Targeting eukaryotic elongation factor 2 kinase (eEF2K) with small-molecule inhibitors for cancer therapy.

Eukaryotic elongation factor 2 kinase (eEF2K) is a member of the α-kinase family that is activated by calcium/calmodulin. Of note, eEF2K is crucial for regulating translation and is often highly overexpressed in malignant cells. Therefore in this review, we summarize the molecular structure of eEF2K and its oncogenic roles in cancer. Moreover, we further discuss the inhibition of eEF2K with small-molecule inhibitors and other new emerging therapeutic strategies in cancer therapy. Taken together, these inspiring findings provide new insights into a promising strategy for inhibiting eEF2K to greatly improve future cancer therapy.

Friend or foe? Using eye-tracking technology to investigate the visual discrimination ability of giant pandas.

The role that visual discriminative ability plays among giant pandas in social communication and individual discrimination has received less attention than olfactory and auditory modalities. Here, we used an eye-tracker technology to investigate pupil fixation patterns for 8 captive male giant pandas Ailuropoda melanoleuca. We paired images (N = 26) of conspecifics against: 1) sympatric predators (gray wolves and tigers), and non-threatening sympatric species (golden pheasant, golden snub-nosed monkey, takin, and red panda), 2) conspecifics with atypical fur coloration (albino and brown), and 3) zookeepers/non-zookeepers wearing either work uniform or plain clothing. For each session, we tracked the panda's pupil movements and measured pupil first fixation point (FFP), fixation latency, total fixation count (TFC), and duration (TFD) of attention to each image. Overall, pandas exhibited similar attention (FFPs and TFCs) to images of predators and non-threatening sympatric species. Images of golden pheasant, snub-nosed monkey, and tiger received less attention (TFD) than images of conspecifics, whereas images of takin and red panda received more attention, suggesting a greater alertness to habitat or food competitors than to potential predators. Pandas' TFCs were greater for images of black-white conspecifics than for albino or brown phenotypes, implying that familiar color elicited more interest. Pandas reacted differently to images of men versus women. For images of women only, pandas gave more attention (TFC) to familiar combinations (uniformed zookeepers and plain-clothed non-zookeepers), consistent with the familiarity hypothesis. That pandas can use visual perception to discriminate intra-specifically and inter-specifically, including details of human appearance, has applications for panda conservation and captive husbandry.

A contrast-enhanced computed tomography-based radiomics nomogram for preoperative differentiation between benign and malignant cystic renal lesions.

Background: There is lack of discrimination as to traditional imaging diagnostic methods of cystic renal lesions (CRLs). This study aimed to evaluate the value of machine learning models based on clinical data and contrast-enhanced computed tomography (CECT) radiomics features in the differential diagnosis of benign and malignant CRL. Methods: There were 192 patients with CRL (Bosniak class ≥ II) enrolled through histopathological examination, including 144 benign cystic renal lesions (BCRLs) and 48 malignant cystic renal lesions (MCRLs). Radiomics features were extracted from CECT images taken during the medullary phase. Using the light gradient boosting machine (LightGBM) algorithm, the clinical, radiomics and combined models were constructed. A comprehensive nomogram was developed by integrating the radiomics score (Rad-score) with independent clinical factors. Receiver operating characteristic (ROC) curves were plotted. The corresponding area under the curve (AUC) value was worked out to quantify the discrimination performance of the three models in training and validation cohorts. Calibration curves were worked out to assess the accuracy of the probability values predicted by the models. Decision curve analysis (DCA) was worked out to assess the performance of models at different thresholds. Results: Maximum diameter and Bosniak class were independent risk factors of patients with MCRL in the clinical model. Twenty-one radiomics features were extracted to work out a Rad-score. The performance of the clinical model in the training cohort was AUC =0.948, 95% confidence interval (CI): 0.917-0.980, and the performance in the validation cohort was AUC =0.936, 95% CI: 0.859-1.000 (P<0.05). The performance of the radiomics model in the training cohort was AUC =0.990, 95% CI: 0.979-1.000, and the performance in the validation cohort was AUC =0.959, 95% CI: 0.903-1.000 (P<0.05). Compared with the above models, the combined radiomics nomogram had an AUC of 0.989 (95% CI: 0.977-1.000) in the training cohort and an AUC of 0.962 (95% CI: 0.905-1.000) in the validation cohort (P<0.05), showing the best diagnostic efficacy. Conclusions: The radiomics nomogram integrating clinical independent risk factors and radiomics signature improved the diagnostic accuracy in differentiating between BCRL and MCRL, which can provide a reference for clinical decision-making and help clinicians develop individualized treatment strategies for patients.

Emergent normal fluid in the superconducting ground state of overdoped cuprates.

The microscopic mechanism for the disappearance of superconductivity in overdoped cuprates is still under heated debate. Here we use scanning tunneling spectroscopy to investigate the evolution of quasiparticle interference phenomenon in Bi2Sr2CuO6+δ over a wide range of hole densities. We find that when the system enters the overdoped regime, a peculiar quasiparticle interference wavevector with arc-like pattern starts to emerge even at zero bias, and its intensity grows with increasing doping level. Its energy dispersion is incompatible with the octet model for d-wave superconductivity, but is highly consistent with the scattering interference of gapless normal carriers. The gapless quasiparticles are mainly located near the antinodes and are independent of temperature, consistent with the disorder scattering mechanism. We propose that a branch of normal fluid emerges from the pair-breaking scattering between flat antinodal bands in the quantum ground state, which is the primary cause for the reduction of superfluid density and suppression of superconductivity in overdoped cuprates.

Nanozymes: Potential Therapies for Reactive Oxygen Species Overproduction and Inflammation in Ischemic Stroke and Traumatic Brain Injury.

Nanozymes, which can selectively scavenge reactive oxygen species (ROS), have recently emerged as promising candidates for treating ischemic stroke and traumatic brain injury (TBI) in preclinical models. ROS overproduction during the early phase of these diseases leads to oxidative brain damage, which has been a major cause of mortality worldwide. However, the clinical application of ROS-scavenging enzymes is limited by their short in vivo half-life and inability to cross the blood-brain barrier. Nanozymes, which mimic the catalytic function of natural enzymes, have several advantages, including cost-effectiveness, high stability, and easy storage. These advantages render them superior to natural enzymes for disease diagnosis and therapeutic interventions. This review highlights recent advancements in nanozyme applications for ischemic stroke and TBI, emphasizing their potential to mitigate the detrimental effect of ROS overproduction, oxidative brain damage, inflammation, and blood-brain barrier compromise. Therefore, nanozymes represent a promising treatment modality for ROS overproduction conditions in future medical practices.

2-APQC, a small-molecule activator of Sirtuin-3 (SIRT3), alleviates myocardial hypertrophy and fibrosis by regulating mitochondrial homeostasis.

Sirtuin 3 (SIRT3) is well known as a conserved nicotinamide adenine dinucleotide+ (NAD+)-dependent deacetylase located in the mitochondria that may regulate oxidative stress, catabolism and ATP production. Accumulating evidence has recently revealed that SIRT3 plays its critical roles in cardiac fibrosis, myocardial fibrosis and even heart failure (HF), through its deacetylation modifications. Accordingly, discovery of SIRT3 activators and elucidating their underlying mechanisms of HF should be urgently needed. Herein, we identified a new small-molecule activator of SIRT3 (named 2-APQC) by the structure-based drug designing strategy. 2-APQC was shown to alleviate isoproterenol (ISO)-induced cardiac hypertrophy and myocardial fibrosis in vitro and in vivo rat models. Importantly, in SIRT3 knockout mice, 2-APQC could not relieve HF, suggesting that 2-APQC is dependent on SIRT3 for its protective role. Mechanically, 2-APQC was found to inhibit the mammalian target of rapamycin (mTOR)-p70 ribosomal protein S6 kinase (p70S6K), c-jun N-terminal kinase (JNK) and transforming growth factor-ß (TGF-ß)/ small mother against decapentaplegic 3 (Smad3) pathways to improve ISO-induced cardiac hypertrophy and myocardial fibrosis. Based upon RNA-seq analyses, we demonstrated that SIRT3-pyrroline-5-carboxylate reductase 1 (PYCR1) axis was closely assoiated with HF. By activating PYCR1, 2-APQC was shown to enhance mitochondrial proline metabolism, inhibited reactive oxygen species (ROS)-p38 mitogen activated protein kinase (p38MAPK) pathway and thereby protecting against ISO-induced mitochondrialoxidative damage. Moreover, activation of SIRT3 by 2-APQC could facilitate AMP-activated protein kinase (AMPK)-Parkin axis to inhibit ISO-induced necrosis. Together, our results demonstrate that 2-APQC is a targeted SIRT3 activator that alleviates myocardial hypertrophy and fibrosis by regulating mitochondrial homeostasis, which may provide a new clue on exploiting a promising drug candidate for the future HF therapeutics.

Effect of Lycium barbarum polysaccharide on osteoblast proliferation and differentiation in postmenopausal osteoporosis.

OBJECTIVE: We aimed to investigate the effect of Lycium barbarum polysaccharide (LBP) on the proliferation and differentiation of osteoblasts in postmenopausal individuals with osteoporosis using in vitro cell experiments. METHODS: We assessed the effect of long-term LBP consumption on the intestinal metabolites of individuals using a simulation of the human intestinal microbiota ecosystem. We also tested the capacity of LBP in proliferating MC3T3-E1 cells using the cell counting kit-8 (CCK-8) method and analyzed the effect of intestinal metabolites on the osteogenic differentiation of MC3T3-E1 cells by testing bone metabolism viability with relevant indicators. RESULTS: The level of short-chain fatty acids (SCFAs) significantly increased (p < 0.05), and the concentrations of acetic acid, propionic acid, and butyric acid all showed an upward trend after the treatment using LBP. At appropriate concentrations, the fermentation supernatant can enhance osteoblast proliferation by significantly increasing the active expression of bone-alkaline phosphatase (B-ALP) and osteocalcin (OCN) in osteoblasts (p < 0.05). CONCLUSION: By modulating the metabolites of intestinal microbiota, production of SCFAs, the prebiotic properties of LBP can enhance osteoblast differentiation through in vitro simulation experiment and cell-based assay.

Discovery of an Ortho-Substituted N-Cyclopropylmethyl-7α-phenyl-6,14-endoethano-tetrahydronorthebaine Derivative as a Selective and Potent Kappa Opioid Receptor Agonist with Subsided Sedative Effect.

Research into kappa opioid receptor (KOR) agonists with attenuated central-nervous-system side effects is a critical focus for developing productive and safe analgesics. Herein, a series of ortho-substituted N-cyclopropylmethyl-7α-phenyl-6,14-endoethano-tetrahydronorthebaines were designed, synthesized, and subjected to bioassays. Compound 7a exhibited high subtype selectivity and potent agonistic activity toward KOR (KOR, Ki = 3.9 nM, MOR/KOR = 270, DOR/KOR = 1075; [35S]GTPγS binding, EC50 = 3.4 nM). Additionally, this compound exhibited robust and persistent antinociceptive effects in rodent models with different animal strains (hot plate test, ED50 = 0.20-0.30 mg/kg, i.p.; abdominal constriction test, ED50 = 0.20-0.60 mg/kg, i.p.), with its KOR-mediated mechanism for antinociception firmly established. Notably, compound 7a, unlike conventional KOR agonists, displayed minimal sedation and aversion at the antinociceptive ED50 dose. This feature addresses a crucial limitation in existing KOR agonists, positioning compound 7a as a promising novel therapeutic agent.

Non-Hermitian Strongly Interacting Dirac Fermions.

Exotic quantum phases and phase transition in the strongly interacting Dirac systems have attracted tremendous interests. On the other hand, non-Hermitian physics, usually associated with dissipation arising from the coupling to environment, emerges as a frontier of modern physics in recent years. In this Letter, we investigate the interplay between non-Hermitian physics and strong correlation in Dirac-fermion systems. We generalize the projector quantum Monte-Carlo (PQMC) algorithm to the non-Hermitian interacting fermionic systems. Employing PQMC simulation, we decipher the ground-state phase diagram of the honeycomb Hubbard model with spin resolved non-Hermitian asymmetric hopping processes. The antiferromagnetic (AFM) ordering induced by Hubbard interaction is enhanced by the non-Hermitian asymmetric hopping. Combining PQMC simulation and renormalization group analysis, we reveal that the quantum phase transition between Dirac semi-metal and AFM phases belongs to Hermitian chiral XY universality class, implying that a Hermitian Gross-Neveu transition is emergent at the quantum critical point although the model is non-Hermitian.

Synthesis of easily-modified and useful dibenzo-[b,d]azepines by palladium(II)-catalyzed cyclization/addition with a green solvent.

A novel strategy in which palladium(II)-catalyzed tandem cyclization is used to obtain N-heterocyclic architectures containing a seven-membered ring has been developed and used to synthesize a series of derivatives. The reaction uses an eco-friendly mixed solvent (water : EtOH = 2 : 1) instead of DMSO and maintains a high yield (91%). Its potential application value and reaction mechanism have also been explored.

Emergence of Competing Orders and Possible Quantum Spin Liquid in SU(N) Fermions.

In the past few decades, tremendous efforts have been made toward understanding the exotic physics emerging from competition between various ordering tendencies in strongly correlated systems. Employing state-of-the-art quantum Monte Carlo simulation, we investigate an interacting SU(N) fermionic model with varying interaction strength and value of N, and we unveil the ground-state phase diagram of the model exhibiting a plethora of exotic phases. For small values of N-namely, N=2, 3-the ground state is an antiferromagnetic (AFM) phase, whereas in the large-N limit, a staggered valence bond solid (VBS) order is dominant. For intermediate values of N such as N=4, 5, remarkably, our study reveals that distinct VBS orders appear in the weak and strong coupling regimes. More fantastically, the competition between staggered and columnar VBS ordering tendencies gives rise to a Mott insulating phase without spontaneous symmetry breaking (SSB), existing in a large interacting parameter regime, which is consistent with a gapped quantum spin liquid. Our study not only provides a platform to investigate the fundamental physics of quantum many-body systems-it also offers a novel route toward searching for exotic states of matter such as quantum spin liquid in realistic quantum materials.

Reinforcement Learning-Based Multiobjective Evolutionary Algorithm for Mixed-Model Multimanned Assembly Line Balancing Under Uncertain Demand.

In practical assembly enterprises, customization and rush orders lead to an uncertain demand environment. This situation requires managers and researchers to configure an assembly line that increases production efficiency and robustness. Hence, this work addresses cost-oriented mixed-model multimanned assembly line balancing under uncertain demand, and presents a new robust mixed-integer linear programming model to minimize the production and penalty costs simultaneously. In addition, a reinforcement learning-based multiobjective evolutionary algorithm (MOEA) is designed to tackle the problem. The algorithm includes a priority-based solution representation and a new task-worker-sequence decoding that considers robustness processing and idle time reductions. Five crossover and three mutation operators are proposed. The Q -learning-based strategy determines the crossover and mutation operator at each iteration to effectively obtain Pareto sets of solutions. Finally, a time-based probability-adaptive strategy is designed to effectively coordinate the crossover and mutation operators. The experimental study, based on 269 benchmark instances, demonstrates that the proposal outperforms 11 competitive MOEAs and a previous single-objective approach to the problem. The managerial insights from the results as well as the limitations of the algorithm are also highlighted.

Evidence for Quantum Stripe Ordering in a Triangular Optical Lattice.

Understanding strongly correlated quantum materials, such as high-T_{c} superconductors, iron-based superconductors, and twisted bilayer graphene systems, remains as one of the outstanding challenges in condensed matter physics. Quantum simulation with ultracold atoms in particular optical lattices, which provide orbital degrees of freedom, is a powerful tool to contribute new insights to this endeavor. Here, we report the experimental realization of an unconventional Bose-Einstein condensate of ^{87}Rb atoms populating degenerate p orbitals in a triangular optical lattice, exhibiting remarkably long coherence times. Using time-of-flight spectroscopy, we observe that this state spontaneously breaks the rotational symmetry and its momentum spectrum agrees with the theoretically predicted coexistence of exotic stripe and loop-current orders. Like certain strongly correlated electronic systems with intertwined orders, such as high-T_{c} cuprate superconductors, twisted bilayer graphene, and the recently discovered chiral density-wave state in kagome superconductors AV_{3}Sb_{5} (A=K, Rb, Cs), the newly demonstrated quantum state, in spite of its markedly different energy scale and the bosonic quantum statistics, exhibits multiple symmetry breakings at ultralow temperatures. These findings hold the potential to enhance our comprehension of the fundamental physics governing these intricate quantum materials.

Flubendazole Enhances the Inhibitory Effect of Paclitaxel via HIF1α/PI3K/AKT Signaling Pathways in Breast Cancer.

Paclitaxel, a natural anticancer drug, is widely recognized and extensively utilized in the treatment of breast cancer (BC). However, it may lead to certain side effects or drug resistance. Fortunately, combination therapy with another anti-tumor agent has been explored as an option to improve the efficacy of paclitaxel in the treatment of BC. Herein, we first evaluated the synergistic effects of paclitaxel and flubendazole through combination index (CI) calculations. Secondly, flubendazole was demonstrated to synergize paclitaxel-mediated BC cell killing in vitro and in vivo. Moreover, we discovered that flubendazole could reverse the drug resistance of paclitaxel-resistant BC cells. Mechanistically, flubendazole was demonstrated to enhance the inhibitory effect of paclitaxel via HIF1α/PI3K/AKT signaling pathways. Collectively, our findings demonstrate the effectiveness of flubendazole in combination with paclitaxel for treating BC, providing an insight into exploiting more novel combination therapies for BC in the future.

A Body Shape Index and Its Changes in Relation to All-Cause Mortality among the Chinese Elderly: A Retrospective Cohort Study.

Although recent evidence has revealed that a body shape index (ABSI) is correlated with the incidence of death among different ethnicities, there remains a paucity of studies investigating the impact of ABSI on mortality within the Chinese elderly. Our objective was to ascertain the link between ABSI, as well as its alterations over time, and all-cause mortality among Chinese aged 65 y and above. A total of 3789 participants were enrolled from the Chinese Longitudinal Healthy Longevity Survey (CLHLS). Cox regressions and restricted cubic splines were employed to assess the association of ABSI and relative changes with all-cause mortality. When nonlinearity was detected, a restricted cubic spline regression was subsequently conducted to compute hazard ratios and 95% confidence intervals. The median survival time was 46 months, and 1342 individuals (35.4%) were reported to have died. ABSI contributed independently to rising death rates among Chinese old populations according to univariate and multivariate Cox regressions. Statistically significant associations were also found stratified by age, sex, and lifestyle. A U-shaped association of ABSI changes with all-cause mortality (p = 0.027) was observed, indicating that old adults with stable ABSI during the follow-up period experienced the lowest risk of mortality. After multivariable adjustment, participants with a 10% reduction in ABSI changes had an increased 9.4% risk of death, while participants with a 10% rise in ABSI changes had an increased 1.9% risk. ABSI and its changes are predictors for all-cause mortality among the elderly Chinese population, which emphasizes the clinical importance of monitoring ABSI and keeping it stable over time.

Reversal of subtype-selectivity and function by the introduction of a para-benzamidyl substituent to N-cyclopropylmethyl nornepenthone.

The discovery and development of novel µ-opioid receptor (MOR) antagonists is a significant area to combat Opioid Use Disorder (OUD). In this work, a series of para-substituted N-cyclopropylmethyl-nornepenthone derivatives were designed and synthesized and pharmacologically assayed. Compound 6a was identified as a selective MOR antagonist both in vitro and in vivo. Its molecular basis was elucidated using molecular docking and MD simulations. A subpocket on the extracellular side of the TM2 domain of MOR, in particular the residue Y2.64, was proposed to be responsible for the reversal of subtype selectivity and functional reversal of this compound.

Adenophorone, An Unprecedented Sesquiterpene from Eupatorium adenophorum: Structural Elucidation, Bioinspired Total Synthesis and Neuroprotective Activity Evaluation.

(-)-Adenophorone (1), a caged polycyclic sesquiterpene featuring an unprecedented tricyclo[4.3.1.05,9 ]decane skeleton, was isolated from Eupatorium adenopharum Spreng. The structure of 1 was unambiguously established by a combination of spectroscopic analysis, X-ray crystallography, and bioinspired total synthesis. Key synthetic features include a sequential Reformatsky/oxidation/regio- and stereoselective hydrogenation, and subsequent merged MBH-Tsuji-Trost cyclization. The concise synthetic sequence efficiently constructs the bicyclic skeleton of cadinene sesquiterpene (+)-euptox A (2) in 8 steps from commercially available monoterpene (-)-carvone (6), with outstanding performance on diastereocontrol. The bioinspired synthesis of 1 was achieved from 2, a plausible biogenetic precursor, via transannular Michael addition. This work provides experimental evidence of our proposed biosynthetic hypothesis of 1. Additionally, compound 1 showed potent neuroprotective activity in H2 O2 -treated SH-SY5Y and PC12 cells.

Targeting VPS34 in autophagy: An update on pharmacological small-molecule compounds.

VPS34 is well-known to be the unique member of the class III phosphoinositide 3-kinase (PI3K) family, forming VPS34 complex 1 and complex 2, which are involved in several key physiological processes. Of note, VPS34 complex 1 is an important node of autophagosome generation, which controls T cell metabolism and maintains cellular homeostasis through the autophagic pathway. And, VPS34 complex 2 is involved in endocytosis as well as vesicular transport, and is closely related to neurotransmission, antigen presentation and brain development. Due to the two important biological functions of VPS34, its dysregulation can lead to the development of cardiovascular disease, cancer, neurological disorders, and many types of human diseases by altering normal human physiology. Thus, in this review, we not only summarize the molecular structure and function of VPS34, but demonstrate the relationships between VPS34 and human diseases. Moreover, we further discuss the current small molecule inhibitors targeting VPS34 based upon the structure and function of VPS34, which may provide an insight into the future targeted drug development.

Boosting Glioblastoma Therapy with Targeted Pyroptosis Induction.

Glioblastoma (GBM) is a highly aggressive cancer that currently lacks effective treatments. Pyroptosis has emerged as a promising therapeutic approach for cancer, but there is still a need for new pyroptosis boosters to target cancer cells. In this study, it is reported that Aloe-emodin (AE), a natural compound derived from plants, can inhibit GBM cells by inducing pyroptosis, making it a potential booster for pyroptosis-mediated GBM therapy. However, administering AE is challenging due to the blood-brain barrier (BBB) and its non-selectivity. To overcome this obstacle, AE@ZIF-8 NPs are developed, a biomineralized nanocarrier that releases AE in response to the tumor's acidic microenvironment (TAM). Further modification of the nanocarrier with transferrin (Tf) and polyethylene glycol-poly (lactic-co-glycolic acid) (PEG-PLGA) improves its penetration through the BBB and tumor targeting, respectively. The results show that AE-NPs (Tf-PEG-PLGA modified AE@ZIF-8 NPs) significantly increase the intracranial distribution and tumor tissue accumulation, enhancing GBM pyroptosis. Additionally, AE-NPs activate antitumor immunity and reduce AE-related toxicity. Overall, this study provides a new approach for GBM therapy and offers a nanocarrier that is capable of penetrating the BBB, targeting tumors, and attenuating toxicity.