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Tumor cells exhibit unique metabolic adaptations that are increasingly viewed as potential targets for novel and specific cancer therapies. Among these targets, the carnitine palmitoyltransferase system is responsible for delivering the long-chain fatty acid (FA) from cytoplasm into mitochondria for oxidation, where carnitine palmitoyltransferase I (CPTI) catalyzes the rate-limiting step of fatty acid oxidation (FAO). With increasing understanding of the crucial role had by fatty acid oxidation in cancer, CPTI has received renewed attention as a pivotal mediator in cancer metabolic mechanism. CPTI activates FAO and fuels cancer growth via ATP and NADPH production, constituting an essential part of cancer metabolism adaptation. Moreover, CPTI also functionally intertwines with other key pathways and factors to regulate gene expression and apoptosis of cancer cell. Here, we summarize recent findings and update the current understanding of FAO and CPTI in cancer and provide theoretical basis for this enzyme as an emerging potential molecular target in cancer therapeutic intervention.

In Alzheimer’s disease (AD), neurodegenerative signals such as amyloid-beta (Aβ) and the precursors of neurotrophins, outbalance neurotrophic signals, causing synaptic dysfunction and neurodegeneration. The neurotrophin receptor p75 (p75NTR) is a receptor of Aβ and mediates Aβ-induced neurodegenerative signals. The shedding of its ectodomain from the cell surface is physiologically regulated; however, the function of the diffusible p75NTR ectodomain (p75ECD) after shedding remains largely not known. Here, we show that p75ECD levels in cerebrospinal fluid and in the brains of Alzheimer’s patients and amyloid-beta precursor protein (APP)/PS1 transgenic mice were significantly reduced, due to inhibition of the sheddase-tumor necrosis factor-alpha-converting enzyme by Aβ. Restoration of p75ECD to the normal level by brain delivery of the gene encoding human p75ECD before or after Aβ deposition in the brain of APP/PS1 mice reversed the behavioral deficits and AD-type pathologies, such as Aβ deposit, apoptotic events, neuroinflammation, Tau phosphorylation and loss of dendritic spine, neuronal structures and synaptic proteins. Furthermore, p75ECD can also reduce amyloidogenesis by suppressing β-secretase expression and activities. Our data demonstrate that p75ECD is a physiologically neuroprotective molecule against Aβ toxicity and would be a novel therapeutic target and biomarker for AD.

Tropical cyclones (TCs) are a hazard to life and property and a prominent element of the global climate system; therefore, understanding and predicting TC location, intensity, and frequency is of both societal and scientific significance. Methodologies exist to predict basinwide, seasonally aggregated TC activity months, seasons, and even years in advance. It is shown that a newly developed high-resolution global climate model can produce skillful forecasts of seasonal TC activity on spatial scales finer than basinwide, from months and seasons in advance of the TC season. The climate model used here is targeted at predicting regional climate and the statistics of weather extremes on seasonal to decadal time scales, and comprises high-resolution (50 km × 50 km) atmosphere and land components as well as more moderate-resolution (∼100 km) sea ice and ocean components. The simulation of TC climatology and interannual variations in this climate model is substantially improved by correcting systematic ocean biases through “flux adjustment.” A suite of 12-month duration retrospective forecasts is performed over the 1981–2012 period, after initializing the climate model to observationally constrained conditions at the start of each forecast period, using both the standard and flux-adjusted versions of the model. The standard and flux-adjusted forecasts exhibit equivalent skill at predicting Northern Hemisphere TC season sea surface temperature, but the flux-adjusted model exhibits substantially improved basinwide and regional TC activity forecasts, highlighting the role of systematic biases in limiting the quality of TC forecasts. These results suggest that dynamical forecasts of seasonally aggregated regional TC activity months in advance are feasible.

Several previous researches had found artery stiffness associated skeletal muscle mass, but not considering muscle strength and physical performance, which also were compositions of sarcopenia. This study aims to reveal the relationship of artery stiffness and sarcopenia using the Asian Working Group for Sarcopenia criteria. Study was performed on 1002 Chinese community dwelling participants aged ≥65 years from November 2016 to March 2017. Body composition, muscle strength, physical performance, and brachial-ankle pulse wave velocity (baPWV) considering as artery stiffness index were measured. In multiple regression analysis, baPWV was associated with handgrip (β=−0.13, P=0.04) and Relative skeletal muscle mass index (ASM/Ht2) (β=−0.02, P<0.01), but not with 4-meter velocity (P=0.21). Multiple logistic regression analysis showed that 1-SD (3.50m/s) increased in baPWV was still associated with a 11% (CI, 4%–20%; P<0.01) higher odds of being sarcopenia. In the gender subgroup analysis, the relationship of baPWV and sarcopenia remain significant in men (OR, 1.23; 95% CI, 1.07–1.42, P<0.01), but not in women (P=0.07). High brachial-ankle pulse wave velocity is associated with sarcopenia in Chinese community-dwelling elderly, with gender differences.

Dilatancy-generated structural disordering, an inherent feature of metallic glasses (MGs), has been widely accepted as the physical mechanism for the primary origin and structural evolution of shear banding, as well as the resultant shear failure. However, it remains a great challenge to determine, to what degree of dilatation, a shear banding will evolve into a runaway shear failure. In this work, using in situ acoustic emission monitoring, we probe the dilatancy evolution at the different stages of individual shear band in MGs that underwent severely plastic deformation by the controlled cutting technology. A scaling law is revealed that the dilatancy in a shear band is linearly related to its evolution degree. A transition from ductile-to-brittle shear bands is observed, where the formers dominate stable serrated flow, and the latter lead to a runaway instability (catastrophe failure) of serrated flow. To uncover the underlying mechanics, we develop a theoretical model of shear-band evolution dynamics taking into account an atomic-scale deformation process. Our theoretical results agree with the experimental observations, and demonstrate that the atomic-scale volume expansion arises from an intrinsic shear-band evolution dynamics. Importantly, the onset of the ductile–brittle transition of shear banding is controlled by a critical dilatation.

The amyloid-β protein (Aβ) protein plays a pivotal role in the pathogenesis of Alzheimer’s disease (AD). It is believed that Aβ deposited in the brain originates from the brain tissue itself. However, Aβ is generated in both brain and peripheral tissues. Whether circulating Aβ contributes to brain AD-type pathologies remains largely unknown. In this study, using a model of parabiosis between APPswe/PS1dE9 transgenic AD mice and their wild-type littermates, we observed that the human Aβ originated from transgenic AD model mice entered the circulation and accumulated in the brains of wild-type mice, and formed cerebral amyloid angiopathy and Aβ plaques after a 12-month period of parabiosis. AD-type pathologies related to the Aβ accumulation including tau hyperphosphorylation, neurodegeneration, neuroinflammation and microhemorrhage were found in the brains of the parabiotic wild-type mice. More importantly, hippocampal CA1 long-term potentiation was markedly impaired in parabiotic wild-type mice. To the best of our knowledge, our study is the first to reveal that blood-derived Aβ can enter the brain, form the Aβ-related pathologies and induce functional deficits of neurons. Our study provides novel insight into AD pathogenesis and provides evidence that supports the development of therapies for AD by targeting Aβ metabolism in both the brain and the periphery.

We describe the baseline model configuration and simulation characteristics of the Geophysical Fluid Dynamics Laboratory (GFDL)'s Land Model version 4.1 (LM4.1), which builds on component and coupled model developments over 2013–2019 for the coupled carbon‐chemistry‐climate Earth System Model Version 4.1 (ESM4.1) simulation as part of the sixth phase of the Coupled Model Intercomparison Project. Analysis of ESM4.1/LM4.1 is focused on biophysical and biogeochemical processes and interactions with climate. Key features include advanced vegetation dynamics and multi‐layer canopy energy and moisture exchanges, daily fire, land use representation, and dynamic atmospheric dust coupling. We compare LM4.1 performance in the GFDL Earth System Model (ESM) configuration ESM4.1 to the previous generation component LM3.0 in the ESM2G configuration. ESM4.1/LM4.1 provides significant improvement in the treatment of ecological processes from GFDL's previous generation models. However, ESM4.1/LM4.1 likely overestimates the influence of land use and land cover change on vegetation characteristics, particularly on pasturelands, as it overestimates the competitiveness of grasses versus trees in the tropics, and as a result, underestimates present‐day biomass and carbon uptake in comparison to observations. Plain Language Summary The Geophysical Fluid Dynamics Laboratory (GFDL) has developed a new Land Model (LM4.1) as part of its 4th generation coupled model development. This model includes advances from the previous generation and introduces a new vegetation demography model, multi‐layer canopy, plant hydraulics, fire, and land use representation as well as dynamic atmospheric dust coupling. Coupled within an Earth System Model (ESM4.1), LM4.1 features an improved representation of many ecological processes from the previous generation of GFDL ESMs. Key Points A new land model LM4.1 is developed at the Geophysical Fluid Dynamics Laboratory (GFDL) for the next‐generation Earth System Model (ESM) ESM4.1 LM4.1 integrates age‐height structured vegetation dynamics, multi‐layer canopy‐soil‐snow energy exchanges, and prognostic fires and mineral dust ESM4.1/LM4.1 improves patterns of land surface climate and carbon cycle compared to the previous generation GFDL model ESM2G/LM3.0

Human papillomavirus (HPV) is the major causative agent for cervical and many head and neck cancers (HNCs). HPVs randomly acquire single nucleotide polymorphisms (SNPs) that may become established via positive selection. Within an HPV type, viral isolates differing by <2% in the L1 region are termed “variants” and classified based on combinations of SNPs. Studies in cervical cancer demonstrate clear differences between HPV16 intratypic variants in terms of persistence of infection, tumor histology, cancer risk, and death. Much less is known about the frequency of HPV16 variants in HNC, and their effects on clinical outcomes. We combined HPV16 positive (HPV16+) HNC samples from a local Southwestern Ontario, Canada cohort with those from the Cancer Genome Atlas to create a larger North American cohort of 149 cases with clinical data and determined the distribution of intratypic variants and their impact on clinical outcomes. Most isolates were lineage A, sublineage A1, or A2, with roughly half exhibiting the T350G polymorphism in E6. Univariable analysis identified significant differences between 350T and 350G intratypic variants in clinical T, N, and O staging, as well as disease-free survival. Multivariable analysis failed to identify any clinical factor as a statistically significant covariate for disease-free survival differences between 350T and 350G. Significant differences in several measures of B-cell mediated immune response were also observed between 350T and 350G intratypic variants. We suggest that HPV genetic variation may be associated with HNC clinical characteristics and may have prognostic value.

Albeit oxidative stress has been implied in the pathogenesis of tubal pregnancy (TP), there are scant data to suggest that ferroptosis occurs in TP. Shikonin plays a pivotal role in redox status, but whether it can regulate ferroptosis to treat TP remains unknown. We collected and analyzed ferroptosis-related indices from the villous tissue (VT) of women suffering from TP and from women with a normal pregnancy. In vitro, we used shikonin and/or RAS-selective lethal 3 (RSL3) to intervene HTR-8/SVneo cells and further detected ferroptosis indices and cell functions. Finally, the expression of the nuclear factor erythroid 2-related factor 2 (Nrf2) is pharmacologically activated to explore the effect of Nrf2 on shikonin regulating ferroptosis. Increased malondialdehyde content, reduced levels of glutathione and glutathione peroxidase (GPx), and upregulated protein expression which promoted ferroptosis were observed in the VT of TP patients, suggesting that ferroptosis occurred during TP. In vitro, shikonin enhanced ferroptosis sensitivity in HTR-8/SVneo cells induced by RSL3 via amplifying lipid peroxidation, which mainly included increasing cellular reactive oxygen species (ROS), lipid ROS and Fe level. RSL3 and/or shikonin inhibited Nrf2 and downregulated protein expression of SLC7A11 and GPx4 caused by RSL3 + shikonin co-treatment, which could be reversed under activation of Nrf2. Hence, shikonin facilitated lipid peroxidation by inhibiting Nrf2 signaling. Additionally, shikonin and/or RSL3 potently inhibited the invasion and migration of HTR-8/SVneo cells. This study firstly showed that ferroptosis may be involved in TP pathogenesis and shikonin potentially targeted ferroptosis to treat TP.

The control of complex oxide heterostructures at atomic level generates a rich spectrum of exotic properties and unexpected states at the interface between two separately prepared materials. The frustration of magnetization and conductivity of manganite perovskite at surface/interface which is inimical to their device applications, could also flourish in tailored functionalities in return. Here we prove that the exchange bias (EB) effect can unexpectedly emerge in a (La,Sr)MnO 3 (LSMO) “single” film when large compressive stress imposed through a lattice mismatched substrate. The intrinsic EB behavior is directly demonstrated to be originating from the exchange coupling between ferromagnetic LSMO and an unprecedented LaSrMnO 4 -based spin glass, formed under a large interfacial strain and subsequent self-assembly. The present results not only provide a strategy for producing a new class of delicately functional interface by strain engineering, but also shed promising light on fabricating the EB part of spintronic devices in a single step.