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Breast cancer was the leading cause of newly diagnosed cases of tumors in 2020, ranking as the second highest cause of female death. Chemotherapy remains the conventional treatment of choice for breast tumors in most clinical cases. However, it is often accompanied by a poor prognosis and severe side effects, resulting from an insufficient accumulation of the drug at tumor sites and an unsystematic distribution of the drug across the body. Inspired by the fact that breast tumor cells overexpress integrin α2β1 on the surface, we designed and constructed an integrin α2β1 targeting DGEA-modified liposomal doxorubicin (DGEA-Lipo-DOX) platform for application in breast cancer therapy. The DGEA-Lipo-DOX was stable with a uniform particle size of 121.1 ± 3.8 nm and satisfactory drug encapsulation. Demonstrated in vitro and in vivo, the constructed platform exhibited improved antitumor ability. The DGEA-Lipo-DOX showed 4-fold enhanced blood circulation and 6-fold increased accumulation of DOX at the tumor sites compared to those of free DOX, resulting in a significantly enhanced antitumor efficacy in tumor-bearing mice. A preliminary safety evaluation suggested that the systemic toxicity of DOX was relieved by DGEA-Lipo delivery. Collectively, binding integrin α2β1 by DGEA may represent an alternative therapeutic strategy for potentially safer breast cancer treatment.

Background. Sugar-sweetened beverage (SSB) consumption is highly associated with obesity, but the metabolic mechanism underlying this correlation is not understood. Objective. Our objective was to examine metabolomic links between SSB intake and obesity to understand metabolic mechanisms. Design. We examined the association of plasma metabolomic profiles with SSB intake and obesity risk in 781 participants, aged 45–75 y, in the Boston Puerto Rican Health Study (BPRHS) using generalized linear models, controlling for potential confounding factors. Based on identified metabolites, we conducted pathway enrichment analysis to identify potential metabolic pathways that link SSB intake and obesity risk. Variants in genes encoding enzymes known to function in identified metabolic pathways were examined for their interactions with SSB intake on obesity. Results. SSB intake was correlated with BMI (β = 0.607, P=0.045). Among 526 measured metabolites, 86 showed a significant correlation with SSB intake and 148 with BMI (P≤0.05); 28 were correlated with both SSB intake and BMI (P≤0.05). Pathway enrichment analysis identified the phosphatidylcholine and lysophospholipid pathways as linking SSB intake to obesity, after correction for multiple testing. Furthermore, 8 of 10 genes functioning in these two pathways showed strong interaction with SSB intake on BMI. Our results further identified participants who may exhibit an increased risk of obesity when consuming SSB. Conclusions. We identified two key metabolic pathways that link SSB intake to obesity, revealing the potential of phosphatidylcholine and lysophospholipid to modulate how SSB intake can increase obesity risk. The interaction between genetic variants related to these pathways and SSB intake on obesity further supports the mechanism.

Optical parametric chirped-pulse amplification (OPCPA) is prone to undesired spatiotemporal couplings. This Letter studies a family of OPCPA couplings resulting from the nonlinear phase shift induced by frequency-dependent phase mismatch. These OPCPA couplings manifest as pulse-front deformation, transversely varying pulse duration, and spectrally varying wavefront curvature, which are directly linked with the phase–mismatch dispersion terms. The numerical study in this Letter also reveals that the focused signal intensity severely degrades with increasing signal bandwidth and pump depletion.

Currently, prostate cancer is the most frequently diagnosed cancer in males and chemotherapy is often essential for treating advanced prostate cancer. However, common chemotherapies for prostate cancer suffer from serious adverse effects due to poor drug targeting ability and tissue penetration, even with the help of conventional drug delivery systems. Here, encouraged by recent studies showing possible drug retention and tissue penetration advantages of unconventional non-spherical nanoparticles over conventional spherical nanoparticles, we design and construct a novel non-spherical nanodisk drug delivery system for treating prostate cancer. In order to enhance tumor-targeting capability, these nanodisks are further modified with targeting peptide CR(NMe)EKA, which recognizes extracellular matrix fibronectin and its complexes specifically expressed on the walls of tumor vessels and in tumor stroma. Compared with conventional nanospheres, the nanodisks achieve much higher drug accumulation at prostate tumor sites. When loaded with paclitaxel, the CR(NMe)EKA-modified nanodisks display superior antitumor efficacy to free paclitaxel, unmodified nanodisks and nanospheres. In summary, our study provides an attractive therapeutic strategy for targeted therapy against prostate cancer with simple preparation, high efficiency and low toxicity, and supplements a theoretical support for treatments realized by different shaped nanoplatforms. Our study also offers valuable data for understanding biological effects of non-spherical nanodisks and highlights the great potential of unconventional nanoparticles in biomedical applications.

OBJECTIVES: Coffee is a commonly consumed beverage in the United States (US). It remains controversial whether coffee consumption is associated with health benefits or harms, especially when cream and/or sugars are added. METHODS: We assessed coffee consumption in association with mortality outcomes among 36,758 US adults ages 20+ years who participated in the National Health and Nutrition Examination Survey (NHANES) 1999–2014. Consumption of total, caffeinated, and decaffeinated coffee, with and without additives, was assessed using dietary data collected from 24-hour diet recalls (24HR) and compared to coffee consumption assessed using a food-frequency questionnaire (FFQ). Mortalities from all causes, heart disease, and cancer were obtained from linkage to the National Death Index through December 31, 2015. We used Cox proportional hazard models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) after multivariable adjustments. RESULTS: The mean (SE) of the total, caffeinated, and decaffeinated coffee consumption among US adults was 1.36 (0.02), 1.19 (0.02), and 0.17 (0.004) cups/day, respectively. The Spearman correlation coefficient on coffee consumption for a subset of participants with both 24HR and FFQ is 0.78 (P-value

Optical parametric chirped-pulse amplification (OPCPA) provides an efficient route to push ultrafast pulses toward ultrahigh peak powers. However, in high average power regime, the unavoidable thermal effects in nonlinear crystals will intrinsically destroy the phase-matching (PM) condition, which fundamentally limit average power scaling. Here, we present a theoretical design of high average power OPCPA based on simultaneous temperature and wavelength insensitive PM. By regulating the temperature set for PM as well as the wavelength of interacting waves in lithium triborate crystal, the noncollinear angles for temperature insensitive PM and wavelength insensitive PM will coincide and thus ensures simultaneous temperature and wavelength insensitive PM condition. We investigate the performances of the proposed PM scheme in comparison with traditional wavelength insensitive noncollinear PM. Because of the larger temperature bandwidth, higher average power can be anticipated in OPCPA with the proposed PM scheme. Besides, the large spectral bandwidth also allows the amplification of sub-10 fs pulses in the visible spectral range. The proposed PM scheme will provide a promising approach in generating ultrashort pulses with high peak and average powers.

Enhanced geothermal system (EGS) is considered as a solution for current energy crisis and environmental pollution; however, thermal reservoir of EGS is difficult to be accurately quantified. In reservoir evaluating processes, it is very hard to precise the unknown reservoir parameters. This paper, through reviewing the disadvantages of EGS reservoir evaluation methods and parameters estimation methods in previous studies, found that the reservoir evaluation based on probability model is inaccurate. It is also found that there is less previous studies on resources evaluation by solving inverse problem of heat conduction, while the used methods for solving inverse heat conduction problem (including Tikhonov regularization, Gradient Optimization and Decentralized Fuzzy Inference) have their drawbacks. Then, we proposed a novel fuzzy inversion model for reservoir evaluation. This three-dimensional fuzzy inverting model, including three main strategies of heat transfer direct problem modeling, inverse problem modeling and experimental validation, is built in terms of thermal physical parameters of reservoir. The fuzzy inversion model is able to compute the entire geothermal field temperature, establish the quantitative relationship between heat storage quantity and reservoir thermal property, and evaluate EGS heat reservoir. The proposed framework in this study can be used as a guidance for geothermal researchers and companies to build an evaluation tool of energy resources of EGS.

Renewable energy is considered as a solution for mitigating energy crisis and environmental pollution. However, there are two main issues in techno-economic assessment of renewable energy resource: difficult to quantify assessment indicators and lack of a general indicator for multi-criteria evaluation. This study aims to develop a calculation methodology to quantify the techno-economic indicators including power generation, economic costs, incomes, and carbon emissions, through simulating the long-term implementation of solar, wind and biomass energy based renewable power systems. Moreover, by using normalization, weighting methods and Radar plot, all the indicators mentioned above are combined into a general evaluation indicator, which is able to provide a numerical result of multi-criteria quality evaluation of renewable energy resources. Hunan Province located in subtropical China where abundant of solar, wind and biomass energy resources, is studied as a case to present the evaluation methodology and its application. Through collecting the resource data of solar, wind and biomass energy and their facility costs data as the inputs, the long-term implementation of renewable power generation systems located in fourteen cities of Hunan Province are simulated; and then the numerical values of the general indicator are compared among different types of renewable energy resource. The general indicator evaluation results show that southern region including Yongzhou city have higher feasibility for wind power, while the eastern and northern areas including Loudi city have better feasibility of solar energy; for biomass energy resource assessment, the Huaihua system has the best feasibility while the Xiangtan system has the lowest among all the cities in Hunan province. The developed evaluation model and general indicator are able to provide a reference for investment decision making and subsidy policy optimizing.

Currently, most anti-cancer therapies are still haunted by serious and deleterious adverse effects. Here, we report a highly biocompatible tumor cell-targeting delivery systems utilizing exosome-like vesicles (ELVs) that delivers a low-toxicity anti-cancer agent imperialine against non-small cell lung cancer (NSCLC). First, we introduced a novel micelle-aided method to efficiently load imperialine into intact ELVs. Then, integrin α3β1-binding octapeptide cNGQGEQc was modified onto ELV platform for tumor targeting as integrin α3β1 is overexpressed on NSCLC cells. This system not only significantly improved imperialine tumor accumulation and retention, but also had extremely low systemic toxicity both in vitro and in vivo. Our discoveries offer new ways to utilize ELV more efficiently for both drug loading and targeting. The solid pharmacokinetics improvement and extraordinary safety of this system also highlight possibilities of alternative long course cancer therapies using similar strategies.

Resonant cascaded nonlinearity (RCN) induced by optical parametric amplification (OPA) in a chirped quasi-phase-matching chip can be applied to control the group velocity of ultrafast lasers. However, the group delay produced in a single-stage OPA is limited to the pulse duration, and its sign cannot be altered. In this study, we propose a tandem RCN configuration with multiple OPA stages that can produce large-magnitude and sign-controllable group delays. The group delay produced in the multi-stage configuration is shown to be a linear superposition of each single-stage group delay. By virtue of the byproduct idler in the OPA process, the signal-group delay can be altered from positive to negative (and vice versa) with the same chip structure and pump condition. In the numerical simulation with two OPA stages, both a positive and negative group delay of six-fold pulse duration were achieved for 100-fs pulses at 1550 nm. A much larger group delay can be achieved by increasing the number of OPA stages.

Increased drug resistance and acute side effects on normal organs are the major disadvantages of traditional cancer chemotherapy and radiotherapy. This has increased the focus on targeted therapeutic strategies such as monoclonal antibody-based cancer therapies. The major advantage of antibody-based therapies is the specific inhibition of cancer-related targets, with reduced off-target side effects. Anterior gradient-2 (AGR2) is a prometastatic and proangiogenic tumor marker that is overexpressed in multiple cancers. Therefore, anti-AGR2 antibodies may be potential therapeutic agents for treating different cancers. In the present study, we examined a novel anti-AGR2 monoclonal antibody mAb18A4 and found that this antibody inhibited lung cancer progression and metastasis without exerting any adverse side effects on the major organs and blood in mice. Moreover, we found that mAb18A4 activated p53 pathway and attenuated ERK1/2-MAPK pathway. Furthermore, mAb18A4-treated cancer cell lines showed attenuated proliferation and colony formation, enhanced apoptosis, increased p53 expression, and reduced phosphorylated ERK1/2 expression. Treatment with mAb18A4 significantly reduced tumor size and suppressed tumor metastasis in and increased the survival of different xenograft tumor models. In addition, mAb18A4 potently suppressed AGR2-induced angiogenesis. Results of pharmacokinetic and toxicological analyses confirmed the safety of mAb18A4 as an antitumor treatment.

Previous work has elegantly demonstrated that, unlike adult mammalian heart, the neonatal heart is able to regenerate after injury from postnatal day (P) 1 to 7. Recently, macrophages are found to be required in the repair process as depletion of which abolishes endogenous regenerative capability of the neonatal heart. Nevertheless, whether innate immunity alone is sufficient for neonatal heart regeneration is obscure. Here, we investigate a hitherto novel role of FOXP3+ regulatory T-cells (Treg) in neonatal heart regeneration. Unlike their wild type counterparts, NOD/SCID mice that are deficient for T-cells but innate immune cells including macrophages fail to regenerate their injured heart as early as P3. In wild type mice, both conventional CD4+ T-cells and Treg are recruited to cardiac muscle within the first week after injury. Treatment with the lytic anti-CD4 antibody that specifically depletes conventional CD4+ T-cells leads to reduced cardiac fibrosis; while treatment with the lytic anti-CD25 antibody that specifically depletes CD4+CD25hiFOXP3+ Treg contributes to increased fibrosis of the neonatal heart after injury. Moreover, adoptive transfer of Treg to NOD/SCID mice results in mitigated fibrosis and increased proliferation and function of cardiac muscle of the neonatal heart after injury. Mechanistically, single cell transcriptomic profiling reveals that Treg are a source of chemokines and cytokines that attract monocytes and macrophages previously known to drive neonatal heart regeneration. Furthermore, Treg directly promote proliferation of both mouse and human cardiomyocytes in a paracrine manner. Our findings uncover an unappreciated mechanism in neonatal heart regeneration; and offer new avenues for developing novel therapeutics targeting Treg-mediated heart regeneration.

Frequency-domain optical parametric amplification (FOPA) is a new scheme that enables extremely broadband amplification of ultraintense pulses. The spatiotemporal coupling property of signal pulses can make the coherent noise of FOPA sharply different from that of conventional OPCPA. This paper presents a first theoretical study on the coherent noise produced in a FOPA system. We reveal that the coherent noise acquires the spatiotemporal coupling, and thus distinguishes the compressed signal pulse not only in time but also in space, which allows the suppression of coherent noise via optical manipulations in the spatial domain. The quantitative impacts of spatiotemporal coherent noise originated from the imperfections in either pump laser or crystal surfaces, are numerically studied. The result provides a new perspective on improving the coherent contrast of ultraintense lasers.

The pulse contrast of state-of-the-art petawatt lasers is limited by coherent noise. This paper reports on a new family of noise, termed nonlinear beat noise, which is generated by the nonlinear mixing of two kinds of coherent noise in optical parametric chirped-pulse amplification (OPCPA). We theoretically study the various nonlinear beat noises and reveal their intensity evolutions in an OPCPA amplifier. The results suggest that nonlinear beat noise will be destructive to the future hundred-petawatt lasers.

Quasi-parametric chirped pulse amplification (QPCPA) is a new scheme that enables the amplification of chirped signal pulses without back conversion by depleting the idler pulses. In this paper, we present a numerical study on the bandwidth, efficiency, and robustness of QPCPA. Self-locked phase among the interacting waves is found to be the underlying mechanism for the suppression of back conversion, which allows signal efficiency approaching to the quantum limit even under the phase-mismatch condition, and thus greatly increases the phase-mismatch tolerance of QPCPA. We demonstrate that QPCPA can break through the trade-off between the efficiency and bandwidth encountered in conventional optical parametric amplification, hence supporting highly efficient amplification of few-cycle pulses.

Optical parametric phase (OPP), inherently induced in optical parametric chirped-pulse amplification (OPCPA), will significantly degrade pulse compression in the few-cycle pulse regime. While OPP is a well-known nonlinear phenomenon, its nonlinearity origin has remained unclear in physics. Here, we present a systematic theoretical investigation on OPP and demonstrate that OPP originates from the cascaded quadratic nonlinearity in a broadband OPCPA with intrinsic phase-mismatch. Because the intrinsic phase-mismatch is frequency dependent, OPP manifests itself as a nonlinear spectral phase. We show that OPP increases with the parametric gain, approaches to half the intrinsic phase-mismatch in the high-gain limit, and thus directly links with the crystal dispersion. We also find that the effect of OPP in the spatial domain is typically negligible, which makes the OPP compensation necessary only in the spectral domain. The results presented in this paper are of importance to guide the design of few-cycle intense OPCPA systems.

Optical parametric chirped-pulse amplification (OPCPA) has been demonstrated to be a promising approach for pushing femtosecond pulses towards ultra-high peak powers. However, the future success of OPCPA strongly relies on the ability to manipulate its phase-matching (PM) configuration. When a high average power pump laser is involved, the thermal effects in nonlinear crystals induce phase-mismatch distortions that pose an inherent limitation on the conversion efficiency. Here, we demonstrate that the noncollinear configuration previously adopted for wavelength-insensitive PM can be employed for temperature-insensitive PM when the noncollinear angle is properly reset. Simultaneous temperature- and wavelength-insensitive PM is realized for the first time by imposing such a temperature-insensitive noncollinear configuration with an angularly dispersed seed signal. Based on the lithium triborate crystal, the proposed noncollinear achromatic PM has a thermal acceptance 6 times larger than that of the conventional wavelength-insensitive noncollinear PM and has a sufficient spectral acceptance to support pulse durations of ~20 fs at 800 nm. These achievements open new possibilities for generating ultra-high peak power lasers with high average power.

A two-stage 2.2 μm OPCPA system is built with amplified chirped-pulse energy of 5 J. After compression, 1.8 J, 82 fs mid-IR pulses will be potentially obtained, providing an important driving source for strong-field physics. Article not available.

Slow and fast light are ubiquitous in optical amplifiers. In this Letter, we show for the first time, to the best of our knowledge, that optical parametric amplification (OPA) in chirped quasi-phase-matching structures can act as a platform for group-velocity control in the femtosecond regime. The resonant cascaded nonlinear phase underlies the group-velocity control, which manifests an unusual effect that both slow and fast light can be achieved under the normal condition of signal amplification. As numerically demonstrated in the OPA based on the lithium niobate crystal, the signal and idler pulse can be significantly delayed in time comparable to the signal duration and can also keep high fidelity for durations down to 100 fs until the crystal dispersion becomes effective. The broad bandwidth, large group delay, and direct compatibility with integrated optics will make the proposed platform attractive to both fundamental research and applied science.

Second-harmonic generation (SHG) provides a promising route for generating vortex beams of both short wavelength and large topological charge. Here we theoretically investigate the efficiency optimization and beam characteristics of focused vortex-beam SHG. Owing to the increasing beam divergence, vortex beams have distinct features in SHG optimization compared with a Gaussian beam. We show that, under the noncritical phase-matching condition, the Boyd and Kleinman prediction of the optimal focusing parameter for Gaussian-beam SHG remains valid for vortex-beam SHG. However, under the critical phase-matching condition, which is sensitive to the beam divergence, the Boyd and Kleinman prediction is no longer valid. In contrast, the optimal focusing parameter for maximizing the SHG efficiency strongly depends on the vortex order. We also investigate the effects of focusing and phase-matching conditions on the second-harmonic beam characteristics.

In high-average-power second-harmonic generation (SHG) devices, the unavoidable thermal distortion induces a nonuniform phase mismatch that poses an inherent limitation on the conversion efficiency. Here we introduce a temperature-insensitive noncollinear (TIN) phase-matching scheme, which can significantly improve the performance of high-power SHG devices and is versatile to a broad range of laser wavelengths. In the proof-of-principle experiment with a lithium triborate crystal and a 1053 nm nanosecond laser, we demonstrate a large temperature bandwidth of ∼50 K×cm1/2 and a high SHG efficiency of ∼56%. This temperature bandwidth is 13 times that of the conventional collinear phase matching. We also numerically investigate the performance of the proposed TIN phase-matching scheme in high-power lasers. The demonstrated large temperature bandwidth allows efficient SHG in the high-power regime of 5–10 kW. The simplicity, high efficiency, and wavelength versatility will make the TIN phase matching attractive for wide applications in high-power lasers.

SummaryThe brain vasculature supplies neurons with glucose and oxygen, but little is known about how vascular plasticity contributes to brain function. Using longitudinal in vivo imaging, we reported that a substantial proportion of blood vessels in the adult brain sporadically occluded and regressed. Their regression proceeded through sequential stages of blood-flow occlusion, endothelial cell collapse, relocation or loss of pericytes, and retraction of glial endfeet. Regressing vessels were found to be widespread in mouse, monkey and human brains. Both brief occlusions of the middle cerebral artery and lipopolysaccharide-mediated inflammation induced an increase of vessel regression. Blockage of leukocyte adhesion to endothelial cells alleviated LPS-induced vessel regression. We further revealed that blood vessel regression caused a reduction of neuronal activity due to a dysfunction in mitochondrial metabolism and glutamate production. Our results elucidate the mechanism of vessel regression and its role in neuronal function in the adult brain.