Up-regulation of a disintegrin and metalloproteinase 10 (ADAM10) to prevent the formation of β-amyloid (Aβ) peptides might be a promising strategy to treat Alzheimer’s disease (AD). RNA G-quadruplex ...motif within the 5′-UTR of the ADAM10 mRNA is an inhibitory element for ADAM10 translation. Thus, mitigation of the suppressive effect of this motif using an RNA G-quadruplex-forming G-rich sequence (QGRS) binder might be a new approach for AD therapy. Herein, a series of new methylquinolinium derivatives were synthesized and screened by surface plasmon resonance (SPR) and the dual-luciferase reporter assay. Among them, compound 24 showed selective affinity for the QGRS of ADAM10 and could strongly up-regulate the translation of it. Moreover, treatment with 24 led to a significant increase of the secretion of sAPPα, consequently decreasing the Aβ40 in cellular. These results illustrate that the interaction between the RNA QGRS and a small molecule may be a new molecular strategy to modulate the translation of ADAM10.
Interferon therapy, used in the treatment of chronic hepatitis B (CHB), is one of the means by which patients can achieve a functional cure. Pegylated interferon is currently used in the treatment of ...CHB. There are two main types of pegylated interferon: α-2b and α-2a.
This study explored the efficacy, safety, and predictors of treatment response for α-2b plus entecavir among children in a real-world setting.
The study included 76 patients aged 3-18 years, all of whom were treated with interferon α-2b plus entecavir. The mean duration of treatment was 401.99 days, and 31.6% (24/76) of patients achieved HBsAg clearance. Competing risk model analyses showed that children with baseline HBsAg <1500 IU/mL (subdistribution hazard ratio sHR=2.643, P=0.022) and a higher baseline alanine aminotransferase (ALT) level (sHR=1.005, P=0.000) had a higher probability of achieving HBsAg clearance during treatment. Conversely, children with a higher hepatitis B virus loading level (sHR=0.835, P=0.043) and age ≥10 years (sHR=0.243, P=0.002) had a lower probability of achieving HBsAg clearance during treatment. A decrease of >1 log
in HBsAg level (sHR=3.479, P=0.001) at 12 weeks of treatment was associated with a higher probability of achieving surface antigen clearance.
These results indicated that interferon plus entecavir therapy is a promising means of achieving HBsAg clearance in children with CHB. Moreover, HBsAg, ALT, virus loading, and age are indicators of treatment success probability.
The roles of oncogenic KRAS in tumor immune evasion remain poorly understood. Here, mutant KRAS is identified as a key driver of tumor immune evasion in colorectal cancer (CRC). In human CRC ...specimens, a significant reduction in cytotoxic CD8+ T‐cell tumor infiltration is found in patients with mutant versus wild type KRAS. This phenomenon is confirmed by preclinical models of CRC, and further study showed KRAS mutant tumors exhibited poor response to anti‐PD‐1 and adoptive T‐cell therapies. Mechanistic analysis revealed lactic acid derived from mutant KRAS‐expressing tumor cells sensitized tumor‐specific cytotoxic CD8+ T‐cells to activation‐induced cell death via NF‐κB inactivation; this may underlie the inverse association between intratumoral cytotoxic CD8+ T‐cells and KRAS mutation. Importantly, KRAS mutated tumor resistance to immunotherapies can be overcome by inhibiting KRAS or blocking lactic acid production. Together, this work suggests the KRAS‐mediated immune program is an exploitable therapeutic approach for the treatment of patients with KRAS mutant CRC.
KRAS mutation in colorectal cancer drives immune evasion by sensitizing cytotoxic T‐cells to activation‐induced cell death through lactic acid‐mediated NF‐κB inactivation, and thus impairs immunotherapeutic efficacy. KRAS inhibition or blockade of lactic acid production represents an exploitable approach to improve cancer immunotherapies.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
The rate of improvement of sugar content in sugarcane remains low for decades worldwide. Our previous transcriptome studies provided an atlas of sucrose accumulation-related gene expression, but ...little is known about the proteins involved. Here, we conducted a proteomic analysis of experimentally altered sucrose accumulation in sugarcane. Analysis of stem proteomes of sugarcane ripener ethephon treated high- and low-sugar genotypes had identified 2983 proteins of which 139 were significantly differentially expressed (DEPs). These DEPs were found to be associated with sugar metabolism-related processes with 25 of them may have a regulatory role in sucrose accumulation. The key proteins identified include UDP-glucose 6-dehydrogenase associated with amino sugar and nucleotide sugar metabolism; those involved in carbon fixation; and fructokinase, β-D-glucosidase, and α-glucan phosphorylase involved in starch and sucrose metabolism. Distinct genotype- and ethephon-dependent DEP expression was evident providing new insights into one of the most intractable sugarcane traits to breeding.
Ruthenium dioxide is the most promising alternative to the prevailing but expensive iridium-based catalysts for the oxygen evolution reaction in proton-exchange membrane water electrolyzers. However, ...the under-coordinated lattice oxygen of ruthenium dioxide is prone to over-oxidation, and oxygen vacancies are formed at high oxidation potentials under acidic corrosive conditions. Consequently, ruthenium atoms adjacent to oxygen vacancies are oxidized into soluble high-valence derivatives, causing the collapse of the ruthenium dioxide crystal structure and leading to its poor stability. Here, we report an oxyanion protection strategy to prevent the formation of oxygen vacancies on the ruthenium dioxide surface by forming coordination-saturated lattice oxygen. Combining density functional theory calculations, electrochemical measurements, and a suite of operando spectroscopies, we showcase that barium-anchored sulfate can greatly impede ruthenium loss and extend the lifetime of ruthenium-based catalysts during acidic oxygen evolution, while maintaining the activity. This work paves a new way for designing stable and active anode catalysts toward acidic water splitting.
Many bioinformatics resources with unique perspectives on the protein landscape are currently available. However, generating new knowledge from these resources requires interoperable workflows that ...support cross-resource queries. In this study, we employ federated queries linking information from the Protein Kinase Ontology, iPTMnet, Protein Ontology, neXtProt, and the Mouse Genome Informatics to identify key knowledge gaps in the functional coverage of the human kinome and prioritize understudied kinases, cancer variants and post-translational modifications (PTMs) for functional studies. We identify 32 functional domains enriched in cancer variants and PTMs and generate mechanistic hypotheses on overlapping variant and PTM sites by aggregating information at the residue, protein, pathway and species level from these resources. We experimentally test the hypothesis that S768 phosphorylation in the C-helix of EGFR is inhibitory by showing that oncogenic variants altering S768 phosphorylation increase basal EGFR activity. In contrast, oncogenic variants altering conserved phosphorylation sites in the 'hydrophobic motif' of PKCβII (S660F and S660C) are loss-of-function in that they reduce kinase activity and enhance membrane translocation. Our studies provide a framework for integrative, consistent, and reproducible annotation of the cancer kinomes.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
A series of 7,8-dehydrorutaecarpine derivatives were synthesized and characterized as potential multifunctional agents for treatment of Alzheimer's disease (AD). All of these synthetic compounds ...showed high acetylcholinesterase (AChE) inhibitory activity with IC50 values ranged from 0.60 to 196.7 nM, and good selectivity for AChE over butyrylcholinesterase (BuChE) (125- to 3225-fold). A Lineweaver–Burk plot and molecular modeling study indicated these compounds could bind to both catalytic active site and the peripheral anionic site of AChE. Besides, compounds showed higher activity of inhibiting AChE-induced amyloid-beta (Aβ) aggregation than curcumin, higher anti-oxidative activity than Trolox, and could also be good metal chelators. Considering their low cytotoxicity, our results indicated that these derivatives provide good templates for developing new multifunctional agents for AD treatment.
Display omitted Twenty seven new 3-aminoalkanamido-substituted 7,8-dehydrorutaecarpine derivatives were synthesized as multifunctional anti-Alzheimer agents, these compounds showed activities of cholinesterase inhibition, self and AChE-induced Aβ aggregation inhibition, antioxidation, and metal chelation.
► 3-Aminoalkanamido-substituted 7,8-dehydrorutaecarpine derivatives were synthesized. ► Compounds showed high inhibitory potencies and selectivity for AChE. ► Compounds had high activities inhibiting AChE-induced Aβ aggregation. ► Compounds could act as antioxidants and metal chelators.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Species richness is the most basic concept of diversity and is crucial to biodiversity conservation and sustainable fisheries. To understand the fish species richness of the Minjiang Estuary and its ...adjacent waters, eight documents and surveyed data were collected and compared from 1990–2021. To obtain suitable analysis data, the content of the data was compared and evaluated. Explore the suitability of data based on several criteria. Among them, the bottom trawling survey carried out in 2006–2007, and non-parametric estimation methods such as Chao 2, Jackknife 1, Jackknife 2 and Bootstrap were used to estimate the fish species richness. The results of this case show that a total of 153 species of fish were caught in the trawling survey in the fourth quarter, belonging to 14 orders, 57 families and 101 genera. The 2006–2007 cruise is more complete for studying species richness. The Estimable expectations of fish species richness are: 250 (Chao 2), 204 (Jackknief 1), 241 (Jackknief 2) and 174 (Bootstrap). The number of fish species was significantly higher in summer and autumn than winter and spring. To manage fishery resources and sustainability in the sea area of Fujian Province, biological information and stock assessment are required. This meaningful information, especially for endemic and economically important species such as can set a baseline. Once species change exceeds the baseline range, it provides decision-making basis for marine biodiversity conservation and fisheries management.
In extending the understanding of how school bullying impacts student learning, this research explored the relationships among school bullying, students' sense of belonging at school and academic ...performance in science, maths and reading. Data analysis was conducted using Beijing, Shanghai, Jiangsu and Guangdong (China) data of the 2015 Programme for International Student Assessment (PISA2015). The results showed that both bullying victimisation and bullying climate had significant and negative relationships with students' science, maths and reading performance. Students' sense of belonging at school partially mediated the effects of both bullying victimisation and bullying climate on academic performance in science, maths and reading. Implications for bullying intervention and further research were also discussed.
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BFBNIB, NUK, PILJ, SAZU, UL, UM, UPUK
High-fidelity two-qubit gates are essential for the realization of large-scale quantum computation and simulation. Tunable coupler design is used to reduce the problem of parasitic coupling and ...frequency crowding in many-qubit systems and thus thought to be advantageous. Here we design an extensible 5-qubit system in which center transmon qubit can couple to every four near-neighboring qubits via a capacitive tunable coupler and experimentally demonstrate high-fidelity controlled-phase (CZ) gate by manipulating central qubit and one near-neighboring qubit. Speckle purity benchmarking and cross entropy benchmarking are used to assess the purity fidelity and the fidelity of the CZ gate. The average purity fidelity of the CZ gate is 99.69±0.04% and the average fidelity of the CZ gate is 99.65±0.04%, which means that the control error is about 0.04%. Our work is helpful for resolving many challenges in implementation of large-scale quantum systems.
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