SLFN11 Blocks Stressed Replication Forks Independently of ATR.

SLFN11 sensitizes cancer cells to a broad range of DNA-targeted therapies. Here we show that, in response to replication stress induced by camptothecin, SLFN11 tightly binds chromatin at stressed replication foci via RPA1 together with the replication helicase subunit MCM3. Unlike ATR, SLFN11 neither interferes with the loading of CDC45 and PCNA nor inhibits the initiation of DNA replication but selectively blocks fork progression while inducing chromatin opening across replication initiation sites. The ATPase domain of SLFN11 is required for chromatin opening, replication block, and cell death but not for the tight binding of SLFN11 to chromatin. Replication stress by the CHK1 inhibitor Prexasertib also recruits SLFN11 to nascent replicating DNA together with CDC45 and PCNA. We conclude that SLFN11 is recruited to stressed replication forks carrying extended RPA filaments where it blocks replication by changing chromatin structure across replication sites.

Sensation Seeking and Substance use in Chinese Adolescents: Longitudinal Trajectories and Prospective Within-person Associations.

Sensation seeking has been extensively demonstrated as a risk factor for substance use. Potential bidirectional associations between sensation seeking and substance use at the within-person level are incompletely understood. The present study examined longitudinal trajectories of sensation seeking and substance use and bidirectional longitudinal associations between sensation seeking and substance use in Chinese adolescents during a 3-year period over three time points. A total of 10,138 adolescents (59.8%) male; Mage = 16.77, SD = 0.83 at time (1) were surveyed. Sensation seeking and substance use frequency increased concomitantly over time. At the within-person level, sensation seeking and substance use were reciprocally predictable, and there were no evidence of sex difference in longitudinal associations. This study provides unique data concerning the relationship between sensation seeking and substance use in a sample of Chinese adolescents, and highlights the importance of identifying sensation seeking behaviors to prevent substance use.

Solid Fe Resources Separated from Rolling Oil Sludge for CO Oxidation.

The efficient recycling of valuable resources from rolling oil sludge (ROS) to gain new uses remains a formidable challenge. In this study, we reported the recycling of solid Fe resources from ROS by a catalytic hydrogenation technique and its catalytic performance for CO oxidation. The solid Fe resources, after calcination in air (Fe2O3-H), exhibited comparable activity to those prepared by the calcinations of ferric nitrate (Fe2O3-C), suggesting that the solid resources have excellent recycling value when used as raw materials for CO oxidation catalyst preparation. Further studies to improve the catalytic performance by supporting the materials on high surface area 13X zeolite and by pretreating the materials with CO atmosphere, showed that the CO pretreatment greatly improved the CO oxidation activity and the best activity was achieved on the 20 wt.%Fe2O3-H/13X sample with complete CO conversion at 250 °C. CO pretreatment could produce more oxygen vacancies, facilitating O2 activation, and thus accelerate the CO oxidation reaction rate. The excellent reducibility and sufficient O2 adsorption amount were also favorable for its performance. The recycling of solid Fe resources from ROS is quite promising for CO oxidation applications.

A novel antibody-cell conjugation method to enhance and characterize cytokine-induced killer cells.

BACKGROUND: Cytokine-induced killer (CIK) cells are an ex vivo-expanded cellular therapy product with potent anti-tumor activity in a subset of patients with solid and hematologic malignancies. We hypothesize that directing CIK cells to a specific tumor antigen will enhance CIK cell anti-tumor cytotoxicity. METHODS: We present a newly developed method for affixing antibodies directly to cell surface proteins. First, we evaluated the anti-tumor potential of CIK cells after affixing tumor-antigen targeting monoclonal antibodies. Second, we evaluated whether this antibody-conjugation method can profile the surface proteome of CIK cells. RESULTS: We demonstrated that affixing rituximab or daratumumab to CIK cells enhances cytotoxic killing of multiple lymphoma cell lines in vitro. These 'armed' CIK cells exhibited enhanced intracellular signaling after engaging tumor targets. Cell surface proteome profiling suggested mechanisms by which antibody-armed CIK cells concurrently activated multiple surface proteins, leading to enhanced cytolytic activity. Our surface proteome analysis indicated that CIK cells display enhanced protein signatures indicative of immune responses, cellular activation and leukocyte migration. CONCLUSIONS: Here, we characterize the cell surface proteome of CIK cells using a novel methodology that can be rapidly applied to other cell types. Our study also demonstrates that without genetic modification CIK cells can be rapidly armed with monoclonal antibodies, which endows them with high specificity to kill tumor targets.

An atomic scale study of two-dimensional quasicrystal nucleation controlled by multiple length scale interactions.

Formation of quasicrystal structures has always been mysterious since the discovery of these magic structures. In this work, the nucleation of decagonal, dodecagonal, heptagonal, and octagonal quasicrystal structures controlled by the coupling among multiple length scales is investigated using a dynamic phase-field crystal model. We observe that the nucleation of quasicrystals proceeds through local rearrangement of length scales, i.e., the generation, merging and stacking of 3-atom building blocks constructed by the length scales, and accordingly, propose a geometric model to describe the cooperation of length scales during structural transformation in quasicrystal nucleation. Essentially, such cooperation is crucial to quasicrystal formation, and controlled by the match and balance between length scales. These findings clarify the scenario and microscopic mechanism of the structural evolution during quasicrystal nucleation, and help us to understand the common rule for the formation of periodic crystal and quasicrystal structures with various symmetries.

miR-100-3p inhibits cell proliferation and induces apoptosis in human gastric cancer through targeting to BMPR2.

BACKGROUND: miR-100 has been reported to closely associate with gastric cancer (GC) initiation and progression. However, the underlying mechanism of miR-100-3p in GC is still largely unclear. In this study, we intend to study how miR-100-3p regulates GC malignancy. METHODS: The expression levels of miR-100-3p in vitro (GES-1 and GC cell lines) and in vivo (cancerous and normal gastric tissues) were examined by quantitative real-time PCR (qRT-PCR). MTT and PE/Annexin V analyses were responsible for measurement of the effects of miR-100-3p on GC cell proliferation and apoptosis. Transwell assay with or without matrigel was used to examine the capacity of migration and invasion in GC cells. The interaction of miR-100-3p with bone morphogenetic protein receptor 2 (BMPR2) was confirmed through transcriptomics analysis and luciferase reporter assay. qRT-PCR and Western blot analyses were applied to determine the expression of ERK/AKT and Bax/Bcl2/Caspase3, which were responsible for the dysfunction of miR-100-3p. RESULTS: miR-100-3p was down-regulated in GC cell lines and cancerous tissues, and was negatively correlated with BMPR2. Loss of miR-100-3p promoted tumor growth and BMPR2 expression. Consistently, the effects of miR-100-3p inhibition on GC cells were partially neutralized by knockdown of BMPR2. Over-expression of miR-100-3p simultaneously inhibited tumor growth and down-regulated BMPR2 expression. Consistently, over-expression of BMPR2 partially neutralized the effects of miR-100-3p over-expression. Further study demonstrated that BMPR2 mediated the effects downstream of miR-100-3p, which might indirectly regulate ERK/AKT and Bax/Bcl2/Caspase3 signaling pathways. CONCLUSION: miR-100-3p acted as a tumor-suppressor miRNA that down-regulated BMPR2, which consequently inhibited the ERK/AKT signaling and activated Bax/Bcl2/Caspase3 signaling. This finding provided novel insights into GC and could contribute to identify a new diagnostic and therapeutic target.

Molecular dynamics investigation of the local structure in iron melts and its role in crystal nucleation during rapid solidification.

A comprehensive investigation on local structures in iron melts and their role in nucleation under various cooling rates was performed by means of large-scale molecular dynamics simulations. The embedded atoms method (EAM) was adopted to describe the interactions between iron atoms. Connections between short-range order (SRO), medium-range order (MRO), and crystalline nucleation from iron melts were constructed using several structural analysis techniques, including the radial distribution function, common neighbor analysis method, the Voronoi tessellation, and bond order analysis. The simulation results showed that abundant types of atomic clusters with SRO, mainly including the icosahedral-like (ICO-like) and fcc-like clusters, were predominant in undercooled iron melts. The obtained microstructures were determined by the competition between the ICO-like and crystal-like configurations. There existed a critical cooling rate, below which the fcc-like configurations gain the advantage upon cooling and where crystallization could take place; otherwise, the ICO-like configurations are favored and the glass phases could be obtained. Furthermore, it was proved that the crystal nucleation could be divided into three stages: first, a fluctuation and competition between crystal-like and ICO-like clusters in undercooled melts; second, the formation and growth of MRO clusters via the transformation of atomic configurations from ICO-like to crystal-like; finally, the nucleation of bcc nuclei from the core of steady MRO clusters. This process agrees with the Ostwald's step rule and the findings from other investigations. Based on the analysis of the compositional origin of MRO clusters, we further found that the MRO clusters were mainly composed of fcc-like instead of ICO-like configurations, indicating a negative role of ICO-like configurations in crystal nucleation.

Detection of cognitive impairment using self-rated AD8 and informant-reported AD8.

BACKGROUND/PURPOSE: Screening of dementia can help to initiate proper management of the disorder. The use of the Ascertain Dementia 8-item Questionnaire (AD8) in screening has been promoted in Taiwan recently. The purpose of this study was to compare the psychometric properties and appropriateness of informant-reported and self-rated AD8 in cognitive impairment screening in Taiwan. METHODS: The AD8 were administered to 153 participants and their informants recruited from two neurology out-patient clinics. The discriminative abilities for early cognitive impairment [Clinical Dementia Rating scale (CDR) 0.5 and 1] of informant-based and self-rating AD8 were determined and compared with their areas under the receiver operating curve. κ coefficients representing the agreement between self-rated and informant-reported AD8 scores were also calculated. RESULTS: Participants and their informants were aged 76.9 years and 56.0 years on average, respectively. Only informant-reported AD8 was significantly associated with CDR level (Spearman ρ=0.469, p<0.001) and Cognitive Abilities Screening Instrument score (Spearman ρ=-0.458, p<0.001). The item-by-item agreements between self-rated and informant-reported AD8 were poor (κ coefficients: -0.030 to 0.206). The area under the receiver-operator characteristic curve was 0.59 for self-rated AD8 scores, and 0.77 for informant-reported AD8 scores, indicating that the discriminating ability of AD8 scores between CDR 0 and CDR 0.5 or greater is better when reported by informant than when rated by self. CONCLUSION: Informant-rated AD8 gave more accurate screening results than self-reported AD8 in an out-patient clinic setting.

The association of APOC4 polymorphisms with premature coronary artery disease in a Chinese Han population.

BACKGROUND: Hypercholesterolemia arising from abnormal lipid metabolism is one of the critical risk factors for coronary artery disease (CAD), however the roles of genetic variants in lipid metabolism-related genes on premature CAD (≤ 60 years old) development still require further investigation. We herein genotyped four single nucleotide polymorphisms (SNPs) in lipid metabolism-related genes (rs1132899 and rs5167 in APOC4, rs1801693 and rs7765781 in LPA), aimed to shed light on the influence of these SNPs on individual susceptibility to early-onset CAD. METHODS: Genotyping of the four SNPs (rs1132899, rs5167, rs1801693 and rs7765781) was performed in 224 premature CAD cases and 297 control subjects (≤ 60 years old) using polymerase chain reaction-ligation detection reaction (PCR-LDR) method. The association of these SNPs with premature CAD was performed with SPSS software. RESULTS: Multivariate logistic regression analysis showed that C allele (OR = 1.50, P = 0.027) and CC genotype (OR = 2.84, P = 0.022) of APOC4 rs1132899 were associated with increased premature CAD risk, while the other three SNPs had no significant effect. Further stratified analysis uncovered a more evident association with the risk of premature CAD among male subjects (C allele, OR = 1.65, and CC genotype, OR = 3.33). CONCLUSIONS: Our data provides the first evidence that APOC4 rs1132899 polymorphism was associated with an increased risk of premature CAD in Chinese subjects, and the association was more significant among male subjects.

LincRNA-p21: Implications in Human Diseases.

Long noncoding RNAs (lncRNAs), which lack significant protein-coding capacity, regulate various biological processes through diverse and as yet poorly understood molecular mechanisms. However, a number of studies in the past few years have documented important functions for lncRNAs in human diseases. Among these lncRNAs, lincRNA-p21 has been proposed to be a novel regulator of cell proliferation, apoptosis and DNA damage response, and involved in the initiation and progression of human diseases. In this review, we summarize the current knowledge of lincRNA-p21, mainly focus on the known biological functions and its underlying mechanisms. Moreover, we highlight the growing body of evidences for the importance of lincRNA-p21 in diverse human diseases, which indicate lincRNA-p21 as a potential diagnostic marker and/or a valuable therapeutic target for these diseases.

The cellular autophagy pathway modulates human T-cell leukemia virus type 1 replication.

Autophagy, a general homeostatic process for degradation of cytosolic proteins or organelles, has been reported to modulate the replication of many viruses. The role of autophagy in human T-cell leukemia virus type 1 (HTLV-1) replication has, however, been uncharacterized. Here, we report that HTLV-1 infection increases the accumulation of autophagosomes and that this accumulation increases HTLV-1 production. We found that the HTLV-1 Tax protein increases cellular autophagosome accumulation by acting to block the fusion of autophagosomes to lysosomes, preventing the degradation of the former by the latter. Interestingly, the inhibition of cellular autophagosome-lysosome fusion using bafilomycin A increased the stability of the Tax protein, suggesting that cellular degradation of Tax occurs in part through autophagy. Our current findings indicate that by interrupting the cell's autophagic process, Tax exerts a positive feedback on its own stability.

Numerical Simulation and Machine Learning Prediction of the Direct Chill Casting Process of Large-Scale Aluminum Ingots.

The large-scale ingot of the 7xxx-series aluminum alloys fabricated by direct chill (DC) casting often suffers from foundry defects such as cracks and cold shut due to the formidable challenges in the precise controlling of casting parameters. In this manuscript, by using the integrated computational method combining numerical simulations with machine learning, we systematically estimated the evolution of multi-physical fields and grain structures during the solidification processes. The numerical simulation results quantified the influences of key casting parameters including pouring temperature, casting speed, primary cooling intensity, and secondary cooling water flow rate on the shape of the mushy zone, heat transport, residual stress, and grain structure of DC casting ingots. Then, based on the data of numerical simulations, we established a novel model for the relationship between casting parameters and solidification characteristics through machine learning. By comparing it with experimental measurements, the model showed reasonable accuracy in predicting the sump profile, microstructure evolution, and solidification kinetics under the complicated influences of casting parameters. The integrated computational method and predicting model could be used to efficiently and accurately determine the DC casting parameters to decrease the casting defects.

Regulatory T cells use heparanase to access IL-2 bound to extracellular matrix in inflamed tissue.

Although FOXP3+ regulatory T cells (Treg) depend on IL-2 produced by other cells for their survival and function, the levels of IL-2 in inflamed tissue are low, making it unclear how Treg access this critical resource. Here, we show that Treg use heparanase (HPSE) to access IL-2 sequestered by heparan sulfate (HS) within the extracellular matrix (ECM) of inflamed central nervous system tissue. HPSE expression distinguishes human and murine Treg from conventional T cells and is regulated by the availability of IL-2. HPSE-/- Treg have impaired stability and function in vivo, including in the experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis. Conversely, endowing monoclonal antibody-directed chimeric antigen receptor (mAbCAR) Treg with HPSE enhances their ability to access HS-sequestered IL-2 and their ability to suppress neuroinflammation in vivo. Together, these data identify a role for HPSE and the ECM in immune tolerance, providing new avenues for improving Treg-based therapy of autoimmunity.

Risk of colorectal cancer in type 2 diabetic patients: a population-based cohort study.

OBJECTIVE: Most of the existing findings on the association between diabetes mellitus and colorectal cancer were generated from studies in Western societies. However, significant differences in cancer incidence and cancer-prone lifestyles are apparent between Asian and Western countries. This study aims to estimate the risks of colorectal cancer in the diabetic population in Taiwan by conducting a large-scale, controlled cohort study. METHODS: From Taiwan's Longitudinal Health Insurance Database 2005 (LHID2005), a total of 37 001 diabetic patients were identified. We also obtained data for four controls per patient, matched for sex, age and year of first entry into the LHID2005. All patients were followed up from the date of entry into the LHID2005 until they developed colorectal cancer or to the end of 2006, whichever was earlier. We used Cox's regression models to assess the risk of developing colorectal cancer, with adjustment for sex, age, comorbid disorders, and socioeconomic characteristics. RESULTS: We identified 37 001 diabetic patients and 148 004 controls. The adjusted hazard ratio for colorectal cancer in diabetes mellitus patients was 2.1 (95% confidence interval, 1.82-2.42) compared with controls. The risk was significant to both men and women. The adjusted hazard ratios for colorectal cancer were 2.03 (95% confidence interval, 1.68-2.47) in male diabetes mellitus patients and 2.17 (95% confidence interval, 1.77-2.67) in female diabetes mellitus patients. CONCLUSIONS: Our findings based on a large population-based cohort study provide evidence that diabetes mellitus may increase the risk of colorectal cancer in Asians.

Efficient downstream valorization of lignocellulose after organosolv fractionation: Synergistic enhancement of waterborne coatings by co-assembled lignin@cellulose nanocrystals.

The simultaneous downstream valorization of cellulose and lignin is an important aspect of efficiently extracting value from lignocellulose. The present work, we demonstrated the preparation of a novel bio-based filler by the co-assembly of cellulose and lignin obtained from a one-pot ethanosolv lignocellulose fractionation process. The cellulose was valorized by forming cellulose nanocrystals (CNCs) through simple bleaching and ultrasonication processes. The lignin fractions demonstrated greater solubility (19.2 mg/mL) and lower molecular weight (6980 g/mol) than conventional industrial lignins. Various lignin@CNCs specimens were prepared via a facile co-assembly of the lignin and CNCs. These entirely bio-based materials could be used as a multifunctional filler to enhance the properties of a waterborne coating (WBC). Specifically, the mechanical properties, coating performance and ultraviolet resistance of a WBC were all significantly improved, demonstrating a synergistic enhancement effect obtained from the CNCs and lignin. In this manner, both cellulose and lignin components were efficiently transformed to value-added fillers for WBC, demonstrating a highly efficient pathway for lignocellulose utilization and downstream value-added applications.

Efficient extraction of nanocellulose from lignocellulose using aqueous butanediol fractionation to improve the performance of waterborne wood coating.

The highly efficient extraction of cellulose from lignocellulose with an excellent yield of 95.2 % and purity of 96.7 % was demonstrated using acid-catalyzed fractionation with aqueous butanediol. This cellulose was subsequently transformed into cellulose nanofibers (CNFs) and cellulose nanocrystals (CNCs) with specific dimensions and surface functional groups through various chemomechanical treatments. The average diameters of CNFs and CNCs produced by sulfuric acid hydrolysis-ultrasonication and deep eutectic solvent treatment-ultrasonication (DES-CNCs) were 29.7, 21.9 and 17.3 nm, respectively. The DES-CNCs were obtained in a good yield of 71 ± 1.27 wt% and exhibited a high zeta potential of -33.5 ± 2.51 mV following posthydrolysis and esterification during the DES treatment. These CNFs and CNCs were used as nanofillers in a waterborne wood coating (WWC), which significantly improved its dynamic viscosity and storage modulus. The addition of these materials also enhanced the mechanical strength of the WWC but had little effect on transmittance. Glossiness, hardness, abrasion resistance and adhesion strength were evaluated, and the DES-CNCs provided the greatest improvements at a low concentration. A plausible reinforcement mechanism was presented. This work provided an efficient cellulose extraction method and detailed structure elucidation of the nanocellulose together with suggestions for value-added applications of cellulosic nanofillers for reinforcing WWC.

The Effect of Lattice Misfits on the Precipitation at Dislocations: Phase-Field Crystal Simulation.

An atomic-scale approach was employed to simulate the formation of precipitates with different lattice misfits in the early stages of the aging of supersaturated aluminum alloys. The simulation results revealed that the increase in lattice misfits could significantly promote the nucleation rate of precipitates, which results in a larger number and smaller size of the precipitates. The morphologies of the precipitates also vary with the degree of a lattice misfit. Moreover, the higher the lattice misfit, the earlier the nucleation of the second phase occurs, which can substantially inhibit the movement of dislocations. The research on the lattice misfit of precipitation can provide theoretical guidance for the design of high-strength aluminum alloys.

Atomic-Scale Insights into the Deformation Mechanism of the Microstructures in Precipitation-Strengthening Alloys.

Clarifying the deformation behaviors of microstructures could greatly help us understand the precipitation-strengthening mechanism in alloys. However, it is still a formidable challenge to study the slow plastic deformation of alloys at the atomic scale. In this work, the phase-field crystal method was used to investigate the interactions between precipitates, grain boundary, and dislocation during the deformation processes at different degrees of lattice misfits and strain rates. The results demonstrate that the pinning effect of precipitates becomes increasingly strong with the increase of lattice misfit at relatively slow deformation with a strain rate of 10-4. The cut regimen prevails under the interaction between coherent precipitates and dislocations. In the case of a large lattice misfit of 19.3%, the dislocations tend to move toward the incoherent phase interface and are absorbed. The deformation behavior of the precipitate-matrix phase interface was also investigated. Collaborative deformation is observed in coherent and semi-coherent interfaces, while incoherent precipitate deforms independently of the matrix grains. The faster deformations (strain rate is 10-2) with different lattice misfits all are characterized by the generation of a large number of dislocations and vacancies. The results contribute to important insights into the fundamental issue about how the microstructures of precipitation-strengthening alloys deform collaboratively or independently under different lattice misfits and deformation rates.

Atomic-Scale Insights into the Self-Assembly of Alternating AlN/TiN Lamellar Nanostructures via Spinodal Decomposition in AlTiN Coating.

The self-assembly mechanism of alternating AlN/TiN nano-lamellar structures in AlTiN coating is still a mystery, though this coating has been widely used in industry. Here, by using the phase-field crystal method, we studied the atomic-scale mechanisms of the formation of nano-lamellar structures during spinodal decomposition transformation of an AlTiN coating. The results show that the formation of a lamella is characterized by four distinct stages including the generation of dislocations (stage I), formation of islands (stage II), merging of islands (stage III), and flattening of lamellae (stage IV). The locally periodic fluctuation of the concentration along the lamella leads to the generation of periodically distributed misfit dislocations and then AlN/TiN islands, while the fluctuation of the composition in the direction normal to the lamella is responsible for the merging of islands and flattening of a lamella and more importantly the cooperative growth between neighboring lamellae. Moreover, we found that misfit dislocations play a crucial role in all the four stages, promoting the cooperative growth of TiN and AlN lamellae. Our results demonstrate that the TiN and AlN lamellae could be produced through the cooperative growth of AlN/TiN lamellae in spinodal decomposition of the AlTiN phase.

A Novel Allogeneic Rituximab-Conjugated Gamma Delta T Cell Therapy for the Treatment of Relapsed/Refractory B-Cell Lymphoma.

Chimeric antigen receptor T cell (CAR-T) therapy has been applied in the treatment of B-cell lymphoma; however, CAR-T manufacturing requires virus- or non-virus-based genetic modification, which causes high manufacturing costs and potential safety concerns. Antibody-cell conjugation (ACC) technology, which originated from bio-orthogonal click chemistry, provides an efficient approach for arming immune cells with cancer-targeting antibodies without genetic modification. Here, we applied ACC technology in Vγ9Vδ2 T (γδ2 T) cells to generate a novel off-the-shelf CD20-targeting cell therapy ACE1831 (rituximab-conjugated γδ2 T cells) against relapsed/refractory B-cell lymphoma. ACE1831 exhibited superior cytotoxicity against B-cell lymphoma cells and rituximab-resistant cells compared to γδ2 T cells without rituximab conjugation. The in vivo xenograft study demonstrated that ACE1831 treatment strongly suppressed the aggressive proliferation of B-cell lymphoma and prolonged the survival of tumor-bearing mice with no observed toxicity. Mass spectrometry analysis indicated that cell activation receptors including the TCR complex, integrins and cytokine receptors were conjugated with rituximab. Intriguingly, the antigen recognition of the ACC-linked antibody/receptor complex stimulated NFAT activation and contributed to ACE1831-mediated cytotoxicity against CD20-expressing cancer cells. This study elucidates the role of the ACC-linked antibody/receptor complex in cytotoxicity and supports the potential of ACE1831 as an off-the-shelf γδ2 cell therapy against relapsed/refractory B-cell lymphoma.