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High-strength low-alloy steels are widely used, but their traditional heat-treatment process is complex, energy-intensive, and makes it difficult to fully exploit the material's potential. In this paper, the electropulsing processing technology was applied to the quenching and tempering process of ZG25SiMn2CrB steel. Through microstructural characterization and mechanical property testing, the influence of electropulsing on the solid-state phase transition process of annealing steel was systematically studied. The heating process of the specimen with the annealing state (initial state) is the diffusion-type transition. As the discharge time increased, the microstructure gradually transformed from ferrite/pearlitic to slate martensite. Optimal mechanical properties and fine microstructure were achieved after quenching at 500 ms. The steel subjected to rapid tempering with 160 ms electropulsing exhibited good, comprehensive mechanical properties (tensile strength 1609 MPa, yield strength 1401.27 MPa, elongation 11.63%, and hardness 48.68 HRC). These favorable mechanical properties are attributed to the coupled impact of thermal and non-thermal effects induced by high-density pulse current. Specifically, the thermal effect provides the thermodynamic conditions for phase transformation, while the non-thermal effect reduces the nucleation barrier of austenite, which increases the nucleation rate during instantaneous heating, and the following rapid cooling suppresses the growth of austenite grains. Additionally, the fine microstructure prevents the occurrence of temper brittleness. [ABSTRACT FROM AUTHOR]

Background: The development of immune checkpoint inhibitors has made a significant breakthrough in the treatment of non‐small‐cell lung cancer (NSCLC). However, there remains a huge unmet clinical need for patients with acquired resistance after initial treatment response. Methods: This study evaluated the combination of IBI310 (an anti‐cytotoxic T lymphocyte‐associated antigen‐4 [CTLA‐4] antibody) and sintilimab (an anti‐programmed death 1 [PD‐1]) antibody) in NSCLC patients who have previously been treated with anti‐PD‐1/ligand (L)1 and acquired resistance. The patients were randomly assigned to receive either a lower dose of IBI310 (1 mg/kg Q3W, cohort A) or a higher dose of IBI310 (3 mg/kg Q3W, cohort B) in combination with sintilimab (200 mg Q3W). The primary endpoints of the study were objective response rate (ORR) assessed by RECISTv1.1 and safety, while secondary endpoints included disease control rate (DCR), progression‐free survival (PFS), and overall survival (OS). Results: As of November 2, 2023, the study had enrolled 30 patients, with 15 patients in each cohort. The ORR was 13.3% (2/15, 95% confidence interval [CI], 1.7–40.5) in cohort B. DCR were 46.7% (95% CI, 21.3–73.4) and 66.7% (95% CI, 38.4–88.2) in cohorts A and B, respectively. In cohorts A and B of this trial, the median follow‐up times were 4.2 and 5.6 months, respectively. Median PFS was 1.45 (95% CI, 1.35–2.73) versus 2.73 (95% CI, 1.41–4.90) months for cohort A versus B; the median OS was 7.03 (95% CI, 3.09–not calculable [NC]) months in cohort A and 8.90 (95% CI, 5.13–NC) months in cohort B. Of the 30 patients, 86.7% in both cohorts experienced treatment‐related adverse events (TRAEs) with Grade ≥3 TRAEs occurring in 40% and 53.3% of patients in cohorts A and B, respectively. Conclusion: IBI310 3 mg/kg Q3W plus sintilimab was effective in a small number of previously treated anti‐PD‐1/L1‐resistant NSCLC patients. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) has been one of the most common cancers and maintains the second-highest incidence and mortality rates among all cancers. The high risk of recurrence and metastasis and poor survival are still huge challenges in CRC therapy, in which the discovery of ferroptosis provides a novel perspective. It has been ten years since a unique type of regulated cell death driven by iron accumulation and lipid peroxidation was proposed and named ferroptosis. During the past decade, there have been multiple pieces of evidence suggesting that ferroptosis participates in the pathophysiological processes during disease progression. In this review, we describe ferroptosis as an imbalance of oxidant systems and anti-oxidants which results in lipid peroxidation, membrane damage, and finally cell death. We elaborate on the mechanisms of ferroptosis and systematically summarize recent studies on the regulatory pathways of ferroptosis in CRC from various perspectives, ranging from encoding genes, noncoding RNAs to regulatory proteins. Finally, we discuss the potential therapeutic role of ferroptosis in CRC treatments. [ABSTRACT FROM AUTHOR]

Echoviruses, for which there are currently no approved vaccines or drugs, are responsible for a range of human diseases, for example echovirus 11 (E11) is a major cause of serious neonatal morbidity and mortality. Decay-accelerating factor (DAF, also known as CD55) is an attachment receptor for E11. Here, we report the structure of the complex of E11 and the full-length ectodomain of DAF (short consensus repeats, SCRs, 1–4) at 3.1 Å determined by cryo-electron microscopy (cryo-EM). SCRs 3 and 4 of DAF interact with E11 at the southern rim of the canyon via the VP2 EF and VP3 BC loops. We also observe an unexpected interaction between the N-linked glycan (residue 95 of DAF) and the VP2 BC loop of E11. DAF is a receptor for at least 20 enteroviruses and we classify its binding patterns from reported DAF/virus complexes into two distinct positions and orientations, named as E6 and E11 poses. Whilst 60 DAF molecules can attach to the virion in the E6 pose, no more than 30 can attach to E11 due to steric restrictions. Analysis of the distinct modes of interaction and structure and sequence-based phylogenies suggests that the two modes evolved independently, with the E6 mode likely found earlier. [ABSTRACT FROM AUTHOR]

Sizzled (Szl) is both a secreted frizzled related protein (sFRP) and a naturally occurring inhibitor of the zinc metalloproteinase bone morphogenetic protein-1 (BMP-1), a key regulator of extracellular matrix assembly and growth factor activation. Here we present a new crystal structure for Szl which differs from that previously reported by a large scale (90°) hinge rotation between its cysteine-rich and netrin-like domains. We also present results of a molecular docking analysis showing interactions likely to be involved in the inhibition of BMP-1 activity by Szl. When compared with known structures of BMP-1 in complex with small molecule inhibitors, this reveals features that may be helpful in the design of new inhibitors to prevent the excessive accumulation of extracellular matrix that is the hallmark of fibrotic diseases. [ABSTRACT FROM AUTHOR]

Signaling by the human C-type lectin-like receptor, natural killer (NK) cell inhibitory receptor NKR-P1, has a critical role in many immune-related diseases and cancer. C-type lectin-like receptors have weak affinities to their ligands; therefore, setting up a comprehensive model of NKR-P1-LLT1 interactions that considers the natural state of the receptor on the cell surface is necessary to understand its functions. Here we report the crystal structures of the NKR-P1 and NKR-P1:LLT1 complexes, which provides evidence that NKR-P1 forms homodimers in an unexpected arrangement to enable LLT1 binding in two modes, bridging two LLT1 molecules. These interaction clusters are suggestive of an inhibitory immune synapse. By observing the formation of these clusters in solution using SEC-SAXS analysis, by dSTORM super-resolution microscopy on the cell surface, and by following their role in receptor signaling with freshly isolated NK cells, we show that only the ligation of both LLT1 binding interfaces leads to effective NKR-P1 inhibitory signaling. In summary, our findings collectively support a model of NKR-P1:LLT1 clustering, which allows the interacting proteins to overcome weak ligand-receptor affinity and to trigger signal transduction upon cellular contact in the immune synapse. NKR-P1 is an inhibitory receptor on the surface of natural killer cells, and its engagement with the ligand LLT1 on activated monocytes and B cells triggers NK cell self-tolerance and other immunological processes. Here authors set up a comprehensive, structure-based model of NKR-P1-LLT1 interaction that involves NKR-P1 homodimer formation and subsequent bridging of two LLT1 molecules. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) are associated with healing or deteriorating degenerated intervertebral disc (IVD) tissues in spinal cord diseases, including intervertebral disc degeneration (IDD). IDD represents a chronic process of extracellular matrix destruction, but the relevant molecular mechanisms implicated in the regenerative effects of miRNAs are unclear. Here, we investigated the regenerative effects of microRNA-140 (miR-140-3p) in an IDD model induced by annulus needle puncture. Bioinformatics analysis was conducted to identify regulatory factors (KLF5/N-cadherin/MDM2/Slug) linked to miR-140-3p effects in IDD. Mesenchymal stem cells (MSCs) were extracted from degenerated IVD nucleus pulposus (NP), and the expression of miR-140-3p/KLF5/N-cadherin/MDM2/Slug was manipulated to explore their effects on cell proliferation, migration, apoptosis and differentiation. The results showed that miR-140-3p was under-expressed in the degenerated IVD NP, whereas its overexpression alleviated IDD. Mechanistic studies suggested that miR-140-3p targeted KLF5 expression, and high KLF5 expression impeded the migration and differentiation of MSCs. In degenerated IVD NP-derived MSCs, MiR-140-3p-mediated KLF5 downregulation simultaneously elevated N-cadherin expression and transcriptionally inhibited MDM2, thus upregulating Slug expression. The experimental data indicated that miR-140-3p enhanced the proliferation, migration and differentiation of degenerated IVD NP-derived MSCs and repressed their apoptosis. The in vivo validation experiment also demonstrated that miR-140-3p inhibited IDD by modulating the KLF5/N-cadherin/MDM2/Slug axis. Collectively, our results uncovered the regenerative role of miR-140-3p in IDD via regulation of the KLF5/N-cadherin/MDM2/Slug axis, which could be a potential therapeutic target for IDD. Abbreviations: miR-140-3p: microRNA-140-3p; IDD: intervertebral disc degeneration; MSCs: Mesenchymal stem cells; IVD: intervertebral disc; MSCs: mesenchymal stem cells; KLF5: Kruppel-like factor 5; MDM2: mouse double minute 2; NC: negative control; DHI: disc height index [ABSTRACT FROM AUTHOR]

The degradation behaviors of as‐received and as‐solutionized AZ31 alloys in Hanks' solution are in situ studied by a 3D digital optical microscope. The initiation and extension processes of corrosion are investigated. Long‐time immersion and electrochemical tests are applied to investigate the corrosion mechanism systematically. The corrosion attacks of as‐received and as‐solutionized AZ31 alloy both start from the grain boundaries (with and without the Al8Mn5 phase) while show no preferential propagation, and the scratches also can act as the corrosion starting positions. The Al8Mn5 phase does not show an obvious accelerated effect on the Mg matrix's corrosion, and it also suffers corrosion. Solid solution treatment can enhance the corrosion resistance of AZ31 alloy is primarily due to the reduced dislocation density. Degradation products on as‐received AZ31 alloy are studied, the Al, Zn, and Mn elements degrade as Al2O3, ZnO, and MnO, respectively. [ABSTRACT FROM AUTHOR]

The study examined the potential nutritive value of rice protein (RP) through Maillard reaction. Structures and properties of synthetic conjugates of RP and exopolysaccharide (EPS) from Arthrobacter ps‐5 were investigated systematically. Fluorescence characteristics and high molecular weight compounds appeared in Maillard reaction products (MRPs). Moreover, EPS or its degradation products in the form of covalent bond cross‐linked with RP were identified, where –NH2 disappeared and C=O, C=N and C–N increased. Determination of free –SH residues suggested mutual conversion between disulfide bonds and sulfhydryl groups occurred during Maillard reaction. HPLC analysis identified conjugates with different molecular weight, where melanoprotein was formed by covalent bonds. As RP conjugated with EPS, the molecules spread out and changed the spatial structure. Functional properties of MRPs, including solubility, foaming activity, emulsifying ability and resistance to oxidation, were greatly improved. The study has discovered an efficient method for increasing the application value of plant protein. [ABSTRACT FROM AUTHOR]

Most studies examining neurocognitive aging are based on the blood‐oxygen level‐dependent signal obtained during functional magnetic resonance imaging (fMRI). The physiological basis of this signal is neural–vascular coupling, the process by which neurons signal cerebrovasculature to dilate in response to an increase in active neural metabolism due to stimulation. These fMRI studies of aging rely on the hemodynamic equivalence assumption that this process is not disrupted by physiologic deterioration associated with aging. Studies of neural–vascular coupling challenge this assumption and show that neural–vascular coupling is closely related to cognition. In this review, we put forward a theory of processing speed decline in aging and how it is related to age‐related neural–vascular coupling changes based on the results of studies elucidating the relationships between cognition, cerebrovascular dynamics, and aging. Impact Statement: Theories of neurocognitive aging are based on conflicting results of functional magnetic resonance imaging‐blood‐oxygen‐level‐dependent imaging studies that probably reflect age‐differences in complex neural‐vascular signaling processes. In this review, we present evidence that supports a theory centering on the importance of cerebrovascular dynamics in age‐related cognitive decline. [ABSTRACT FROM AUTHOR]

The present and future research efforts in cognitive neuroscience and psychophysiology rely on the measurement, understanding, and interpretation of blood oxygenation level‐dependent (BOLD) functional magnetic resonance imaging (fMRI) to effectively investigate brain function. Aging and age‐associated pathophysiological processes change the structural and functional integrity of the cerebrovasculature which can significantly alter how the BOLD signal is recorded and interpreted. In order to gain an improved understanding of the benefits, drawbacks, and methodological implications for BOLD fMRI in the context of cognitive neuroscience, it is crucial to understand the cellular and molecular mechanism of age‐related vascular pathologies. This review discusses the multifaceted effects of aging and the contributions of age‐related pathologies on structural and functional integrity of the cerebral microcirculation as they has been investigated in animal models of aging, including age‐related alterations in neurovascular coupling responses, cellular and molecular mechanisms involved in microvascular damage, vascular rarefaction, blood–brain barrier disruption, senescence, humoral deficiencies as they relate to, and potentially introduce confounding factors in the interpretation of BOLD fMRI. Impact Statement: This review discusses the multifaceted effects of aging and the contributions of age‐related pathologies on structural and functional integrity of the cerebral microcirculation. Animal models of aging research allows for investigation of alterations in neurovascular coupling responses, cellular and molecular mechanisms involved in microvascular damage, vascular rarefaction, blood–brain barrier disruption, senescence, humoral deficiencies as they relate to, and potentially introduce confounding factors in the interpretation of BOLD fMRI. [ABSTRACT FROM AUTHOR]

Purpose: Nonsmall cell lung cancer (NSCLC) patients with brain metastases (BM) have a poor prognosis. Despite the traditional methods including radiotherapy and chemotherapy, epidermal growth factor receptor‐tyrosine kinase inhibitors (EGFR‐TKIs) might benefit patients on survival and quality of life. We investigated the cost‐effectiveness of icotinib compared with whole‐brain irradiation (WBI) with or without chemotherapy for NSCLC patients with BM. Materials and methods: A Markov model was conducted based on the data of BRAIN trial. We compared the economic benefit between icotinib and the combination of WBI and WBI plus chemotherapy group. We considered disease progression as intracranial progression and overall progression separately. Sensitivity analyses were performed to observe the stability of the model. The willingness‐to‐pay (WTP) was set as 3× per capita gross domestic product ($25929/quality‐adjusted life year [QALY]) from the Chinese healthcare perspective. Results: When considering progression as intracranial progression and overall progression, respectively, the incremental cost‐effectiveness ratio was $14 882.64/QALY and $13 484.21/QALY between icotinib and WBI/WBI‐chemotherapy. Besides, both of the average cost‐effective ratio (ACER) and net benefit showed advantage of icotinib (ACER: $34 521.42/QALY for intracranial progression and $36 562.63/QALY for overall progression; net benefit: –$8407.36 for intracranial progression and –$9836.41 for overall progression). One‐way sensitivity analyses demonstrated that no thresholds were encountered. The probabilistic sensitivity analyses showed even at a WTP under $18 000/QALY, icotinib could be cost‐effective. Conclusion: : Icotinib was cost‐effective compared with WBI with or without chemotherapy. [ABSTRACT FROM AUTHOR]

The π‐conjugation of molecules has a large influence on their excited state properties, especially for red thermally activated delayed fluorescence (TADF) materials. Two orange‐red TADF compounds comprising dual dicyano‐substituted pyrazine/quinoxaline acceptors have been designed and synthesized. TPA‐2DCNQ (3,3′‐((phenylazanediyl)bis(4,1‐phenylene))bis(2‐phenylquinoxaline‐6,7‐dicarbonitrile) with extended π‐conjugated quinoxaline as the acceptor exhibits higher photoluminescence quantum yields (ca. 0.67–0.71) in doped films. A smaller energy splitting (ΔEst) between the first singlet excited state and triplet excited state is also achieved, indicating that extending the π‐conjugation of the acceptor rationally is an effective approach to designing highly efficient long‐wavelength TADF materials. Devices with TPA‐2DCNQ as the emitter display maximum external quantum efficiencies (EQEs) of 12.6–14.0 %, which are more than twice those of devices containing TPA‐2DCNPZ (6,6′‐((phenylazanediyl)bis(4,1‐phenylene))bis(5‐phenylpyrazine‐2,3‐dicarbonitrile). [ABSTRACT FROM AUTHOR]

The study was focussed on the inhibitory mechanism associated with the ability of an endophytic bacterium - Bacillus altitudinis Q7, obtained from Ginkgo biloba, to inhibit the growth of Alternaria alternata in vitro. A fungus, identified as Alternaria alternata was isolated from the rotten part of an apple. One of the endophytes was identified as Bacillus altitudinis Q7. Effect of Bacillus altitudinis Q7 on Alternaria alternata was characterized by measuring membrane permeability and lipid peroxidation. Antioxidant enzymes in Alternaria alternata were determined before and after exposure to Bacillus altitudinis Q7. Results indicated that cell membranes in Alternaria alternata were damaged, lipid peroxidation was enhanced, and superoxide dismutase, peroxidase, and polyphenol oxidase were significantly inhibited. Content of lipopeptides produced by Bacillus altitudinis Q7 was higher than other metabolites. The FTIR spectra revealed that the prepared antibacterial lipopeptides is a cyclic lipopeptides. The effect of lipopeptides produced by Bacillus altitudinis Q7 at 2 mg/mL against Alternaria alternata in vitro reached 83.2%. The lipopeptide-treated group showed the same trend as Q7 fermentation broth in inhibition mode of action. Moreover, the utilization of proteins and sugars during culturing of Alternaria alternata decreased when adding lipopeptides to the growth medium. Bacillus altitudinis Q7 from Ginkgo biloba significantly inhibited the growth of Alternaria alternata and is a very promising biocontrol strain against Alternaria alternata. The study of endophytic bacteria and its metabolites is being done to identify biological control alternatives. The results provide a theoretical basis for understanding their antagonistic properties. [ABSTRACT FROM AUTHOR]

Background: Cognitive slowing occurs in ~70% of multiple sclerosis (MS) patients. The pathophysiology of this slowing is unknown. Neurovascular coupling, acute localized blood flow increases following neural activity, is essential for efficient cognition. Loss of vascular compliance along the cerebrovascular tree would result in suboptimal vasodilation, neurovascular uncoupling, and cognitive slowing. Objective: To assess vascular compliance along the cerebrovascular tree and its relationship to MS-related cognition. Methods: We tested vascular compliance along the cerebrovascular tree by dividing cerebral cortex into nested layers. MS patients and healthy controls were scanned using a dual-echo functional magnetic resonance imaging (fMRI) sequence while they periodically inhaled room air and hypercapnic gas mixture. Cerebrovascular reactivity was calculated from both cerebral blood flow (arterial) and blood-oxygen-level-dependent signal (venous) increases per unit increase in end-tidal CO2. Results: Arterial cerebrovascular reactivity changes along the cerebrovascular tree were reduced in cognitively slow MS compared to cognitively normal MS and healthy controls. These changes were fit to exponential functions, the decay constant (arterial compliance index; ACI) of which was associated with individual subjects' reaction time and predicted reaction time after controlling for disease processes. Conclusion: Such associations suggest prospects for utility of ACI in predicting future cognitive disturbances, monitoring cognitive deficiencies and therapeutic responses, and implicates neurovascular uncoupling as a mechanism of cognitive slowing in MS. [ABSTRACT FROM AUTHOR]

Coxsackievirus A10 (CV-A10) is responsible for an escalating number of severe infections in children, but no prophylactics or therapeutics are currently available. KREMEN1 (KRM1) is the entry receptor for the largest receptor-group of hand-foot-and-mouth disease causing viruses, which includes CV-A10. We report here structures of CV-A10 mature virus alone and in complex with KRM1 as well as of the CV-A10 A-particle. The receptor spans the viral canyon with a large footprint on the virus surface. The footprint has some overlap with that seen for the neonatal Fc receptor complexed with enterovirus E6 but is larger and distinct from that of another enterovirus receptor SCARB2. Reduced occupancy of a particle-stabilising pocket factor in the complexed virus and the presence of both unbound and expanded virus particles suggests receptor binding initiates a cascade of conformational changes that produces expanded particles primed for viral uncoating. Here, the authors provide the structure of mature Coxsackie Virus A10 alone and in complex with its receptor KREMEN1, and of A-particles. This shows how the receptor spans the viral canyon and suggests that receptor binding triggers pocket factor release and conformational changes resulting in expanded particles. [ABSTRACT FROM AUTHOR]

Short-term efficacy and safety of prednisone in herpes zoster and the effect on IL-6 and IL-10 were investigated. A total of 125 patients (aged 40–70 years) with acute infective herpes zoster who were admitted to Daqing Oilfield General Hospital were selected and divided into 3 groups according to different treatment methods: low-dose (n=44), middle-dose (n=42) and high-dose (n=39) groups. The therapeutic effect, visual analogue scale (VAS) pain score, pain relieving and disappearing time, herpes stopping and disappearing time, incrustation and decrustation time, and incidence of adverse reactions in the three groups were recorded. The changes of IL-6 and IL-10 levels in the peripheral blood of patients before and after treatment were detected by enzyme-linked immunosorbent assay (ELISA) in order to analyze their relationship with pain degree and the time of symptom remission and subsidence. There were no significant differences in cure rate, significant effective rate, effective rate, ineffective rate and total effective rate among the three groups (P>0.05). The pain relieving and disappearing time in the middle-dose group were shorter than those in the low- and high-dose groups (P<0.05). The levels of IL-6 and IL-10 showed no statistical differences in the 3 groups before treatment (P>0.05). Pearson correlation analysis showed that IL-6 was positively correlated with VAS pain score, pain relieving and disappearing time, herpes stopping and disappearing time, incrustation and decrustation time (P<0.05), while IL-10 was negatively correlated with the above indicators (P<0.05). In conclusion, middle-dose prednisone has similar short-term efficacy to high-dose prednisone in the treatment of herpes zoster, but with lower complication and higher safety. IL-6 and IL-10 are closely related to the pain degree and the time of symptom remission and subsidence, which may provide a reference for clinical evaluation of the therapeutic effect of patients with herpes zoster. [ABSTRACT FROM AUTHOR]

Resveratrol, as a natural product compound, has been recently attracted much attention for its potent effects on cancer. Cancer is a serious disease threatening human survival and social development. Autophagy is a cellular pathway to realize the metabolic needs of the cell itself and the renewal of some organelles and plays opposing, context-dependent role in tumorigenesis. So the regulation of autophagy is of great significance in the treatment of cancer. p62, as an autophagy adaptor protein, is a preferred target for autophagy and is constantly controlled by constitutive autophagy. As a tumor-suppression mechanism, autophagy deficiency is common in tumors, which results in aberrant accumulation of p62 and activates p62-regulated pathways, such as activation of mTOR in nutrient sensing, and the activation of the Keap1-Nrf2 pathway for antioxidant stress, which are associated with cancer development. In this review, we emphasize that resveratrol can induce autophagy in the treatment of cancer and accelerates the degradation of p62, and then, the mTOR activation is blocked and Nrf2 activation is suppressed. As a result, the multidrug resistance of cancer cells can be reversed by resveratrol. [ABSTRACT FROM AUTHOR]

Alkaline Ni–Fe battery has attracted extensive attentions due to low cost, fast preparation and easy portability. However, the energy-storage capacity of Ni–Fe battery is greatly restricted by low active area and poor electronic conductivity, so it is highly desirable to design suitable electrode materials. In our work, Ni–Mn hydroxides/Ni3S2 (Ni2Mn1-S) nanohybrid with nanosheet structure was successfully fabricated via tuning the Mn content and reaction conditions. The orderly open structure, heterogeneous Mn atoms and even-distributed Ni3S2 phase not only generate more electrochemical active sites, but also significantly promote electronic conductivity, thus enhancing electrochemical performance of hybrid structure. Servered as supercapacitive electrode, the Ni2Mn1-S presents high capacitance (1386.8 C g−1 at 1 A g−1), excellent rate performance (71% retention at 30 A g−1) and suitable cycling stability (79% retention after 5000 cycles). After the coating of RGO nanosheet, the FeOOH@RGO electrode achieves high capacity performance (180 C g−1 at 1 A g−1) and rate performance (66% retention even at 10 A g−1). Furthermore, quasi-solid-state Ni–Fe battery was developed, utilizing a positive Ni2Mn1-S electrode and a negative FeOOH@RGO electrode. The hybrid device could achieve high energy densities (53.8 Wh kg−1 at 820 W kg−1 and 26.2 Wh kg−1 at 8200 W kg−1) and still maintain 75% capacitance after enduring 5000 cycles, which attributes to fast diffusion dynamics of Ni2Mn1-S and FeOOH@RGO electrodes. [ABSTRACT FROM AUTHOR]

Efficient, robust and safe energy storage systems occupy a vital position in the development of the electronics industry; they rely strongly on the rational design of electrode materials. In this manuscript, a one-pot hydrothermal route was employed to prepare sheet-membrane Mn-doped nickel hydroxide encapsulated via heterogeneous Ni3S2 nanoparticles. The inner large nanosheets, outer ultrathin membranes and encapsulated Ni3S2 nanoparticles construct a mechanically robust three-dimensional structure which provides abundant active sites to participate in electrochemical reactions. Density functional theory (DFT) calculations further reveal that the introduction of Ni3S2 and Mn-doping in nickel hydroxide obviously decrease the deprotonation energy and shorten the energy gap of Ni(OH)2, which greatly favors the electrochemical performance of the electrode material. When directly employed in a three-electrode alkaline supercapacitive electrode, NiMn-1 displays excellent capacitance of 385.6 mA h g−1 at 0.68 A g−1, enhanced rate performance (reaching 56.7% retention at 34 A g−1) and outstanding cycling stability (retaining 95.6% after 3000 cycles). Furthermore, a battery–supercapacitor hybrid device was developed based on this electrode material. The device also exhibits excellent capacitance of 59.7 mA h g−1 (at 0.47 A g−1), a high energy density of 51.5 W h kg−1 (at 404 W kg−1) and a suitable service lifespan. Therefore, this high-capacitance electrochemical performance endows the device with further advantages in the energy storage field. [ABSTRACT FROM AUTHOR]

Ly6/urokinase‐type plasminogen activator receptor (uPAR) (LU) domain containing 6 (LYPD6) is a Wnt signaling enhancer that promotes phosphorylation of the Wnt coreceptor low density lipoprotein receptor‐related protein 6 (LRP6). It also binds the nicotinic acetylcholine receptor (nAChR). We report here the 1.25 Å resolution structure of the LYPD6 extracellular LU domain and map its interaction with LRP6 by mutagenesis and surface plasmon resonance. The LYPD6LU structure reveals a ‘trifingered protein domain’ fold with the middle fingertip bearing an ‘NxI’ motif, a tripeptide motif associated with LRP5/6 binding by Wnt inhibitors. Of the Ly6 protein family members, only LYPD6 has an NxI motif. Since mutations in the LYPD6 NxI motif abolish or severely reduce interaction with LRP6, our results indicate its key role in the interaction of LYPD6 with LRP6. [ABSTRACT FROM AUTHOR]

In order to examine the effect of extrusion ratio on the microstructure and mechanical behavior in Al-Cu-Mg-Ag alloy, the Al-6.3Cu-0.48Mg-0.4Ag alloy was subjected to extruding with different extrusion ratios of 17, 30 and 67. The results indicate that the grains are refined and the strength is improved effectively with increasing extrusion ratio. However, further investigation shows that the extrusion ratio of 30 is more effective than the lower extrusion ratio (17) and the higher extrusion ratio (67) to refine the grains in the T6-temper alloy. Moreover, the sample with an extrusion ratio of 30 obtains more precipitates and superior mechanical properties after T6 treatment. This study supports the idea that there exists a critical extrusion ratio for grain refinement and improvement of mechanical properties for the T6-temper alloy. Recrystallization and precipitation during T6 treatment were introduced to explain the effects of extrusion ratio on the microstructure and mechanical properties of the Al-Cu-Mg-Ag alloys. [ABSTRACT FROM AUTHOR]

Background/Aims: Mechanical load can regulate disc nucleus pulposus (NP) biology in terms of cell viability, matrix homeostasis and cell phenotype. N-cadherin (N-CDH) is a molecular marker of NP cells. This study investigated the role of N-CDH in maintaining NP cell phenotype, NP matrix synthesis and NP cell viability under high-magnitude compression. Methods: Rat NP cells seeded on scaffolds were perfusion-cultured using a self-developed perfusion bioreactor for 5 days. NP cell biology in terms of cell apoptosis, matrix biosynthesis and cell phenotype was studied after the cells were subjected to different compressive magnitudes (low- and high-magnitudes: 2% and 20% compressive deformation, respectively). Non-loaded NP cells were used as controls. Lentivirus-mediated N-CDH overexpression was used to further investigate the role of N-CDH under high-magnitude compression. Results: The 20% deformation compression condition significantly decreased N-CDH expression compared with the 2% deformation compression and control conditions. Meanwhile, 20% deformation compression increased the number of apoptotic NP cells, up-regulated the expression of Bax and cleaved-caspase-3 and down-regulated the expression of Bcl-2, matrix macromolecules (aggrecan and collagen II) and NP cell markers (glypican-3, CAXII and keratin-19) compared with 2% deformation compression. Additionally, N-CDH overexpression attenuated the effects of 20% deformation compression on NP cell biology in relation to the designated parameters. Conclusion: N-CDH helps to restore the cell viability, matrix biosynthesis and cellular phenotype of NP cells under high-magnitude compression. [ABSTRACT FROM AUTHOR]

Pr-doped LiTiO in the form of LiTiPrO (x = 0, 0.01, 0.03, 0.05, and 0.07) was synthesized successfully by an electrospinning technique. ICP shows that the doped samples are closed to the targeted samples. XRD analysis demonstrates that traces of Pr can enlarge the lattice parameter of LiTiO from 8.3403 to 8.3765 Å without changing the spinel structure. The increase of lattice parameter is beneficial to the intercalation and de-intercalation of lithium-ion. XPS results identify the existence form of Ti is mainly Ti and Ti in minor quantity in LiTiPrO (x = 0.05) samples due to the small amount of Pr. The transition from Ti to Ti is conducive to the electronic conductivity of LiTiO. FESEM images show that all the nanofibers are well crystallized with a diameter of about 200 nm and distributed uniformly. The results of electrochemical measurement reveal that the 1D LiTiPrO (x = 0.05) nanofibers display enhanced high-rate capability and cycling stability compared with that of undoped nanofibers. The high-rate discharge capacity of the LiTiPrO (x = 0.05) samples is excellent (101.6 mAh g at 50 °C), which is about 58.48 % of the discharge capacity at 0.2 °C and 4.3 times than that of the bare LiTiO (23.5 mA g). Even at 10 °C (1750 mA g), the specific discharge capacity is still 112.8 mAh g after 1000 cycles (87.9 % of the initial discharge capacity). The results of cyclic voltammograms (CV) and electrochemical impedance spectroscopy (EIS) illustrate that the Pr-doped LiTiO electrodes possess better dynamic performance than the pure LiTiO, further confirming the excellent electrochemical properties above. [ABSTRACT FROM AUTHOR]

It has been generally accepted that both natural and man-made sources of ionizing radiation contribute to human exposure and consequently pose a possible risk to human health. However, accumulating evidence has shown that the biological effects of low-dose radiation (LDR) are different from those of high-dose radiation. LDR can stimulate proliferation of normal cells and activate their defense systems, while these biological effects are not observed in some cancer cell types. Although there is still no concordance on this matter, the fact that LDR has the potential to enhance the effects of cancer therapeutics and reduce the toxic side effects of anti-cancer therapy has garnered significant interest. Here, we provide an overview of the current knowledge regarding the experimental data detailing the different responses of normal and cancer tissues to LDR, the underlying mechanisms, and its significance in clinical application. [ABSTRACT FROM AUTHOR]

Dysregulated microRNA-134 (miR-134) has been observed in glioma carcinogenesis, and studies suggested that the ERK pathway plays vital roles in glioma cell growth and proliferation. However, the fundamental relationship between miR-134 and the ERK pathway in glioma has not been fully explained. As a result, this study was aimed to explore the underlying functions of miR-134 in human glioma. Intentionally overexpressed or inhibited miR-134 expression resulted from the transfection of miR-134 mimics, or miR-134 inhibitor within glioma cell line U251 was detected using RT-PCR. Both cell counting kit-8 (CCK-8) assays and Transwell assays were carried out to clarify the proliferation and invasion of U251 cells transfected with miR-134 mimics or miR-134 inhibitors. Our findings showed that miR-134 was significantly downexpressed in glioma tissues, and low miR-134 expression was significantly related to high histopathological grades. However, upregulated miR-134 expression restrained the proliferation and invasion of U251 cells in vitro. Kirsten rat sarcoma viral oncogene (KRAS), a vital factor for the ERK pathway, was directly targeted by miR-134 through its binding with the 3′-UTR of KRAS in glioma. Furthermore, KRAS expression exhibited a positive correlation with the activity of the ERK pathway. Overexpression of KRAS without 3′-UTR partly offsets the suppressive effect of miR-134 on glioma progression. Our data also indicated that miR-134 negatively modulated glioma progression and upregulated miR-134 triggered aberrant activation of the ERK pathway by targeting KRAS. Therefore, miR-134 might be considered as a benign therapeutic target of glioma. [ABSTRACT FROM AUTHOR]

LiTiO (LTO) was synthesized with two different cooling methods by solid-state method, namely fast cooling and air cooling. The samples were characterized by X-ray diffraction (XRD), field-emission scanning electron microscopy (FESEM), galvanostatic charge-discharge test, cyclic voltammetry (CV), and electrochemical impedance spectroscopy (EIS), respectively. XRD revealed that the basic LTO structure was not changed. FESEM images showed that fast cooling effectively reduced the particle sizes and the agglomeration of particles. Galvanostatic charge-discharge test showed that the air cooling sample exhibited a mediocre performance, having an initial discharge capacity of 136.3mAh · g at 0.5 C; however, the fast cooling sample demonstrated noticeable improvement in both of its discharge capacity and rate capability, with a high initial capacity value of 142.7 mAh · g at 0.5 C. CV measurements also revealed that fast cooling enhanced the reversibility of the LTO. EIS confirmed that fast cooling resulted in lower electrochemical polarization and a higher lithium-ion diffusion coefficient. Therefore, fast cooling have a great impact on discharge capacity, rate capability, and cycling performance of LTO anode materials for lithium-ion batteries. [ABSTRACT FROM AUTHOR]

Chitinases are enzymes that catalyze the hydrolysis of chitin. Human chitotriosidase (CHIT1) is one of the two active human chitinases, involved in the innate immune response and highly expressed in a variety of diseases. CHIT1 is composed of a catalytic domain linked by a hinge to its chitin binding domain (ChBD). This latter domain belongs to the carbohydrate-binding module family 14 (CBM14 family) and facilitates binding to chitin. So far, the available crystal structures of the human chitinase CHIT1 and the Acidic Mammalian Chitinase (AMCase) comprise only their catalytic domain. Here, we report a crystallization strategy combining cross-seeding and micro-seeding cycles which allowed us to obtain the first crystal structure of the full length CHIT1 (CHIT1-FL) at 1.95 Å resolution. The CHIT1 chitin binding domain (ChBDCHIT1) structure shows a distorted β-sandwich 3D fold, typical of CBM14 family members. Accordingly, ChBDCHIT1 presents six conserved cysteine residues forming three disulfide bridges and several exposed aromatic residues that probably are involved in chitin binding, including the highly conserved Trp465 in a surface- exposed conformation. Furthermore, ChBDCHIT1 presents a positively charged surface which may be involved in electrostatic interactions. Our data highlight the strong structural conservation of CBM14 family members and uncover the structural similarity between the human ChBDCHIT1, tachycitin and house mite dust allergens. Overall, our new CHIT1-FL structure, determined with an adapted crystallization approach, is one of the few complete bi-modular chitinase structures available and reveals the structural features of a human CBM14 domain. [ABSTRACT FROM AUTHOR]

Niemann-pick type C1 ( NPC1) is an endo/lysosomal membrane protein involved in intracellular cholesterol trafficking, and its luminal domain C is an essential endosomal receptor for Ebola and Marburg viruses. We have determined the crystal structure of glycosylated NPC1 luminal domain C and find all seven possible sites are glycosylated. Mapping the disease mutations onto the glycosylated structure reveals a potential binding face for NPC2. Knowledge-based docking of NPC1 onto Ebola viral glycoprotein and sequence analysis of filovirus susceptible and refractory species reveals four critical residues, H418, Q421, F502 and F504, some or all of which are likely responsible for the species-specific susceptibility to the virus infection. [ABSTRACT FROM AUTHOR]

In order to examine the effect of surplus phase on the microstructure and mechanical properties, different compositions with high Cu/Mg ratio of the T6-temper extruded Al-Cu-Mg-Ag alloys were studied in this investigation. The results show that the Al-5.6Cu-0.56Mg-0.4Ag alloy obtains superior mechanical properties at room temperature, while the yield strength of Al-6.3Cu-0.48Mg-0.4Ag alloy is 378 MPa at 200 °C, which is 200 MPa higher than that of Al-5.6Cu-0.56Mg-0.4Ag alloy. Although the excessive Cu content causes the slight strength loss and elongation decrease in the Al-6.3Cu-0.48Mg-0.4Ag alloy at room temperature, the surplus phases and recrystallized microstructure will play an effective role in strengthening the alloy at elevated temperature. [ABSTRACT FROM AUTHOR]

Chitotriosidase (CHIT1) is a human chitinase belonging to the highly conserved glycosyl hydrolase family 18 (GH18). GH18 enzymes hydrolyze chitin, an N-acetylglucosamine polymer synthesized by lower organisms for structural purposes. Recently, CHIT1 has attracted attention owing to its upregulation in immune-system disorders and as a marker of Gaucher disease. The 39 kDa catalytic domain shows a conserved cluster of three acidic residues, Glu140, Asp138 and Asp136, involved in the hydrolysis reaction. Under an excess concentration of substrate, CHIT1 and other homologues perform an additional activity, transglycosylation. To understand the catalytic mechanism of GH18 chitinases and the dual enzymatic activity, the structure and mechanism of CHIT1 were analyzed in detail. The resolution of the crystals of the catalytic domain was improved from 1.65 Å (PDB entry ) to 0.95-1.10 Å for the apo and pseudo-apo forms and the complex with chitobiose, allowing the determination of the protonation states within the active site. This information was extended by hybrid quantum mechanics/molecular mechanics (QM/MM) calculations. The results suggest a new mechanism involving changes in the conformation and protonation state of the catalytic triad, as well as a new role for Tyr27, providing new insights into the hydrolysis and transglycosylation activities. [ABSTRACT FROM AUTHOR]

Poly(A) binding protein 1 (PABP1) plays a central role in mRNA translation and stability and is a target by many viruses in diverse manners. We report a novel viral translational control strategy involving the recruitment of PABP1 to the 5' leader internal ribosome entry site (5L IRES) of an immediate-early (IE) bicistronic mRNA that encodes the neurovirulence protein (pp14) from the avian herpesvirus Marek’s disease virus serotype 1 (MDV1). We provide evidence for the interaction between an internal poly(A) sequence within the 5L IRES and PABP1 which may occur concomitantly with the recruitment of PABP1 to the poly(A) tail. RNA interference and reverse genetic mutagenesis results show that a subset of virally encoded-microRNAs (miRNAs) targets the inhibitor of PABP1, known as paip2, and therefore plays an indirect role in PABP1 recruitment strategy by increasing the available pool of active PABP1. We propose a model that may offer a mechanistic explanation for the cap-independent enhancement of the activity of the 5L IRES by recruitment of a bona fide initiation protein to the 5' end of the message and that is, from the affinity binding data, still compatible with the formation of ‘closed loop’ structure of mRNA. [ABSTRACT FROM AUTHOR]

In the present study, by adding SiC particles into Al-Si-Mg melt, Mg2Si and SiC particles hybrid reinforced Al matrix composites were fabricated through the Mg2Si in situ synthesis in melt combined with the SiC ex situ stir casting. The as-cast microstructure containing primary Mg2Si and SiC particles that distribute homogenously in Al matrix was successfully achieved. The effects of SiC particle addition on the microstructure of Mg2Si/Al composites were investigated by using scanning electron microscopy (SEM) and XRD. The results show that, with increasing the fraction of the SiC particles from 5wt.% to 10wt.%, the morphologies of the primary Mg2Si particulates in the prepared samples remain polygonal, but the size of the primary phase decreases slightly. However, when the SiC particle addition reaches 15wt.%, the morphologies of the primary Mg2Si particulates change partially from polygonal to quadrangular with a decrease in size from 50 µm to 30 µm. The size of primary Al dendrites decreases with increasing fraction of the SiC particles from 0wt.% to 15wt.%. The morphology of the eutectic Mg2Si phase changes from a fiber-form to a short fiber-form and/or a dot-like shape with increasing fraction of the SiC particles. Furthermore, no significant change in dendrite arm spacing (DAS) was observed in the presence of SiC particles. [ABSTRACT FROM AUTHOR]

Infertility is one of the common complications in diabetic men and mainly due to the loss of germ cells by apoptotic cell death. Although several mechanisms have been proposed to explain the induction of testicular cell death by diabetes, diabetic induction of testicular oxidative stress and damage may be the predominant mechanism responsible for the testicular cell death in diabetes. To explore whether factors that either increase or decrease the testicular oxidative stress and damage will enhance or prevent diabetes-induced testicular cell death, the effect of zinc (Zn) deficiency on diabetes-induced cell death has been examined since Zn was found to play an important role in the protection of testis from oxidative stress and damage. Zn deficiency, induced by its chelator N,N,N,N-Tetrakis(2-pyridylmethyl)-1,2-ethylenediamine, was found to exacerbate diabetes-induced testicular oxidative damage and cell death. In contrast, treatment of diabetic rats with antioxidant N-acetylcysteine or low-dose radiation that can up-regulate endogenous antioxidants significantly attenuated diabetes-induced testicular cell death. These results suggest that diabetes-induced testicular cell death that may eventually cause men's infertility is predominantly mediated by the oxidative stress and damage. To prevent or delay diabetes-caused infertility, diabetic patients should avoid Zn deficiency, and might consider antioxidant supplementation. [ABSTRACT FROM AUTHOR]

The C propeptides of fibrillar procollagens have crucial roles in tissue growth and repair by controlling both the intracellular assembly of procollagen molecules and the extracellular assembly of collagen fibrils. Mutations in C propeptides are associated with several, often lethal, genetic disorders affecting bone, cartilage, blood vessels and skin. Here we report the crystal structure of a C-propeptide domain from human procollagen III. It reveals an exquisite structural mechanism of chain recognition during intracellular trimerization of the procollagen molecule. It also gives insights into why some types of collagen consist of three identical polypeptide chains, whereas others do not. Finally, the data show striking correlations between the sites of numerous disease-related mutations in different C-propeptide domains and the degree of phenotype severity. The results have broad implications for understanding genetic disorders of connective tissues and designing new therapeutic strategies. [ABSTRACT FROM AUTHOR]

Hypoxia-inducible factor (HIF) is a transcriptional complex that is regulated by oxygen sensitive hydroxylation of its α subunits by the prolyl hydroxylases PHD1, 2 and 3. To better understand the role of these enzymes in directing cellular responses to hypoxia, we derived an assay to determine their specific activity in both native cell extracts and recombinant sources of enzyme. We show that all three are capable of high rates of catalysis, in the order PHD2=PHD3 > PHD1, using substrate peptides derived from the C-terminal degradation domain of HIF-α subunits, and that each demonstrates similar and remarkable sensitivity to oxygen, commensurate with a common role in signaling hypoxia. [Copyright &y& Elsevier]

Background: Gene targeting would offer a number of advantages over current transposon-based strategies for insect transformation. These include freedom from both position effects associated with quasi-random integration and concerns over transgene instability mediated by endogenous transposases, independence from phylogenetic restrictions on transposon mobility and the ability to generate gene knockouts. Results: We describe here our initial investigations of gene targeting in the mosquito. The target site was a hygromycin resistance gene, stably maintained as part of an extrachromosomal array. Using a promoter-trap strategy to enrich for targeted events, a neomycin resistance gene was integrated into the target site. This resulted in knockout of hygromycin resistance concurrent with the expression of high levels of neomycin resistance from the resident promoter. PCR amplification of the targeted site generated a product that was specific to the targeted cell line and consistent with precise integration of the neomycin resistance gene into the 5' end of the hygromycin resistance gene. Sequencing of the PCR product and Southern analysis of cellular DNA subsequently confirmed this molecular structure. Conclusions: These experiments provide the first demonstration of gene targeting in mosquito tissue and show that mosquito cells possess the necessary machinery to bring about precise integration of exogenous sequences through homologous recombination. Further development of these procedures and their extension to chromosomally located targets hold much promise for the exploitation of gene targeting in a wide range of medically and economically important insect species. [ABSTRACT FROM AUTHOR]

Osimertinib is a third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) that is clinically effective in patients with EGFR-mutated non-small-cell lung cancer (NSCLC). However, the use of this treatment is limited by its high cost. A cost-effectiveness analysis of different sequences of osimertinib administration in China and the United States was conducted in the present study. Markov models were established based on data from the FLAURA and AURA3 trials. First-line osimertinib was compared with both first-generation EGFR-TKIs and second-line osimertinib after the failure of first-generation EGFR-TKIs. The analysis also considered different payment modalities available in China. Additionally, one-way and probability sensitivity analyses, with a willingness-to-pay threshold (WTP) of three times the per capita gross domestic product [$27,783/quality-adjusted life year (QALY) for China and $100,000/QALY for the United States], were performed. The first-line osimertinib group displayed higher QALYs and costs than those of the first-generation EGFR-TKI group. The first generation EGFR-TKI group displayed an incremental cost-effectiveness ratio (ICER) of $212,252/QALY in China and $151,922/QALY in the United States. In addition, the ICERs were negative in the second-line osimertinib group, with higher QALYs and lower costs compared with those in the first-line osimertinib group. Furthermore, osimertinib company donation was of benefit in China, with an average cost-effectiveness of $836/QALY. The one-way sensitivity analysis highlighted the influence of utilities in different states. First-line osimertinib could be cost-effective either with higher WTP or a price reduction of 68% in China and 9% in the United States. Although first-line osimertinib therapy could have health benefits, it was not cost-effective compared with first-line first-generation EGFR-TKIs and second-line osimertinib therapy. However, paying via company donation may be a good choice in China. [ABSTRACT FROM AUTHOR]