Entanglement on an optical atomic-clock transition.

State-of-the-art atomic clocks are based on the precise detection of the energy difference between two atomic levels, which is measured in terms of the quantum phase accumulated over a given time interval1-4. The stability of optical-lattice clocks (OLCs) is limited both by the interrupted interrogation of the atomic system by the local-oscillator laser (Dick noise5) and by the standard quantum limit (SQL) that arises from the quantum noise associated with discrete measurement outcomes. Although schemes for removing the Dick noise have been recently proposed and implemented4,6-8, performance beyond the SQL by engineering quantum correlations (entanglement) between atoms9-20 has been demonstrated only in proof-of-principle experiments with microwave clocks of limited stability. The generation of entanglement on an optical-clock transition and operation of an OLC beyond the SQL represent important goals in quantum metrology, but have not yet been demonstrated experimentally16. Here we report the creation of a many-atom entangled state on an OLC transition, and use it to demonstrate a Ramsey sequence with an Allan deviation below the SQL after subtraction of the local-oscillator noise. We achieve a metrological gain of [Formula: see text] decibels over the SQL by using an ensemble consisting of a few hundred ytterbium-171 atoms, corresponding to a reduction of the averaging time by a factor of 2.8 ± 0.3. Our results are currently limited by the phase noise of the local oscillator and Dick noise, but demonstrate the possible performance improvement in state-of-the-art OLCs1-4 through the use of entanglement. This will enable further advances in timekeeping precision and accuracy, with many scientific and technological applications, including precision tests of the fundamental laws of physics21-23, geodesy24-26 and gravitational-wave detection27.

Phosphoproteomic analysis reveals CDK5-Mediated phosphorylation of MTDH inhibits protein synthesis in microglia.

CDK5 plays a crucial role in maintaining normal central nervous system (CNS) development and synaptic function, while microglia are the primary immune cells present in the CNS and play vital physiological roles in CNS development, immune surveillance, and regulation of synaptic plasticity. Despite this, our understanding of both the substrate proteins and functional mechanisms of CDK5 in microglia remains limited. To address this, we utilized CRISPR-Cas9 knockout of Cdk5 in BV2 cells and conducted quantitative phosphoproteomics analysis to systematically screen potential CDK5 substrates in microglia. Our findings identified 335 phosphorylation sites on 234 proteins as potential CDK5 substrates in microglia based on the reported sequence motif. Through in vitro kinase assay and intracellular inhibition and knockout of CDK5 experiments, we confirmed that ER proteins MTDH (protein LYRIC) and Calnexin are novel substrate proteins of CDK5. Moreover, we demonstrated for the first time a critical mechanism for regulating protein synthesis in microglia, that the phosphorylation of S565 site on MTDH, a key protein mediating cell growth, by CDK5 inhibits protein synthesis. Our data provide valuable insights for the discovery of new substrate proteins of CDK5 and the in-depth investigation of the function and mechanism of CDK5 in microglia.

Polygenic risk score of metabolic dysfunction-associated steatotic liver disease amplifies the health impact on severe liver disease and metabolism-related outcomes.

BACKGROUND: Although the inherited risk factors associated with fatty liver disease are well understood, little is known about the genetic background of metabolic dysfunction-associated steatotic liver disease (MASLD) and its related health impacts. Compared to non-alcoholic fatty liver disease (NAFLD), MASLD presents significantly distinct diagnostic criteria, and epidemiological and clinical features, but the related genetic variants are yet to be investigated. Therefore, we conducted this study to assess the genetic background of MASLD and interactions between MASLD-related genetic variants and metabolism-related outcomes. METHODS: Participants from the UK Biobank were grouped into discovery and replication cohorts for an MASLD genome-wide association study (GWAS), and base and target cohorts for polygenic risk score (PRS) analysis. Autosomal genetic variants associated with NAFLD were compared with the MASLD GWAS results. Kaplan-Meier and Cox regression analyses were used to assess associations between MASLD and metabolism-related outcomes. RESULTS: Sixteen single-nucleotide polymorphisms (SNPs) were identified at genome-wide significance levels for MASLD and duplicated in the replication cohort. Differences were found after comparing these SNPs with the results of NAFLD-related genetic variants. MASLD cases with high PRS had a multivariate-adjusted hazard ratio of 3.15 (95% confidence interval, 2.54-3.90) for severe liver disease (SLD), and 2.81 (2.60-3.03) for type 2 diabetes mellitus. The high PRS amplified the impact of MASLD on SLD and extrahepatic outcomes. CONCLUSIONS: High PRS of MASLD GWAS amplified the impact of MASLD on SLD and metabolism-related outcomes, thereby refining the process of identification of individuals at high risk of MASLD. Supplementation of this process with relevant genetic backgrounds may lead to more effective MASLD prevention and management.

Abnormal phosphorylation / dephosphorylation and Ca2+ dysfunction in heart failure.

Heart failure (HF) can be caused by a variety of causes characterized by abnormal myocardial systole and diastole. Ca2+ current through the L-type calcium channel (LTCC) on the membrane is the initial trigger signal for a cardiac cycle. Declined systole and diastole in HF are associated with dysfunction of myocardial Ca2+ function. This disorder can be correlated with unbalanced levels of phosphorylation / dephosphorylation of LTCC, endoplasmic reticulum (ER), and myofilament. Kinase and phosphatase activity changes along with HF progress, resulting in phased changes in the degree of phosphorylation / dephosphorylation. It is important to realize the phosphorylation / dephosphorylation differences between a normal and a failing heart. This review focuses on phosphorylation / dephosphorylation changes in the progression of HF and summarizes the effects of phosphorylation / dephosphorylation of LTCC, ER function, and myofilament function in normal conditions and HF based on previous experiments and clinical research. Also, we summarize current therapeutic methods based on abnormal phosphorylation / dephosphorylation and clarify potential therapeutic directions.

Adipocyte maturation impacts daunorubicin disposition and metabolism.

INTRODUCTION: Acute lymphoblastic leukaemia (ALL) is the most common type of childhood leukaemia with effective chemotherapeutic treatment. However, obesity has been associated with higher ALL chemoresistance rates and lower event-free survival rates. The molecular mechanism of how obesity promotes chemotherapy resistance is not well delineated. OBJECTIVES: This study evaluated the effect of adipocyte maturation on sequestration and metabolism of chemotherapeutic drug daunorubicin (DNR). METHODS: Using targeted LC-MS/MS multi-analyte assay, DNR sequestration and metabolism were studied in human preadipocyte and adipocyte cell lines, where expressions of DNR-metabolizing enzymes aldo-keto reductases (AKR) and carbonyl reductases (CBR) were also evaluated. In addition, to identify the most DNR-metabolizing AKR/CBR isoforms, recombinant human AKR and CBR enzymes were subject to DNR metabolism. The results were further validated by AKR-, CBR-specific inhibitors. RESULTS: This report shows that adipocyte maturation upregulates expressions of AKR and CBR enzymes (by 4- to 60- folds, p < .05), which is positively associated with enhanced sequestration and metabolism of DNR in adipocytes compared to preadipocytes (by ~30%, p < .05). In particular, adipocyte maturation upregulates AKR1C3 and CBR1, which are the predominate metabolic enzyme isoforms responsible for DNR biotransformation to its metabolites. CONCLUSION: Fat is an expandable tissue that can sequester and detoxify DNR when stimulated by obesity, likely through the upregulation of DNR-metabolizing enzymes AKR1C3 and CBR1. Our data partially explains why obese ALL patients may be more likely to become chemoresistant towards DNR, and provides evidence for potential clinical investigation targeting obesity to reduce DNR chemoresistance.

Bose-Einstein Condensation by Polarization Gradient Laser Cooling.

Attempts to create quantum degenerate gases without evaporative cooling have been pursued since the early days of laser cooling, with the consensus that polarization gradient cooling (PGC, also known as "optical molasses") alone cannot reach condensation. In the present work, we report that simple PGC can generate a small Bose-Einstein condensate (BEC) inside a corrugated micrometer-sized optical dipole trap. The experimental parameters enabling BEC creation were found by machine learning, which increased the atom number by a factor of 5 and decreased the temperature by a factor of 2.5, corresponding to almost 2 orders of magnitude gain in phase space density. When the trapping light is slightly misaligned through a microscopic objective lens, a BEC of ∼250 ^{87}Rb atoms is formed inside a local dimple within 40 ms of PGC after MOT loading.

SDS3 regulates microglial inflammation by modulating the expression of the upstream kinase ASK1 in the p38 MAPK signaling pathway.

BACKGROUND: Microglia, the main innate immune cells in the central nervous system, are key drivers of neuroinflammation, which plays a crucial role in the pathogenesis of neurodegenerative diseases. The Sin3/histone deacetylase (HDAC) complex, a highly conserved multiprotein co-repressor complex, primarily performs transcriptional repression via deacetylase activity; however, the function of SDS3, which maintains the integrity of the complex, in microglia remains unclear. METHODS: To uncover the regulatory role of the transcriptional co-repressor SDS3 in microglial inflammation, we used chromatin immunoprecipitation to identify SDS3 target genes and combined with transcriptomics and proteomics analysis to explore expression changes in cells following SDS3 knocking down. Subsequently, we validated our findings through experimental assays. RESULTS: Our analysis revealed that SDS3 modulates the expression of the upstream kinase ASK1 of the p38 MAPK pathway, thus regulating the activation of signaling pathways and ultimately influencing inflammation. CONCLUSIONS: Our findings provide important evidence of the contributions of SDS3 toward microglial inflammation and offer new insights into the regulatory mechanisms of microglial inflammatory responses.

Neurovascular decoupling measured with quantitative susceptibility mapping is associated with cognitive decline in patients with type 2 diabetes.

Disturbance of neurovascular coupling (NVC) is suggested to be one potential mechanism in type 2 diabetes mellitus (T2DM) associated mild cognitive impairment (MCI). However, NVC evidence derived from functional magnetic resonance imaging ignores the relationship of neuronal activity with vascular injury. Twenty-seven T2DM patients without MCI and thirty healthy controls were prospectively enrolled. Brain regions with changed susceptibility detected by quantitative susceptibility mapping (QSM) were used as seeds for functional connectivity (FC) analysis. NVC coefficients were estimated using combined degree centrality (DC) with susceptibility or cerebral blood flow (CBF). Partial correlations between neuroimaging indicators and cognitive decline were investigated. In T2DM group, higher susceptibility values in right hippocampal gyrus (R.PHG) were found and were negatively correlated with Naming Ability of Montreal Cognitive Assessment. FC increased remarkably between R.PHG and right middle temporal gyrus (R.MTG), right calcarine gyrus (R.CAL). Both NVC coefficients (DC-QSM and DC-CBF) reduced in R.PHG and increased in R.MTG and R.CAL. Both NVC coefficients in R.PHG and R.MTG increased with the improvement of cognitive ability, especially for executive function. These demonstrated that QSM and DC-QSM coefficients can be promising biomarkers for early evaluation of cognitive decline in T2DM patients and help to better understand the mechanism of NVC.

Assembly and characterization of the complete mitochondrial genome of Ventilago leiocarpa.

KEY MESSAGE: We reported the mitochondrial genome of Ventilago leiocarpa for the first time. Two and one sites lead to the generation of stop and stat codon through editing were verified. Ventilago leiocarpa, a member of the Rhamnaceae family, is frequently utilized in traditional medicine due to the medicinal properties of its roots. In this study, we successfully assembled the mitogenome of V. leiocarpa using both BGI short reads and Nanopore long reads. This mitogenome has a total length of 331,839 bp. The annotated results showed 36 unique protein-coding, 16 tRNA and 3 rRNA genes in this mitogenome. Furthermore, we confirmed the presence of a branched structure through the utilization of long reads mapping, PCR amplification, and Sanger sequencing. Specifically, the ctg1 can form a single circular molecule or combine with ctg4 to form a linear molecule. Likewise, ctg2 can form a single circular molecule or can be connected to ctg4 to form a linear molecule. Subsequently, through a comparative analysis of the mitogenome and cpgenome sequences, we identified ten mitochondrial plastid sequences (MTPTs), including two complete protein-coding genes and five complete tRNA genes. The existence of MTPTs was verified by long reads. Colinear analysis showed that the mitogenomes of Rosales were highly divergent in structure. Finally, we identified 545 RNA editing sites involving 36 protein-coding genes by Deepred-mt. To validate our findings, we conducted PCR amplification and Sanger sequencing, which confirmed the generation of stop codons in atp9-223 and rps10-391, as well as the generation of a start codon in nad4L-2. This project reported the complex structure and RNA editing event of the V. Leiocarpa mitogenome, which will provide valuable information for the study of mitochondrial gene expression.

The intra-S phase checkpoint directly regulates replication elongation to preserve the integrity of stalled replisomes.

DNA replication is dramatically slowed down under replication stress. The regulation of replication speed is a conserved response in eukaryotes and, in fission yeast, requires the checkpoint kinases Rad3ATR and Cds1Chk2 However, the underlying mechanism of this checkpoint regulation remains unresolved. Here, we report that the Rad3ATR-Cds1Chk2 checkpoint directly targets the Cdc45-MCM-GINS (CMG) replicative helicase under replication stress. When replication forks stall, the Cds1Chk2 kinase directly phosphorylates Cdc45 on the S275, S322, and S397 residues, which significantly reduces CMG helicase activity. Furthermore, in cds1Chk2 -mutated cells, the CMG helicase and DNA polymerases are physically separated, potentially disrupting replisomes and collapsing replication forks. This study demonstrates that the intra-S phase checkpoint directly regulates replication elongation, reduces CMG helicase processivity, prevents CMG helicase delinking from DNA polymerases, and therefore helps preserve the integrity of stalled replisomes and replication forks.

Association between sarcopenia-related markers and cholelithiasis: A prospective and Mendelian randomization study.

Cholelithiasis is a common digestive disease that drives a myriad of adverse complications. The correlation between sarcopenia and various digestive disorders has been extensively researched, whereas its association with cholelithiasis remains unreported. We aimed to investigate the association through prospective and Mendelian randomization (MR) analyses and establish a quantitative score reflecting the impact of sarcopenia-related markers on cholelithiasis. The prospective study involved 448 627 participants from the UK Biobank. Cox proportional hazard models were employed to investigate the correlation between sarcopenia-related markers and cholelithiasis. To quantitatively assess cholelithiasis risk, the SARCHO score was derived from a multivariable Cox model. Bidirectional two-sample MR analysis was conducted to validate the causal association. A total of 16 738 individuals developed cholelithiasis during a median follow-up of 12 years. Hazard ratios (HRs) of cholelithiasis decreased stepwise over skeletal muscle index tertiles (highest tertile: reference; middle tertile: 1.23, p < .001; lowest tertile: 1.33, p < .001). The tertiles of grip strength showed a similar pattern. Individuals with slow walking pace had a higher risk of cholelithiasis compared to those with normal walking pace (HR 1.23; p < .001). Our SARCHO score better quantifies the risk of cholelithiasis. MR analysis showed a causal relationship between muscle mass and cholelithiasis (OR 0.81; p < .001). No causal effect of cholelithiasis on lean mass was observed. Prospective and MR analyses have consistently demonstrated an increased risk of cholelithiasis in individuals with decreased muscle mass. Additionally, SARCHO score further quantified the cholelithiasis occurrence risk. These findings provide compelling evidence for muscle strengthening in preventing cholelithiasis.

Fast Lithium Ion Transport Pathways Constructed by Two-Dimensional Boron Nitride Nanoflakes in Quasi-Solid-State Polymer Electrolyte.

Quasi-solid-state electrolytes (QSSEs) are gaining huge popularity because of their significantly improved safety performance over nonaqueous liquid electrolytes and superior process adaptability over all-solid-state electrolytes. However, because of the existence of liquid molecules, QSSEs typically have low lithium ion transference numbers and compromised thermal stability. In this work, we present the fabrication of a well-rounded QSSE by introducing hexagonal boron nitride nanoflakes (BNNFs) as an inorganic filler in a poly(vinylene carbonate) matrix. BNNFs, in contrast to most inorganic fillers used as anion trappers, are used to build fast lithium ion transport pathways directly on their two-dimensional surfaces. We confirm the attractive coupling between lithium ions and BNNFs, and we confirm that with the help of BNNFs, lithium ions can migrate with less damping and a lower transport energy barrier. As a result, the designed electrolyte exhibits good ion transportability, promoted fire retardancy, and good compatibility with lithium metal anodes and commercial cathodes.

Loss of 15-Lipoxygenase in Retinodegenerative RCS Rats.

Retinitis pigmentosa (RP) is a retinal degenerative disease associated with a diversity of genetic mutations. In a natural progression study (NPS) evaluating the molecular changes in Royal College of Surgeons (RCS) rats using lipidomic profiling, RNA sequencing, and gene expression analyses, changes associated with retinal degeneration from p21 to p60 were evaluated, where reductions in retinal ALOX15 expression corresponded with disease progression. This important enzyme catalyzes the formation of specialized pro-resolving mediators (SPMs) such as lipoxins (LXs), resolvins (RvDs), and docosapentaenoic acid resolvins (DPA RvDs), where reduced ALOX15 corresponded with reduced SPMs. Retinal DPA RvD2 levels were found to correlate with retinal structural and functional decline. Retinal RNA sequencing comparing p21 with p60 showed an upregulation of microglial inflammatory pathways accompanied by impaired damage-associated molecular pattern (DAMP) clearance pathways. This analysis suggests that ALXR/FPR2 activation can ameliorate disease progression, which was supported by treatment with an LXA4 analog, NAP1051, which was able to promote the upregulation of ALOX12 and ALOX15. This study showed that retinal inflammation from activated microglia and dysregulation of lipid metabolism were central to the pathogenesis of retinal degeneration in RP, where ALXR/FPR2 activation was able to preserve retinal structure and function.

Unveiling Drivers of Retinal Degeneration in RCS Rats: Functional, Morphological, and Molecular Insights.

Retinal degenerative diseases, including age-related macular degeneration and retinitis pigmentosa, significantly contribute to adult blindness. The Royal College of Surgeons (RCS) rat is a well-established disease model for studying these dystrophies; however, molecular investigations remain limited. We conducted a comprehensive analysis of retinal degeneration in RCS rats, including an immunodeficient RCS (iRCS) sub-strain, using ocular coherence tomography, electroretinography, histology, and molecular dissection using transcriptomics and immunofluorescence. No significant differences in retinal degeneration progression were observed between the iRCS and immunocompetent RCS rats, suggesting a minimal role of adaptive immune responses in disease. Transcriptomic alterations were primarily in inflammatory signaling pathways, characterized by the strong upregulation of Tnfa, an inflammatory signaling molecule, and Nox1, a contributor to reactive oxygen species (ROS) generation. Additionally, a notable decrease in Alox15 expression was observed, pointing to a possible reduction in anti-inflammatory and pro-resolving lipid mediators. These findings were corroborated by immunostaining, which demonstrated increased photoreceptor lipid peroxidation (4HNE) and photoreceptor citrullination (CitH3) during retinal degeneration. Our work enhances the understanding of molecular changes associated with retinal degeneration in RCS rats and offers potential therapeutic targets within inflammatory and oxidative stress pathways for confirmatory research and development.

High Performance Aqueous Zinc-Ion Batteries Developed by PANI Intercalation Strategy and Separator Engineering.

Aqueous zinc-ion batteries (ZIBs) have attracted burgeoning attention and emerged as prospective alternatives for scalable energy storage applications due to their unique merits such as high volumetric capacity, low cost, environmentally friendly, and reliable safety. Nevertheless, current ZIBs still suffer from some thorny issues, including low intrinsic electron conductivity, poor reversibility, zinc anode dendrites, and side reactions. Herein, conductive polyaniline (PANI) is intercalated as a pillar into the hydrated V2O5 (PAVO) to stabilize the structure of the cathode material. Meanwhile, graphene oxide (GO) was modified onto the glass fiber (GF) membrane through simple electrospinning and laser reduction methods to inhibit dendrite growth. As a result, the prepared cells present excellent electrochemical performance with enhanced specific capacity (362 mAh g-1 at 0.1 A g-1), significant rate capability (280 mAh g-1 at 10 A g-1), and admirable cycling stability (74% capacity retention after 4800 cycles at 5 A g-1). These findings provide key insights into the development of high-performance zinc-ion batteries.

In Situ Hybridization Strategy Constructs Heterogeneous Interfaces to Form Electronically Modulated MoS2/FeS2 as the Anode for High-Performance Lithium-Ion Storage.

The interfacial effect is important for anodes of transition metal dichalcogenides (TMDs) to achieve superior lithium-ion storage performance. In this paper, a MoS2/FeS2 heterojunction is synthesized by a simple hydrothermal reaction to construct the interface effect, and the heterostructure introduces an inherent electric field that accelerates the de-embedding process of lithium ions, improves the electron transfer capability, and effectively mitigates volume expansion. XPS analysis confirms evident chemical interaction between MoS2 and FeS2 via an interfacial covalent bond (Mo-S-Fe). This MoS2/FeS2 anode shows a distinct interfacial effect for efficient interatomic electron migration. The electrochemical performance demonstrated that the discharge capacity can reach up to 1217.8 mA h g-1 at 0.1 A g-1 after 200 cycles, with a capacity retention rate of 72.9%. After 2000 cycles, the capacity retention is about 61.6% at 1.0 A g-1, and the discharge capacity can still reach 638.9 mA h g-1. Electrochemical kinetic analysis indicated an enhanced pseudocapacitance contribution and that the MoS2/FeS2 had sufficient adsorption of lithium ions. This paper therefore argues that this interfacial engineering is an effective solution for designing sulfide-based anodes with good electrochemical properties.

GmPLP1 negatively regulates soybean resistance to high light stress by modulating photosynthetic capacity and reactive oxygen species accumulation in a blue light-dependent manner.

High light stress is an important factor limiting crop yield. Light receptors play an important role in the response to high light stress, but their mechanisms are still poorly understood. Here, we found that the abundance of GmPLP1, a positive blue light receptor protein, was significantly inhibited by high light stress and mainly responded to high blue light. GmPLP1 RNA-interference soybean lines exhibited higher light energy utilization ability and less light damage and reactive oxygen species (ROS) accumulation in leaves under high light stress, while the phenotype of GmPLP1:GmPLP1-Flag overexpression soybean showed the opposite characteristics. Then, we identified a protein-protein interaction between GmPLP1 and GmVTC2, and the intensity of this interaction was primarily affected by sensing the intensity of blue light. More importantly, overexpression of GmVTC2b improved soybean tolerance to high light stress by enhancing the ROS scavenging capability through increasing the biosynthesis of ascorbic acid. This regulation was significantly enhanced after interfering with a GmPLP1-interference fragment in GmVTC2b-ox soybean leaves, but was weakened when GmPLP1 was transiently overexpressed. These findings demonstrate that GmPLP1 regulates the photosynthetic capacity and ROS accumulation of soybean to adapt to changes in light intensity by sensing blue light. In summary, this study discovered a new mechanism through which GmPLP1 participates in high light stress in soybean, which has great significance for improving soybean yield and the adaptability of soybean to high light.

Study of radiochemotherapy decision-making for young high-risk low-grade glioma patients using a macroscopic and microscopic combined radiomics model.

OBJECTIVES: As a few types of glioma, young high-risk low-grade gliomas (HRLGGs) have higher requirements for postoperative quality of life. Although adjuvant chemotherapy with delayed radiotherapy is the first treatment strategy for HRLGGs, not all HRLGGs benefit from it. Accurate assessment of chemosensitivity in HRLGGs is vital for making treatment choices. This study developed a multimodal fusion radiomics (MFR) model to support radiochemotherapy decision-making for HRLGGs. METHODS: A MFR model combining macroscopic MRI and microscopic pathological images was proposed. Multiscale features including macroscopic tumor structure and microscopic histological layer and nuclear information were grabbed by unique paradigm, respectively. Then, these features were adaptively incorporated into the MFR model through attention mechanism to predict the chemosensitivity of temozolomide (TMZ) by means of objective response rate and progression free survival (PFS). RESULTS: Macroscopic tumor texture complexity and microscopic nuclear size showed significant statistical differences (p < 0.001) between sensitivity and insensitivity groups. The MFR model achieved stable prediction results, with an area under the curve of 0.950 (95% CI: 0.942-0.958), sensitivity of 0.833 (95% CI: 0.780-0.848), specificity of 0.929 (95% CI: 0.914-0.936), positive predictive value of 0.833 (95% CI: 0.811-0.860), and negative predictive value of 0.929 (95% CI: 0.914-0.934). The predictive efficacy of MFR was significantly higher than that of the reported molecular markers (p < 0.001). MFR was also demonstrated to be a predictor of PFS. CONCLUSIONS: A MFR model including radiomics and pathological features predicts accurately the response postoperative TMZ treatment. CLINICAL RELEVANCE STATEMENT: Our MFR model could identify young high-risk low-grade glioma patients who can have the most benefit from postoperative upfront temozolomide (TMZ) treatment. KEY POINTS: • Multimodal radiomics is proposed to support the radiochemotherapy of glioma. • Some macro and micro image markers related to tumor chemotherapy sensitivity are revealed. • The proposed model surpasses reported molecular markers, with a promising area under the curve (AUC) of 0.95.

Tuning Bienenstock-Cooper-Munro learning rules in a two-terminal memristor for neuromorphic computing.

In memristors, the implementation of the Bienenstock-Cooper-Munro (BCM) learning rule plays a significant role in the modulation balance of artificial synapses and the reduction of energy consumption owing to their sliding frequency threshold. At present, the BCM learning rule is mostly achieved by adjusting gating voltage or channel current in field effect transistors. However, owing to the lack of the tunable degrees of freedom, the progress of two-terminal memristors is limited to simulating the BCM learning rule. In this study, by adjusting the series resistance, three types of BCM-like learning rules are found in a two-terminal BaTiO3 memristor. Specifically, the abnormal BCM learning rule with high-frequency depression and low-frequency potentiation is obtained for a small series resistance, the monotonous BCM learning rule with high-frequency potentiation and low-frequency depression is achieved for a large series resistance, and the type of BCM learning rule with the enhanced depression effect is obtained for a moderate series resistance. These three BCM learning rules are related to the non-monotonous conductance modulation caused by the migration of ionized oxygen vacancies and are proved by X-ray photoelectron spectroscopy. Moreover, spike rate-dependent plasticity (SRDP) and history-dependent plasticity are achieved. This study offers promising prospects for neuromorphic computing.

TBK1-medicated DRP1 phosphorylation orchestrates mitochondrial dynamics and autophagy activation in osteoarthritis.

Mitochondrial dynamics, including mitochondrial fission and fusion, are critical for maintaining mitochondrial functions. Evidence shows that TANK-binding kinase 1 (TBK1) regulates mitochondrial fusion and fission and then mitophagy. Since a previous study demonstrates a strong correlation between mitophagy and osteoarthritis (OA), we herein investigated the potential role of TBK1 in OA process and mitochondrial functions. We demonstrated a strong correlation between TBK1 and OA, evidenced by significantly downregulated expression of TBK1 in cartilage tissue samples of OA patients and in the chondrocytes of aged mice, as well as TNF-α-stimulated phosphorylation of TBK1 in primary mouse chondrocytes. TBK1 overexpression significantly attenuated TNF-α-induced apoptosis and abnormal mitochondrial function in primary mouse chondrocytes. Furthermore, TBK1 overexpression induced remodeling of mitochondrial morphology by directly phosphorylating dynamin-related protein 1 (DRP1) at Ser637, abolishing the fission of DRP1 and preventing its fragmentation function. Moreover, TBK1 recruitment and DRP1 phosphorylation at Ser637 was necessary for engulfing damaged mitochondria by autophagosomal membranes during mitophagy. Moreover, we demonstrated that APMK/ULK1 signaling contributed to TBK1 activation. In OA mouse models established by surgical destabilization of the medial meniscus, intraarticular injection of lentivirus-TBK1 significantly ameliorated cartilage degradation via regulation of autophagy and alleviation of cell apoptosis. In conclusion, our results suggest that the TBK1/DRP1 pathway is involved in OA and pharmacological targeting of the TBK1-DRP1 cascade provides prospective therapeutic benefits for the treatment of OA.