the scaled-up production of HNBs up to about 8 L, which is the largest production scale of superhydrophobic paint based on HNBs ever reported. In addition, the design of the 100 L reaction system is also shown. The HNBs can be coated on any substrate with an arbitrary shape by the spray-coating technique. The self-cleaning ability in air and oil, high-temperature stability, and excellent mechanical durability of the as-prepared superhydrophobic coatings are demonstrated. More importantly, the HNBs are coated on large-sized practical objects to form large-area superhydrophobic coatings.

Cognitive abilities, insurance decisions, and labor supply behavior: evidence from rural China.

Introduction: How cognitive abilities affect financial and economic decision is an important issue that has attracted the attention of economics. Method: This paper uses the China Family Panel Studies (CFPS) 2010, 2014, and 2018 survey data to empirically test the impact of cognitive skills on the insurance participation decisions in rural China. Results and discussion: The results show that higher word ability is correlated to higher social health insurance participation and both word and math ability leads to higher social pension participation. Mechanism analysis reveals that individuals with higher cognitive skills are more likely to be affected by peers in insurance decision, and higher cognitive skills increase personal income that enables them to enroll in the social insurance. Further investigation of labor supply behavior suggests that while cognitive skills positively affect non-agricultural labor participation, cognitive skills amplify the negative effect of social security on labor supply.