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Nanoplastics (NPs) are easily ingested by organisms and their major accumulation organ was determined to be liver. To date, the size-dependent cytotoxicity of NPs on mammalian hepatocytes remains unclear. This study utilized mouse primary hepatocytes and catalase (CAT) as specific receptors to investigate the toxicity of NPs from cells to molecules, focusing on size-dependent effects. Results showed that the larger the particle size of NP at low doses (≤50 mg/L), the most pronounced inhibitory effect on hepatocyte viability. 20 nm NPs significantly inhibit cell viability only at high doses (100 mg/L). Larger NP particles (500 nm and 1000 nm) resulted in a massive release of lactate dehydrogenase (LDH) from the cell (cell membrane damage). Reactive oxygen species (ROS), superoxide dismutase (SOD) and CAT tests suggest that NPs disturbed the cellular antioxidant system. 20 nm NPs show great strength in oxidizing lipids and disrupting mitochondrial function compared to NPs of other particle sizes. The degree of inhibition of CAT activity by different sized NPs was coherent at the cellular and molecular levels, and NP-500 had the most impact. This suggests that the structure and microenvironment of the polypeptide chain in the vicinity of the CAT active site is more susceptible to proximity and alteration by NP-500. In addition, the smaller NPs are capable of inducing relaxation of CAT backbone, disruption of H-bonding and reduction of α-helix content, whereas the larger NPs cause contraction of CAT backbone and increase in α-helix content. All NPs induce CAT fluorescence sensitization and make the chromophore microenvironment hydrophobic. This study provides new insights for NP risk assessment and applications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Despite major advances in non-small-cell lung cancer (NSCLC) treatment, the five-year survival rates for patients with non-oncogene-driven tumors remain low, necessitating combinatory approaches to improve outcomes. Our prior high-throughput RNAi screening identified Aurora kinase A (AURKA) as a potential key player in cisplatin resistance. In this study, we investigated AURKA's role in platinum and radiation sensitivity in multiple NSCLC cell lines and xenograft mouse models, as well as its effect on immune checkpoints, including PD-L1, B7x, B7-H3, and HHLA2. Of 94 NSCLC patient tumor specimens, 91.5% tested positive for AURKA expression, with 34% showing moderate-to-high levels. AURKA expression was upregulated following cisplatin treatment in NSCLC cell lines PC9 and A549. Both AURKA inhibition by alisertib and inducible AURKA knockdown potentiated the cytotoxic effects of cisplatin and radiation, leading to tumor regression in doxycycline-inducible xenograft mice. Co-treated cells exhibited increased DNA double-strand breaks, apoptosis, and senescence. Additionally, AURKA inhibition alone by alisertib increased PD-L1 and B7-H3 expression. In conclusion, our study demonstrates that AURKA inhibition enhances the efficacy of platinum-based chemotherapy in NSCLC cells and modulates the expression of multiple immune checkpoints. Therefore, combinatory regimens with AURKA inhibitors should be strategically designed and further studied within the evolving landscape of chemo-immunotherapy.

The concurrent environmental contamination by nanoplastics (NPs) and norfloxacin (NOR) is a burgeoning concern, with significant accumulations in various ecosystems and potential ingress into the human body via the food chain, posing threats to both public health and ecological balance. Despite the gravity of the situation, studies on the co-exposure contamination effects of these substances are limited. Moreover, the response mechanisms of key functional proteins to these pollutants are yet to be fully elucidated. In this work, we conducted a comprehensive assessment of the interaction mechanisms of NPs and NOR with lysozyme under both single and co-exposure condition, utilizing dynamic light scattering, ζ-potential measurements, multi-spectroscopy methods, enzyme activity assays and molecular docking, to obtain a relationship between the compound effects of NPs and NOR. Our results indicate that NPs adsorb NOR on their surface, forming more stable aggregates. These aggregates influence the conformation, secondary structure (α-Helix ratio decreased by 3.1 %) and amino acid residue microenvironment of lysozyme. And changes in structure affect the activity of lysozyme (reduced by 39.9 %) with the influence of composited pollutants exerting stronger changes. Molecular simulation indicated the key residues Asp 52 for protein function located near the docking site, suggesting pollutants preferentially binds to the active center of lysozyme. Through this study, we have found the effect of increased toxicity on lysozyme under the compounded conditions of NPs and NOR, confirming that the increased molecular toxicity of NPs and NOR is predominantly realized through the increase in particle size and stability of the aggregates under weak interactions, as well as induction of protein structural looseness. This study proposes a molecular perspective on the differential effects and mechanisms of NPs-NOR composite pollution, providing new insights into the assessment of in vitro responses to composite pollutant exposure., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Atmospheric carbonyl compounds play significant roles in the cycling of radicals and have exhibited surprisingly high levels in winter that were well correlated to particulate matter, for which the reason have not been clearly elucidated. Here we measured carbonyl compounds and other trace gasses together with PM 2.5 over urban Jinan in North China Plain during the winter. Markedly higher carbonyl concentrations (average: 14.63 ± 4.21 ppbv) were found during wintertime haze pollution, about one to three-times relative to those on non-haze days, with slight difference in chemical composition except formaldehyde (HCHO). HCHO (3.68 ppbv), acetone (3.17 ppbv), and acetaldehyde (CH 3 CHO) (2.83 ppbv) were the three most abundant species, accounting for ∼75% of the total carbonylson both haze and non-haze days. Results from observational-based model (OBM) with atmospheric oxidation capacity (AOC) indicated that AOC significantly increased with the increasing carbonyls during the winter haze events. Carbonyl photolysis have supplied key oxidants such as RO 2 and HO 2 , and thereby enhancing the formation of fine particles and secondary organic aerosols, elucidating the observed haze-carbonyls inter-correlation. Diurnal variation with carbonyls exhibiting peak values at early-noon and night highlighted the combined contribution of both secondary formation and primary diesel-fuel sources. 1-butene was further confirmed to be the major precursor for HCHO. This study confirms the great contribution of carbonyls to AOC, and also suggests that reducing the emissions of carbonyls would be an effective way to mitigate haze pollution in urban area of the NCP region., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

By modifying the structures of targeted A 2A R antagonists and tracers, novel compounds 3 , 7a , 9 , 12c , and BIBD-399 were designed and synthesized. In vitro inhibition experiments demonstrated that 3 , 12c , and BIBD-399 have high affinity for A 2A R. [ 18 F]3 and [ 18 F]BIBD-399 were successfully synthesized. In terms of biological distribution, the brain uptake of [ 18 F]MNI-444 exhibits greater than that of [ 18 F]3 and [ 18 F]BIBD-399. PET imaging shows that [ 18 F]3 is off-target in the brain, while [ 18 F]BIBD-399 and [ 18 F]MNI-444 can be specifically imaged in regions with high A 2A R expression. Differently, [ 18 F]BIBD-399 could quickly reach equilibrium in the targeted region within 10 min after administration, while [ 18 F]MNI-444 shows a slowly increasing trend within 2 h of administration. [ 18 F]BIBD-399 is mainly metabolized by the liver and kidney, and there is no obvious defluorination in vivo. Additional in vitro autoradiography showed that the striatal signals of [ 18 F]BIBD-399 and [ 18 F]MNI-444 were inhibited by the A 2A R antagonist SCH442416 but not by the A 1 R antagonist DPCPX, demonstrating the high A 2A R binding specificity of [ 18 F]BIBD-399. Molecular docking further confirms the high affinity of MNI-444 and BIBD-399 for A 2A R. Further tMCAo imaging showed that [ 18 F]BIBD-399 can sensitively distinguish between infarcted and noninfarcted sides, a capability not observed with [ 18 F]MNI-444. Given its pharmacokinetic properties and the ability to identify lesion regions, [ 18 F]BIBD-399 has potential advantages in monitoring A 2A R changes, meriting further clinical investigation.

Background: Whether perceived stress is associated with loneliness and depressive symptoms in general adults, and to what extent sleep quality mediates the associations, remains unknown. The aim of this study was to estimate the associations of perceived stress with loneliness and depressive symptoms, and the mediating role of sleep quality in these associations., Methods: Cross-sectional data on 734 participants (aged 18-87 years) were analyzed. Perceived stress was assessed using the 10-item Perceived Stress Scale (PSS-10; range 0-40). Sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI; range 0-21). Loneliness was assessed using the three-item short form of the Revised University of California, Los Angeles (UCLA) loneliness scale (range 3-9). Depressive symptoms were assessed using the 10-item Center for Epidemiologic Studies Depression (CESD-10) Scale (range 0-30). General linear regression models, multivariable logistic regression models, and formal mediation analysis were performed., Results: After adjustment for age and sex, we found that with each 1-point increment in the perceived stress score, both the loneliness score (β = 0.07; 95% confidence interval [CI]: 0.06, 0.08) and depression score (β = 0.45; 95% CI: 0.40, 0.49) increased significantly. Robust results were observed when adjusting for more confounders. Furthermore, sleep quality mediated 5.3% (95% CI: 1.3%, 10.0%; P = 0.014) and 9.7% (95% CI: 6.2%, 14.0%; P < 0.001) of the associations of perceived stress score with loneliness score and depression score, respectively., Conclusions: In general Chinese adults, perceived stress was positively associated with loneliness and depressive symptoms, and sleep quality partially mediated these associations. The findings reveal a potential pathway from perceived stress to mental health through sleep behaviors, and highlight the importance of implementing sleep intervention programs for promoting mental health among those who feel highly stressed., (© 2024. The Author(s).)

[ 18 F]Gln-OSO 2 F, [ 18 F]Arg-OSO 2 F, and [ 18 F]FSY-OSO 2 F were designed by introducing sulfonyl 18 F-fluoride onto glutamine, arginine, and tyrosine, respectively. [ 18 F]FSY-OSO 2 F can be prepared directly by sulfur 18 F-fluoride exchange, while [ 18 F]Gln-OSO 2 F and [ 18 F]Arg-OSO 2 F require a two-step labeling method. Those tracers retain their typical transport characteristics for unmodified amino acids. Both PET imaging and biodistribution confirmed that [ 18 F]FSY-OSO 2 F visualized MCF-7 and 22Rv1 subcutaneous tumors with high contrast, and its tumor-to-muscle ratio was better than that of [ 18 F]FET. However, [ 18 F]Gln-OSO 2 F and [ 18 F]Arg-OSO 2 F poorly image MCF-7 subcutaneous tumors, possibly due to differences in the types and amounts of transporters expressed in tumors. All three tracers can visualize the U87MG glioma. According to our biological evaluation, none of the tracers evaluated in this study exhibited obvious defluorination, and subtle structural changes led to different imaging characteristics, indicating that the application of sulfur 18 F-fluoride exchange click chemistry in the design of radioactive sulfonyl fluoride amino acids is feasible and offers significant advantages., Competing Interests: The authors declare no competing financial interest., (© 2024 American Chemical Society.)

Currently there is a limited understanding for the optimal combination of immune checkpoint inhibitor and chemotherapy for patients with metastatic triple-negative breast cancer (mTNBC). Here we evaluate the safety, efficacy, and immunogenicity of a phase I trial for patients with mTNBC treated with pembrolizumab plus doxorubicin. Patients without prior anthracycline use and 0-2 lines of prior systemic chemotherapies received pembrolizumab and doxorubicin every 3 weeks for 6 cycles followed by pembrolizumab maintenance until disease progression or intolerance. The primary objectives were safety and objective response rate per RECIST 1.1. Best responses included one complete response (CR), five partial responses (PR), two stable disease (SD), and one progression of disease (PD). Overall response rate was 67% (95% CI 13.7%, 78.8%) and clinical benefit rate at 6 months was 56% (95% CI 21.2%, 86.3%). Median PFS was 5.2 months (95% CI 4.7, NA); median OS was 15.6 months (95% CI 13.3, NA). Grade 3-4 AEs per CTCAE 4.0 were neutropenia n = 4/10 (40%), leukopenia n = 2/10 (20%), lymphopenia n = 2/10 (20%), fatigue n = 2/10 (20%), and oral mucositis n = 1/10 (10%). Immune correlates showed increased frequencies of circulating CD3 + T cells (p = 0.03) from pre-treatment to cycle 2 day 1 (C2D1). An expansion of a proliferative exhausted-like PD-1 + CD8 + T cell population was identified in 8/9 patients, and exhausted CD8 + T cells were significantly expanded from pre-treatment to C2D1 in the patient with CR (p = 0.01). In summary, anthracycline-naïve patients with mTNBC treated with the combination of pembrolizumab and doxorubicin showed an encouraging response rate and robust T cell response dynamics.Trial registration: NCT02648477., (© 2023. The Author(s).)

Background: Hyperglycemia is recognized as a common adverse event for patients receiving alpelisib but has been little studied outside of clinical trials. We report the frequency of alpelisib-associated hyperglycemia in a real-world setting and evaluate proposed risk factors., Patients and Methods: We retrospectively identified patients with PIK3CA-mutated, hormone receptor-positive, metastatic breast cancer who initiated treatment with alpelisib plus fulvestrant between August 2019 and December 2021. Ordinal logistic regression evaluated 5 characteristics (diabetes, prediabetes, body mass index [BMI], age, and Asian ancestry) as independent risk factors for ALP-associated hyperglycemia grades 2-4. Risk of error from multiple hypothesis testing was controlled using the false discovery rate method., Results: The study included n = 92 subjects, all but 1 female, mean age 59.9 (+11.9) years with 50% non-Hispanic White, 15% Hispanic/Latino, 13% Asian, 9% African/Black, and 13% other/unknown. In total 34% of patients had diabetes, 10% had pre-diabetes, and 56% had normoglycemia. Thirty-six percent were obese, 32% were overweight, 25% were normal weight, and 7% were lean. Frequency of grades 1-4 hyperglycemia in current subjects (64.1%) was similar to hyperglycemia reported in the SOLAR-1 trial (63.7%). Our subjects' risk of grades 2-4 hyperglycemia was independently increased by pre-existing diabetes (Odds ratio 3.75, 95% CI, 1.40-10.01), pre-diabetes (6.22, 1.12-34.47), Asian ancestry (7.10, 1.75-28.84), and each unit of BMI above 20 (1.17, 1.07-1.28)., Conclusion: While receiving alpelisib, patients of Asian ancestry, as well as patients with pre-existing hyperglycemia and/or BMI above 20, should be closely monitored for hyperglycemia. The mechanism underlying the current association of alpelisib-associated hyperglycemia with Asian ancestry is independent of BMI and merits further study. The high incidence of hyperglycemia resulted in a change in practice to include consultation with a diabetes nurse educator or endocrinologist at the start of alpelisib., (© The Author(s) 2023. Published by Oxford University Press.)

MYB-NFIB fusion and NOTCH1 mutation are common hallmark genetic events in salivary gland adenoid cystic carcinoma (SACC). However, abnormal expression of MYB and NOTCH1 is also observed in patients without MYB-NFIB fusion and NOTCH1 mutation. Here, we explore in-depth the molecular mechanisms of lung metastasis through single-cell RNA sequencing (scRNA-seq) and exome target capture sequencing in two SACC patients without MYB-NFIB fusion and NOTCH1 mutation. Twenty-five types of cells in primary and metastatic tissues were identified via Seurat clustering and categorized into four main stages ranging from near-normal to cancer-based on the abundance of each cell cluster in normal tissue. In this context, we identified the Notch signaling pathway enrichment in almost all cancer cells; RNA velocity, trajectory, and sub-clustering analyses were performed to deeply investigate cancer progenitor-like cell clusters in primary tumor-associated lung metastases, and signature genes of progenitor-like cells were enriched in the "MYC&#95;TARGETS&#95;V2" gene set. In vitro, we detected the NICD1-MYB-MYC complex by co-immunoprecipitation (Co-IP) and incidentally identified retinoic acid (RA) as an endogenous antagonist of genes in the "MYC&#95;TARGETS&#95;V2" gene set. Following this, we confirmed that all-trans retinoic acid (ATRA) suppresses the lung metastasis of SACC by correcting erroneous cell differentiation mainly caused by aberrant NOTCH1 or MYB expression. Bioinformatic, RNA-seq, and immunohistochemical (IHC) analyses of primary tissues and metastatic lung tissues from patients with SACC suggested that RA system insufficiency partially promotes lung metastasis. These findings imply the value of the RA system in diagnosis and treatment., (© 2023. The Author(s).)

The roles of lamin A/C in adipocyte differentiation and skeletal muscle lipid metabolism are associated with familial partial lipodystrophy of Dunnigan (FPLD). We confirmed that LMNA knockdown (KD) in mouse adipose-derived mesenchymal stem cells (AD-MSCs) prevented adipocyte maturation. Importantly, in in vitro experiments, we discovered a significant increase in phosphorylated lamin A/C levels at serine 22 or 392 sites (pLamin A/C-S22/392) accompanying increased lipid synthesis in a liver cell line (7701 cells) and two hepatocellular carcinoma (HCC) cell lines (HepG2 and MHCC97-H cells). Moreover, HCC cells did not survive after LMNA knockout (KO) or even KD. Evidently, the functions of lamin A/C differ between the liver and adipose tissue. To date, the mechanism of hepatocyte lipid metabolism mediated by nuclear lamin A/C remains unclear. Our in-depth study aimed to identify the molecular connection between lamin A/C and pLamin A/C, hepatic lipid metabolism and liver cancer. Gain- and loss-of-function experiments were performed to investigate functional changes and the related molecular pathways in 7701 cells. Adenosine 5' monophosphate-activated protein kinase α (AMPKα) was activated when abnormalities in functional lamin A/C were observed following lamin A/C depletion or farnesyltransferase inhibitor (FTI) treatment. Active AMPKα directly phosphorylated acetyl-CoA-carboxylase 1 (ACC1) and subsequently inhibited lipid synthesis but induced glycolysis in both HCC cells and normal cells. According to the mass spectrometry analysis, lamin A/C potentially regulated AMPKα activation through its chaperone proteins, ATPase or ADP/ATP transporter 2. Lonafarnib (an FTI) combined with low-glucose conditions significantly decreased the proliferation of the two HCC cell lines more efficiently than lonafarnib alone by inhibiting glycolysis or the maturation of prelamin A.

The volatile organic compounds emitted by plants significantly impact the atmospheric environment. The impacts of drought stress on the biogenic volatile organic compound (BVOC) emissions of plants are still under debate. In this study, the effects of two drought-rehydration cycle groups with different durations on isoprene emissions from Populus nigra (black poplar) seedlings were studied. The P. nigra seedlings were placed in a chamber that controlled the soil water content, radiation, and temperature. The daily emissions of isoprene and physiological parameters were measured. The emission rates of isoprene ( F iso ) reached the maximum on the third day (D3), increasing by 58.0% and 64.2% compared with the controlled groups, respectively, and then F iso significantly decreased. Photosynthesis decreased by 34.2% and 21.6% in D3 in the first and second groups, respectively. After rehydration, F iso and photosynthesis recovered fully in two groups. However, F iso showed distinct inconsistencies in two groups, and the recovery rates of F iso in the second drought group were slower than the recovery rates of F iso in the first groups. The response of BVOC emissions during the drought-rehydration cycle was classified into three phases, including stimulated, inhibited, and restored after rehydration. The emission pattern of isoprene indicated that isoprene played an important role in the response of plants to drought stress. A drought-rehydration model was constructed, which indicated the regularity of BVOC emissions in the drought-rehydration cycle. BVOC emissions were extremely sensitive to drought, especially during droughts of short duration. Parameters in computational models related to BVOC emissions of plants under drought stress should be continuously improved.

This study investigated the safety and antitumor activity of aromatase inhibitors (AI) with immune checkpoint inhibitor (ICI) pembrolizumab in patients with hormone receptor positive (HR + ) human epidermal growth factor receptor 2-negative (HER2 - ) metastatic breast cancer (MBC) in a phase II study with a safety lead-in (NCT02648477). Patients received pembrolizumab plus AI up to 2 years or until confirmed progression or unacceptable toxicity. Key eligibility criteria were HR + HER2 - MBC; RECIST v1.1 measurable disease; adequate organ function; and ECOG 0-1. Primary endpoints were safety and overall response rate. A 3-at-risk design was used for the safety lead-in with a targeted accrual of 20 patients. Grade 2 adverse events (AEs) included 35% fatigue, 20% rash, and 10% hot flashes. Grade 3 immune-related AEs (irAEs) related to pembrolizumab included 5% elevated AST/ALT, 5% rash, and 5% lymphopenia. Two (10%) patients had partial responses, three (15%) had stable disease, and 15 (75%) had progression of disease. Median progression-free survival was 1.8 months (95% CI 1.6, 2.6), median overall survival was 17.2 months (95% CI 9.4, NA), and median follow-up time was 40.1 months (range 31.3-46.8 months). The combination was well tolerated, but clinical activity was comparable to AI alone.

Introduction: Adherence to warfarin is associated with improved outcome in patients with atrial fibrillation (AF), but the adherence status of patients in rural areas of China is not known., Methods: A questionnaire-based study evaluating warfarin adherence of rural residents with AF was carried out in Dongyang, China. Potentially eligible patients were screened and contacted by telephone, and their demographic characteristics were collected. Illness perception was assessed using the Brief Illness Perception Questionnaire (BIPQ), and warfarin adherence was assessed using a Chinese-version adherence scale. Univariate and multivariate analyses were conducted to identify factors associated with unsatisfactory adherence., Results: A total of 201 patients (male, n =99; mean age, 70.3±8.12 years) were included, among whom 95 (47.3%) patients showed good adherence and 63 (31.3%) poor adherence. Number of co-dispensed drugs (multivariate analysis: odds ratio [OR]=3.64, 95% confidence interval [CI] 1.35-9.81, p =0.011) and BIPQ score (OR=1.25, 95% CI 1.17-1.33, p <0.001) were identified as factors associated with good adherence., Conclusion: Medical adherence to warfarin needs to improve in rural patients with AF. Efforts that can reduce the number of co-dispensed drugs and increase illness perception may improve warfarin adherence. This study may benefit future management of warfarin administration to rural patients with AF., Competing Interests: The authors declare no conflict of interest., (© 2022 Chen et al.)

The highly conserved multifunctional polymerase-associated factor 1 (Paf1) complex (PAF1C), which consists of five core subunits: Ctr9, Paf1, Leo1, Cdc73, and Rtf1, acts as a diverse hub that regulates all stages of RNA polymerase II-mediated transcription and various other cellular functions. However, the underlying mechanisms remain unclear. Here, we report the crystal structure of the core module derived from a quaternary Ctr9/Paf1/Cdc73/Rtf1 complex of S. cerevisiae PAF1C, which reveals interfaces between the tetratricopeptide repeat module in Ctr9 and Cdc73 or Rtf1, and find that the Ctr9/Paf1 subcomplex is the key scaffold for PAF1C assembly. Our study demonstrates that Cdc73 binds Ctr9/Paf1 subcomplex with a very similar conformation within thermophilic fungi or human PAF1C, and that the binding of Cdc73 to PAF1C is important for yeast growth. Importantly, our structure reveals for the first time that the extreme C-terminus of Rtf1 adopts an "L"-shaped structure, which interacts with Ctr9 specifically. In addition, disruption of the binding of either Cdc73 or Rtf1 to PAF1C greatly affects the normal level of histone H2B K123 monoubiquitination in vivo. Collectively, our results provide a structural insight into the architecture of the quaternary Ctr9/Paf1/Cdc73/Rtf1 complex and PAF1C functional regulation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The highly conserved multifunctional polymerase-associated factor 1 (Paf1) complex (PAF1C), composed of five core subunits Paf1, Leo1, Ctr9, Cdc73, and Rtf1, participates in all stages of transcription and is required for the Rad6/Bre1-mediated monoubiquitination of histone H2B (H2Bub). However, the molecular mechanisms underlying the contributions of the PAF1C subunits to H2Bub are not fully understood. Here, we report that Ctr9, acting as a hub, interacts with the carboxyl-terminal acidic tail of Rad6, which is required for PAF1C-induced stimulation of H2Bub. Importantly, we found that the Ras-like domain of Cdc73 has the potential to accelerate ubiquitin discharge from Rad6 and thus facilitates H2Bub, a process that might be conserved from yeast to humans. Moreover, we found that Rtf1 HMD stimulates H2Bub, probably through accelerating ubiquitin discharge from Rad6 alone or in cooperation with Cdc73 and Bre1, and that the Paf1/Leo1 heterodimer in PAF1C specifically recognizes the histone H3 tail of nucleosomal substrates, stimulating H2Bub. Collectively, our biochemical results indicate that intact PAF1C is required to efficiently stimulate Rad6/Bre1-mediated H2Bub., Competing Interests: The authors declare no competing interest.

Background: Angiopoietin-2 (Angpt2) is associated with the progression of coronary artery disease (CAD). This research aimed to investigate the possible association between single nucleotide polymorphisms (SNPs) of ANGPT2 and CAD., Methods: This research was performed in a hospital from the eastern region of China. From February 2019 to June 2019, 222 patients with CAD were newly diagnosed and 403 healthy controls were confirmed by physical examinations. The distribution frequency of five SNPs of the ANGPT2 (rs11137037, rs2442598, rs12674822, rs1823375, and rs734701) in all participants was analyzed by real-time polymerase chain reaction (PCR) with SNP locus-specific probes., Results: Our data showed that the participants with the TT genotype of rs2442598 were at reduced risk of CAD compared with wild-types (adjusted odds ratio [AOR] = 0.511, 95% CI: 0.283-0.923). The participants with the AC and AC+CC genotypes of rs11137037 were at greater risk of CAD compared to wild-types (AOR = 1.754, 95% CI: 1.140-2.699; AOR = 1.731, 95% CI: 1.165-2.573, respectively). In addition, carriers of the GG+TT genotypes of rs12674822, showed more significant high-density lipoprotein than those of GG genotype, in addition, carriers of the GG+TT genotypes of rs12674822, showed more significant high-density lipoprotein than those of GG genotype ( P =0.037)., Conclusion: These findings, as well as analysis of the haplotype, clearly indicate that ANGPT2 SNPs were highly correlated with susceptibility to CAD among the Han Chinese population., (© 2021 The Author(s). This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.)

Objective: To explore the therapeutic effect and inflammatory mechanism of fire needles on gouty arthritis., Methods: Sixty male Sprague-Dawley rats were divided into four groups, that is, control group, the model group, the colchicine group, and the fire needle treatment group. Acute gouty arthritis was prepared by injection of monosodium urate in the ankle joint. The inflammation-related protein [toll-like receptor 4 (TLR4), pyrin domain-containing protein 3 (NLRP3), interleukin (IL)-1β, myeloid differentiation factor 88 (MyD88), nuclear factorkappa B (NF-κB), phosphorylated NF-κB (p-NF-κB), caspase-1, and p-caspase-1] in swollen tissues, the inflammation-related mRNAs indicators (TLR4, NLRP3, NF-κB, and caspase-1) and the inflammatory factors [IL-1β, IL-6, IL-8, tumor necrosis factor-α (TNF-α), and C-reactive protein (CRP)] in the serum were detected by Western blot, real-time quantitative polymerase chain reaction, and enzyme-linked immunosorbent assay, respectively., Results: The fire needle treatment could reduce joint swelling, increase mechanical pain threshold and decrease the inflammation index score in the fire needle treatment group. It could also significantly decreased the protein expression of IL-1β, TLR4, MyD88, p-NF-κB and NLRP3 in joint tissue, markedly downregulated the mRNA levels of TLR4 and NLRP3 in joint tissue, and significantly reduce serum levels of IL-1β, IL-6, IL-8, TNF-α, and CRP., Conclusion: The fire needle treatment had positive effect of treating gouty arthritis, and its under- lying mechanism might be associated with NF-κB activation and related inflammatory response.

The crystallization processes of titanates are central to the fabrication of optical and electrical crystals and glasses, but their rich polymorphism is not fully understood. Here, we show when and how polymorphic selection occurs during the crystallization of barium titanate (BaTiO 3 , BT) using in situ high energy synchrotron X-ray diffraction and ab initio molecular dynamic simulation. An anomalous structure transition is found in molten BT during cooling across the cubic-hexagonal transition temperature, which enables nucleation selection of BT by manipulating the undercooling: a cubic phase is preferred if nucleation is triggered at large undercooling, whereas a hexagonal phase is promoted at small undercooling. We further reveal that the nucleation selection between the cubic and the hexagonal phase is regulated by the intrinsic structure property of the melt, in particular, the degree of polymerization between Ti-O polyhedra. These findings provide an innovative perspective to link the polymorphic crystallization to the non-isomorphic structure transition of the melt beyond the conventional cognition of structural heredity., (© 2021. The Author(s).)

De-etiolation consists of a series of developmental and physiological changes that a plant undergoes in response to light. During this process light, an important environmental signal, triggers the inhibition of mesocotyl elongation and the production of photosynthetically active chloroplasts, and etiolated leaves transition from the "sink" stage to the "source" stage. De-etiolation has been extensively studied in maize (Zea mays L.). However, little is known about how this transition is regulated. In this study, we described a quantitative proteomic and phosphoproteomic atlas of the de-etiolation process in maize. We identified 16,420 proteins in proteome, among which 14,168 proteins were quantified. In addition, 8746 phosphorylation sites within 3110 proteins were identified. From the combined proteomic and phosphoproteomic data, we identified a total of 17,436 proteins. Only 7.0% (998/14,168) of proteins significantly changed in abundance during de-etiolation. In contrast, 26.6% of phosphorylated proteins exhibited significant changes in phosphorylation level; these included proteins involved in gene expression and homeostatic pathways and rate-limiting enzymes involved in photosynthetic light and carbon reactions. Based on phosphoproteomic analysis, 34.0% (1057/3110) of phosphorylated proteins identified in this study contained more than 2 phosphorylation sites, and 37 proteins contained more than 16 phosphorylation sites, indicating that multi-phosphorylation is ubiquitous during the de-etiolation process. Our results suggest that plants might preferentially regulate the level of posttranslational modifications (PTMs) rather than protein abundance for adapting to changing environments. The study of PTMs could thus better reveal the regulation of de-etiolation., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: This observational study aimed to compare the outcome and health-related quality of life (HRQOL) amongst breast cancer patients using Chinese herbal medicine (CHM) and those not using CHM during chemotherapy., Methods: A prospective, non-randomised longitudinal study was conducted in two government integrated hospitals over an 8-month period. Early-stage breast cancer patients who were (1) either already using complementary and alternative medicine (CAM) or not and (2) who were on a regime of 5-fluorouracil, epirubicin, and cyclophosphamide were included in the study. Patients who agreed to receive CHM were assigned to receive individualised CHM prescriptions deemed suitable for the individual at a particular time. Those who were not willing to take Chinese herbal medicines (CHM) were assigned to the non-CHM control group. Blood profile and chemotherapy-induced AE were recorded whilst HRQOL assessment was done using the EORTC QLQ-C30 questionnaire on first, third, and sixth cycles., Results: Forty-seven patients [32 female vs. 1 male, p = 0.31; mean year of age: 52.2(SD = 7.6), p = 0.28)}] were recruited during the study period. Demographics of both groups were comparable. Fifty percent of respondents reported using some kind of CAM before chemotherapy. Diet supplements (40.6%) were the most common CAM used by the respondents. The study showed that patients using CHM had significantly less fatigue (p = 0.012), nausea (p = 0.04), and anorexia (p = 0.005) during chemotherapy. There were no significant differences in patients' HRQOL (p = 0.79). There were no AEs reported during the study., Conclusion: The use of CHM as an adjunct treatment with conventional chemotherapy have been shown to reduce fatigue, nausea, and anorexia in breast cancer patients but did not reduce chemotherapy-associated hematologic toxicity. The sample size of this study was not powered to assess the significance of HRQOL between two groups of patients.

The nucleation pathway plays an important role in vitrification, preparation of glass-ceramic composites and synthesis of metastable materials. In this paper, we studied the nucleation pathway of a novel ferroelectric BaTi 2 O 5 (BT2) during crystallization from undercooled liquid by aerodynamic levitation (ADL) containerless processing and structural analysis. An interesting polymorphic transition of BT2 regulated by the undercooling was observed during the crystallization process: the ferroelectric monoclinic phase (γ-BT2) was fabricated at low undercoolings and the paraelectric orthorhombic metastable phase (β-BT2) was obtained from hypercooled liquid. This polymorphic transition phenomenon corresponds to a non-classical nucleation pathway: metastable β-BT2 preferentially nucleates from undercooled melt and γ-BT2 is generated from β phase by solid-state phase transition. The two-step nucleation pathway stems from the structural heredity between the undercooled liquid and crystals. A stronger structural homology exists between the undercooled melt and β-BT2 than γ-BT2 based on diffraction data and atomic configurations analysis. This structural homology coupled with nucleation barrier calculation was used to elucidate the non-classical nucleation pathway of BT2 crystallization: the similarity of the structural unit (Ti-O polyhedra) between the undercooled liquid and the metastable β-BT2 reduces the nucleation barrier and contributes to the preferential precipitation of β-like clusters. This work reveals the formation route of BT2 from cooling melt, which not only benefits the synthesis and application of this novel functional material but also provides a guideline of the crystallization process of titanates from melt at atomic level.

Mechanically mixed γ-Al 2 O 3 and HZSM-5 (Si/Al = 50) with different mass ratio were utilized as support for Cu-Co higher alcohol synthesis catalysts prepared through incipient wetness impregnation. The textural and structural properties were studied using Ar low temperature adsorption and desorption, H 2 -temperature programmed reduction (H 2 -TPR), X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), transmission electron microscope (TEM) and catalytic performance measurements. The results indicated that the mechanically mixed HZSM-5 and γ-Al 2 O 3 supported copper-cobalt catalysts were superior to either γ-Al 2 O 3 or HZSM-5 supported ones with the same metal loading. The results revealed that using HZSM-5 and γ-Al 2 O 3 mechanically mixed benefited the dispersion of metallic phases and stronger synergetic functions between smaller nanoparticles containing copper and/or cobalt, which is essential for HAS from CO hydrogenation. Under working conditions of P = 5.0 MPa, T = 300 °C, V (H 2 ) :  V (CO) :  V (N 2 ) = 4 : 2 : 1 and GHSV = 7200 mL g -1 h -1 , mechanically mixed HZSM-5 and γ-Al 2 O 3 supported catalysts showed higher catalytic activity than those over single support. For CuCo catalysts upon support containing 50.0 wt% HZSM-5 and 50.0 wt% γ-Al 2 O 3 , the CO conversion was 21.3% and the C 2+ alcohol selectivity was 41.8%., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Testing drugs for anti-aging effects has historically been conducted in mouse life-span studies, but are costly and time consuming, and more importantly, difficult to recapitulate in humans. In addition, life-span studies in mice are not well suited to testing drug combinations that target multiple factors involved in aging. Additional paradigms for testing therapeutics aimed at slowing aging are needed. A new paradigm, designated as the Geropathology Grading Platform (GGP), is based on a standardized set of guidelines developed to detect the presence or absence of low-impact histopathological lesions and to determine the level of severity of high-impact lesions in organs from aged mice. The GGP generates a numerical score for each age-related lesion in an organ, summed for total lesions, and averaged over multiple mice to obtain a composite lesion score (CLS). Preliminary studies show that the platform generates CLSs that increase with the age of mice in an organ-dependent manner. The CLSs are sensitive enough to detect changes elicited by interventions that extend mouse life span, and thus help validate the GGP as a novel tool to measure biological aging. While currently optimized for mice, the GGP could be adapted to any preclinical animal model., (© The Author 2017. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Chronic health conditions of the elderly lead to limitations in physical activity with disability, anxiety, and increased need for medical care and assisted living conditions. Physical performance tests are used to screen for pending loss of mobility and can serve as endpoints to monitor the effectiveness of intervention measures. Since limited mobility is associated with the physical and mental health of a person, evaluation of this in preclinical aging studies in mice will provide a translational approach for testing new intervention strategies. We assessed physiological parameters in 4, 12, 20 and 28month old C57BL/6 and CB6F1 male mice using a rotating rod, a free running wheel, and a photo beam activity field, designed to determine changes in coordinated walking ability, self-motivated running distance, and anxiety response to a novel environment, respectively. Older mice showed decreased coordinated walking times and decreased running distances, predictive of physical performance ability and motivation in the elderly. Changes in both lateral and vertical movements were observed in a novel cage environment suggesting different levels of anxiety. Because the genetic background of the two mouse strains influenced test results in an age-dependent manner, it is imperative to recognize that diverse genetic backgrounds in mice may yield different data in preclinical studies and would need to be interpreted individually for translational applications., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The hand grip test has been correlated with mobility and physical performance in older people and has been shown to be a long-term predictor of mortality. Implementation of new strategies for enhancing healthy aging and maintaining independent living are dependent on predictable preclinical studies. The mouse is used extensively as a model in these types of studies, and the paw grip strength test is similar to the hand grip test for people in that it assesses the ability to grip a device with the paw, is non-invasive and easy to perform, and provides reproducible information. However, little has been reported on how grip strength declines with increasing age in mice. This report shows that grip strength was decreased in C57BL/6 (B6) NIA and C57BL/6×BALB/c F1 (CB6F1) NIA male mice at 12 months of age compared to 8-month-old mice, and continued a robust decline to 20 months and then 28 months of age, when the study was terminated. The decline was not related to lean muscle mass, but extensive age-related carpal and digital exostosis could help explain the decreased grip strength times with increasing age. In conclusion, the grip strength test could be useful in mouse preclinical studies to help make translational predictions on treatment strategies to enhance healthy aging., Competing Interests: and funding This work was supported by R24 AG047115 (PI, WL) and P30 AG013280 PI, PR). The authors were not associated with any other funding sources for the conduct of this study.

To better understand the roles of leaves at different stem positions during plant development, we measured the physiological properties of leaves 1-4 on maize seedling stems, and performed a proteomics study to investigate the differences in protein expression in the four leaves using two-dimensional difference gel electrophoresis and tandem mass spectrometry in conjunction with database searching. A total of 167 significantly differentially expressed protein spots were found and identified. Of these, 35% are involved in photosynthesis. By further analysis of the data, we speculated that in leaf 1 the seedling has started to transition from a heterotroph to an autotroph, development of leaf 2 is the time at which the seedling fully transitions from a heterotroph to an autotroph, and leaf maturity was reached only with fully expanded leaves 3 and 4, although there were still some protein expression differences in the two leaves. These results suggest that the different leaves make different contributions to maize seedling growth via modulation of the expression of the photosynthetic proteins. Together, these results provide insight into the roles of the different maize leaves as the plant develops from a heterotroph to an autotroph., (Copyright © 2016 Elsevier GmbH. All rights reserved.)

Aims . To measure plasma levels of superoxide dismutases 1, 2, and 3 (SOD1, 2, 3) and determine whether SODs can function as biomarkers for coronary artery disease (CAD). Patients & Methods . Patient groups were as follows: patients with stable angina pectoris (SAP, n = 33), patients with acute coronary syndrome (ACS, n = 49), and controls ( n = 42). Protein quantification was done using ELISA. Results . The concentrations of plasma SOD1 and SOD2 were higher in CAD than in healthy controls. No difference in SOD3 levels between CAD and control groups was found. Limited correlations were found between SODs and gender, age, and severity of coronary artery stenosis. Conclusions . Plasma levels of SOD1 and SOD2 were elevated in patients with CAD and might serve as surrogate biomarkers for CAD.

Red cell distribution width (RDW) has been found to be a novel prognostic biomarker in patients with coronary artery disease (CAD); however, the association between RDW and the risk of heart events in patients with CAD is yet to be fully elucidated. Thus, the aim of the present study was to determine whether an elevated RDW was associated with the Framingham risk score (FRS) in patients with CAD. Data were retrospectively collected from Affiliated Dongyang Hospital of Wenzhou Medical University (Dongyang, China). The patients had undergone a coronary angiography and their clinical data were integrated. The patients (male, 260; female, 132) were divided into two groups based on the results of the coronary angiography, namely the CAD (n=283) and control groups (n=109). The FRS was calculated for all the subjects, and complete blood count testing with biochemical measurements was performed. The mean RDW level was 13.7±1.8% in the CAD group and 13.1±1.0% in the control group, while the mean FRS was 9.0±4.9 in the CAD group and 6.4±3.9 in the control group. The RDW and FRS were significantly higher in the CAD group compared with the control group (P<0.001). No statistically significant differences were observed between the groups with regard to the hematocrit, mean corpuscular volume, platelets, glucose, urea, albumin, aspartate aminotransferase, total cholesterol, triglycerides (TG), high-density lipoprotein cholesterol, low-density lipoprotein cholesterol and N-terminal pro-brain natriuretic peptide (P>0.05). The RDW was shown to significantly correlate with the red blood cell (RBC) count ( r =-0.133, P=0.029), hemoglobin level ( r =-0.207, P=0.001) and TG level ( r =0.226, P<0.001) within the laboratory parameters, as well as the FRS ( r =0.206, P<0.001). In the stepwise multivariate linear regression, which included the RBC count, hemoglobin level, TG level and RDW, the FRS was predicted by hemoglobin ( r 2 =0.034, P=0.001), TG ( r 2 =0.059, P<0.001) and RDW ( r 2 =0.030, P=0.003) parameters. Therefore, a novel association was revealed between higher levels of RDW and an elevated FRS in patients with CAD, which raises the possibility that a simple marker, RDW, may be associated with an increased risk of heart events in CAD patients.

Salt (NaCl) is a common physiological stressor of plants. To better understand how germinating seeds respond to salt stress, we examined the changes that occurred in the proteome of maize seeds during NaCl-treated germination. Phenotypically, salt concentrations less than 0.2 M appear to delay germination, while higher concentrations disrupt development completely, leading to seed death. The identities of 96 proteins with expression levels altered by NaCl-incubation were established using 2-DE-MALDI-TOF-MS and 2-DE-MALDI-TOF-MS/MS. Of these 96 proteins, 79 were altered greater than twofold when incubated with a 0.2 M salt solution, while 51 were altered when incubated with a 0.1 M salt solution. According to their functional annotations in the Swiss-Prot protein-sequence databases, these proteins are mainly involved in seed storage, energy metabolism, stress response, and protein metabolism. Notably, the expression of proteins that respond to abscisic acid signals increased in response to salt stress. The results of this study provide important clues as to how NaCl stresses the physiology of germinating maize seeds.

Fibroblast growth factor 21 (FGF21) is a liver-secreted endocrine factor with multiple beneficial effects on obesity-related disorders. It enhances glucose uptake by inducing the expression of glucose transporter-1 (GLUT1) in adipocytes. Here we investigated the signaling pathways that mediate FGF21-induced GLUT1 expression and glucose uptake in vitro and in animals. Quantitative real-time PCR and a luciferase reporter assay showed that FGF21 induced GLUT1 expression through transcriptional activation. The truncation of the GLUT1 promoter from -3145 to -3105 bp, which contains two highly conserved serum response element (SRE) and E-Twenty Six (ETS) binding motif, dramatically decreased FGF21-induced promoter activity of the GLUT1 gene. A chromatin immunoprecipitation assay demonstrated that the transcription factors serum response factor (SRF) and Ets-like protein-1 (Elk-1) were recruited to the GLUT1 promoter upon FGF21 stimulation. The siRNA-mediated knockdown of either SRF or Elk-1 resulted in a marked attenuation in FGF21-induced GLUT1 expression and glucose uptake in adipocytes. In C57 lean mice, a single intravenous injection of FGF21 induced phosphorylation of Elk-1 at Ser(383) and SRF at Ser(103) and also led to the recruitment of Elk-1 and SRF to the GLUT1 promoter in epididymal fats. By contrast, such effects of in vivo FGF21 administration were blunted in high fat diet-induced obese mice. In conclusion, FGF21 induces GLUT1 expression and glucose uptake through sequential activation of ERK1/2 and SRF/Elk-1, which in turn triggers the transcriptional activation of GLUT1 in adipocytes. The impairment in this signaling pathway may contribute to FGF21 resistance in obese mice.

The FTIR spectra, SEM-EDXA and copper adsorption capacities of the raw plant materials, alkali-treated straws and cellulose xanthogenate derivatives of Eichhornia crassipes shoot, rape straw and corn stalk were investigated. FTIR spectra indicated that of the three plant materials, the aquatic biomass of E. crassipes shoot contained more OH and CO groups which accounted for the higher Cu(2+) adsorption capacities of the raw and alkali treated plant material. SEM-EDXA indicated the incorporation of sulphur and magnesium in the cellulose xanthogenate. The Cu(2+) adsorption capacities of the xanthogenates increased with their magnesium and sulphur contents. However more copper was adsorbed than that can be explained by exchange of copper with magnesium. Precipitation may contribute to the enhanced uptake of copper by the cellulose xanthogenate., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Mitochondrial dysfunction is involved in the pathogenesis of neurodegenerative diseases, including Parkinson's disease (PD). Uncoupling proteins (UCPs) delink ATP production from biofuel oxidation in mitochondria to reduce oxidative stress. UCP2 is expressed in brain, and has neuroprotective effects under various toxic insults. We observed induction of UCP2 expression by leptin in neuronal cultures, and hypothesize that leptin may preserve neuronal survival via UCP2. We showed that leptin preserved cell survival in neuronal SH-SY5Y cells against MPP+ toxicity (widely used in experimental Parkinsonian models) by maintaining ATP levels and mitochondrial membrane potential (MMP); these effects were accompanied by increased UCP2 expression. Leptin had no effect in modulating reactive oxygen species levels. Stable knockdown of UCP2 expression reduced ATP levels, and abolished leptin protection against MPP+-induced mitochondrial depolarization, ATP deficiency, and cell death, indicating that UCP2 is critical in mediating these neuroprotective effects of leptin against MPP+ toxicity. Interestingly, UCP2 knockdown increased UCP4 expression, but not of UCP5. Our findings show that leptin preserves cell survival by maintaining MMP and ATP levels mediated through UCP2 in MPP+-induced toxicity.