Targeted-delivery of nanomedicine-enabled methylprednisolone to injured spinal cord promotes neuroprotection and functional recovery after acute spinal cord injury in rats.

To date, no therapy has been proven to be efficacious in fully restoring neurological functions after spinal cord injury (SCI). Systemic high-dose methylprednisolone (MP) improves neurological recovery after acute SCI in both animal and human. MP therapy remains controversial due to its modest effect on functional recovery and significant adverse effects. To overcome the limitation of MP therapy, we have developed a N-(2-hydroxypropyl) methacrylamide copolymer-based MP prodrug nanomedicine (Nano-MP) that can selectively deliver MP to the SCI lesion when administered systemically in a rat model of acute SCI. Our in vivo data reveal that Nano-MP is significantly more effective than free MP in attenuating secondary injuries and neuronal apoptosis. Nano-MP is superior to free MP in improving functional recovery after acute SCI in rats. These data support Nano-MP as a promising neurotherapeutic candidate, which may provide potent neuroprotection and accelerate functional recovery with improved safety for patients with acute SCI.

Intense emission at 605†nm from Pr3+-doped fluorotellurite glass fibers.

Pr3+-doped fluorotellurite glass fibers (PDFTFs) were fabricated by using a rod-in-tube method. By using a 976/1400 nm dual-wavelength upconversion pump technique, an intense emission at 605 nm was obtained from a 6 cm long PDFTF, which was attributed to the transition 1D2 → 3H4 of Pr3+ ions. With an increase in power of the 1400 nm laser from ∼34 to ∼136 mW, the spectral bandwidth of the 605 nm emission decreased and the intensity of the 605 nm emission increased monotonically, indicating the generation of 605 nm amplified spontaneous emission (ASE). To the best of our knowledge, this is the first report of 605 nm ASE in PDFTFs. Our results showed that PDFTFs had the potential for constructing red fiber lasers and amplifiers.

Widely tunable S-band ring-cavity Tm3+-doped fluorotellurite fiber laser.

Tm3+-doped fluorotellurite fibers (TDFTFs) are fabricated by using a rod-in-tube method. A 2.1 m long TDFTF is used as the gain medium, in which both ends of the TDFTF are connected to a short piece of a silica fiber by direct fusion splicing. By inserting the above TDFTF and a tunable optical bandpass filter into a ring cavity and employing a 1400/1570 nm dual-wavelength pumping technique, tunable lasing from 1460 to 1526 nm is obtained, which almost covers the whole S-band. To the best of our knowledge, this is the first report of tunable Tm3+-doped fiber laser with a tunable range almost covering the whole S-band. Furthermore, by removing the tunable optical bandpass filter from the ring cavity, free-running multi-wavelength lasers at 1500 and 1901 nm are achieved. Our results show that TDFTFs are promising gain media for constructing S-band fiber lasers.

Species Difference? Bovine, Trout, and Human Plasma Protein Binding of Per- and Polyfluoroalkyl Substances.

Per- and polyfluoroalkyl substances (PFAS) strongly bind to proteins and lipids in blood, which govern their accumulation and distribution in organisms. Understanding the plasma binding mechanism and species differences will facilitate the quantitative in vitro-to-in vivo extrapolation and improve risk assessment of PFAS. We studied the binding mechanism of 16 PFAS to bovine serum albumin (BSA), trout, and human plasma using solid-phase microextraction. Binding of anionic PFAS to BSA and human plasma was found to be highly concentration-dependent, while trout plasma binding was linear for the majority of the tested PFAS. At a molar ratio of PFAS to protein ν < 0.1 molPFAS/molprotein, the specific protein binding of anionic PFAS dominated their human plasma binding. This would be the scenario for physiological conditions (ν < 0.01), whereas in in vitro assays, PFAS are often dosed in excess (ν > 1) and nonspecific binding becomes dominant. BSA was shown to serve as a good surrogate for human plasma. As trout plasma contains more lipids, the nonspecific binding to lipids affected the affinities of PFAS for trout plasma. Mass balance models that are parameterized with the protein-water and lipid-water partitioning constants (chemical characteristics), as well as the protein and lipid contents of the plasma (species characteristics), were successfully used to predict the binding to human and trout plasma.

Baseline Toxicity Model to Identify the Specific and Nonspecific Effects of Per- and Polyfluoroalkyl Substances in Cell-Based Bioassays.

High-throughput screening is a strategy to identify potential adverse outcome pathways (AOP) for thousands of per- and polyfluoroalkyl substances (PFAS) if the specific effects can be distinguished from nonspecific effects. We hypothesize that baseline toxicity may serve as a reference to determine the specificity of the cell responses. Baseline toxicity is the minimum (cyto)toxicity caused by the accumulation of chemicals in cell membranes, which disturbs their structure and function. A mass balance model linking the critical membrane concentration for baseline toxicity to nominal (i.e., dosed) concentrations of PFAS in cell-based bioassays yielded separate baseline toxicity prediction models for anionic and neutral PFAS, which were based on liposome-water distribution ratios as the sole model descriptors. The specificity of cell responses to 30 PFAS on six target effects (activation of peroxisome proliferator-activated receptor (PPAR) gamma, aryl hydrocarbon receptor, oxidative stress response, and neurotoxicity in own experiments, and literature data for activation of several PPARs and the estrogen receptor) were assessed by comparing effective concentrations to predicted baseline toxic concentrations. HFPO-DA, HFPO-DA-AS, and PFMOAA showed high specificity on PPARs, which provides information on key events in AOPs relevant to PFAS. However, PFAS were of low specificity in the other experimentally evaluated assays and others from the literature. Even if PFAS are not highly specific for certain defined targets but disturb many toxicity pathways with low potency, such effects are toxicologically relevant, especially for hydrophobic PFAS and because PFAS are highly persistent and cause chronic effects. This implicates a heightened need for the risk assessment of PFAS mixtures because nonspecific effects behave concentration-additive in mixtures.

Bidirectional mode-locked erbium-doped fiber laser based on an all-fiber gold nanofilm saturable absorber.

We demonstrate a bidirectional mode-locked erbium-doped fiber laser by incorporating gold nanofilm as a saturable absorber (SA). The gold nanofilm SA has the advantages of high stability and high optical damage threshold. Besides, the SA exhibits a large modulation depth of 26% and a low saturation intensity of 1.22 MW/cm2 at 1.56 µm wavelength band, facilitating the mode-locking of bidirectional propagating solitons within a single laser cavity. Bidirectional mode-locked solitons are achieved, with the clockwise pulse centered at 1568.35 nm and the counter-clockwise one at 1568.6 nm, resulting in a slight repetition rate difference of 19 Hz. Moreover, numerical simulations are performed to reveal the counter-propagating dynamics of the two solitons, showing good agreement with the experimental results. The asymmetric cavity configuration gives rise to distinct buildup and evolution dynamics of the two counter-propagating pulses. These findings highlight the advantage of the gold nanofilm SA in constructing bidirectional mode-locked fiber lasers and provide insights for understanding the bidirectional pulse propagation dynamics.

Balanced influence maximization in social networks based on deep reinforcement learning.

Balanced influence maximization aims to balance the influence maximization of multiple different entities in social networks and avoid the emergence of filter bubbles and echo chambers. Recently, an increasing number of studies have drawn attention to the study of balanced influence maximization in social networks and achieves success to some extent. However, most of them still have two major shortcomings. First, the previous works mainly focus on spreading the influence of multiple target entities to more users, ignoring the potential influence of the correlation between the target entities and other entities on information propagation in real social networks. Second, the existing methods require a large amount of diffusion sampling for influence estimation, making it difficult to apply to large social networks. To this end, we propose a Balanced Influence Maximization framework based on Deep Reinforcement Learning named BIM-DRL, which consists of two core components: an entity correlation evaluation module and a balanced seed node selection module. Specifically, in the entity correlation evaluation module, an entity correlation evaluation model based on the users' historical behavior sequences is proposed, which can accurately evaluate the impact of entity correlation on information propagation. In the balanced seed node selection module, a balanced influence maximization model based on deep reinforcement learning is designed to train the parameters in the objective function, and then a set of seed nodes that maximize the balanced influence is found. Extensive experiments on six real-life network datasets demonstrate the superiority of the BIM-DRL over state-of-the-art methods on the metrics of balanced influence spread and balanced propagation accuracy.

Anti-Siglec-15 Antibody Prevents Marked Bone Loss after Acute Spinal Cord Injury-Induced Immobilization in Rats.

Rapid and extensive sublesional bone loss after spinal cord injury (SCI) is a difficult medical problem that has been refractory to available interventions except the antiresorptive agent denosumab (DMAB). While DMAB has shown some efficacy in inhibiting bone loss, its concurrent inhibition of bone formation limits its use. Sialic acid-binding immunoglobulin-like lectin (Siglec)-15 is expressed on the cell surface of mature osteoclasts. Anti-Siglec-15 antibody (Ab) has been shown to inhibit osteoclast maturation and bone resorption while maintaining osteoblast activity, which is distinct from current antiresorptive agents that inhibit the activity of both osteoclasts and osteoblasts. The goal of the present study is to test a Siglec-15 Ab (NP159) as a new treatment option to prevent bone loss in an acute SCI model. To this end, 4-month-old male Wistar rats underwent complete spinal cord transection and were treated with either vehicle or NP159 at 20 mg/kg once every 2 weeks for 8 weeks. SCI results in significant decreases in bone mineral density (BMD, -18.7%), trabecular bone volume (-43.1%), trabecular connectivity (-59.7%), and bone stiffness (-76.3%) at the distal femur. Treatment with NP159 almost completely prevents the aforementioned deterioration of bone after SCI. Blood and histomorphometric analyses revealed that NP159 is able to greatly inhibit bone resorption while maintaining bone formation after acute SCI. In ex vivo cultures of bone marrow cells, NP159 reduces osteoclastogenesis while increasing osteoblastogenesis. In summary, treatment with NP159 almost fully prevents sublesional loss of BMD and metaphysis trabecular bone volume and preserves bone strength in a rat model of acute SCI. Because of its unique ability to reduce osteoclastogenesis and bone resorption while promoting osteoblastogenesis to maintain bone formation, Siglec-15 Ab may hold greater promise as a therapeutic agent, compared with the exclusively antiresorptive or anabolic agents that are currently used, in mitigating the striking bone loss that occurs after SCI or other conditions associated with severe immobilization. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

Watt-level 815†nm lasing from Tm3+-doped fluorotellurite glass fibers.

Tm3+-doped fluorotellurite fibers based on TeO2-BaF2-Y2O3(TBY) glasses were fabricated by using a rod-in-tube method. By using an 81 cm-long Tm3+-doped fluorotellurite fiber as the gain medium and a 1400 / 1570 nm dual-wavelength pump technique, lasing at 815 nm was obtained for a threshold pump power of 629 mW at 1400 nm and a fixed pump power of 960 mW at 1570 nm. As the 1400 nm pump power is increased to 1803 mW, the obtained maximum output power was about 1616 mW. The corresponding optical-to-optical conversion efficiency was about 58.5%. Our results show that Tm3+-doped fluorotellurite fibers are promising gain media for constructing 815 nm fiber lasers.

Over 50 W all-fiber mid-infrared supercontinuum laser.

Broadband supercontinuum laser sources in the mid-infrared region have attracted enormous interest and found significant applications in spectroscopy, imaging, sensing, defense, and security. Despite recent advances in mid-infrared supercontinuum laser sources using infrared fibers, the average power of those laser sources is limited to 10-watt-level, and further power scaling to over 50 W (or hundred-watt-level) remains a significant technological challenge. Here, we report an over 50 W all-fiber mid-infrared supercontinuum laser source with a spectral range from 1220 to 3740 nm, by using low loss (<0.1 dB/m) fluorotellurite fibers we developed as the nonlinear medium and a tilted fusion splicing method for reducing the reflection from the fluorotellurite-silica fiber joint. Furthermore, the scalability of all-fiber mid-infrared supercontinuum laser sources using fluorotellurite fibers is analyzed by considering thermal effects and optical damage, which verifies its potential of power scaling to hundred-watt-level. Our results pave the way for realizing all-fiber hundred-watt-level mid-infrared lasers for real applications.

Introduce Ce3+ Ions to Realize Enhancement of C+L Band Luminescence of KMnF3: Yb, Er Nanoparticles.

Polymer-based waveguide amplifiers are essential components in integrated optical systems, as their gain bandwidths directly determine the operating wavelength of optical circuits. However, development of the wideband gain media has been challenging, making it difficult to fabricate devices with broadband amplification capability. Rare earth ion-doped nanoparticles (NPs) are a key component in the gain media, and their full width at half maximum (FWHM) of the emission peak decides the final gain bandwidth of the gain media. Here, KMnF3: Yb, Er, Ce@KMnF3: Yb NPs with the broad full width at half maximum (FWHM) of the emission peak covering the S+C band was prepared. The NPs were synthesized using a hydrothermal method, and the FWHM of the emission peak of NPs reached 76 nm under the excitation of a 980 nm laser. The introduction of Ce3+ ions and a core-shell structure coating greatly enhanced the emission intensity of NPs at C band. Since KMnF3: Yb, Er, Ce@KMnF3: Yb NPs have exceptional broadband luminescence properties at C band, KMnF3: Yb, Er, Ce@KMnF3: Yb NPs can be the potential gain medium in the future polymer-based waveguide amplifiers.

Gain enhancement technique for S-band polymer-based waveguide amplifiers.

The S-band polymer-based waveguide amplifier has been fabricated, but how to improve the gain performance remains a big challenge. Here, using the technique of establishing the energy transfer between different ions, we successfully improved the efficiency of Tm3+:3F3→3H4 and 3H5→3F4 transitions, resulting in the emission enhancement at 1480 nm and gain improvement in S-band. By doping the NaYF4:Tm,Yb,Ce@NaYF4 nanoparticles into the core layer, the polymer-based waveguide amplifier provided a maximum gain of 12.7 dB at 1480 nm, which was 6 dB higher than previous work. Our results indicated that the gain enhancement technique significantly improved the S-band gain performance and provided guidance for even other communication bands.

Role of bioavailability and protein binding of four anionic perfluoroalkyl substances in cell-based bioassays for quantitative in vitro to in vivo extrapolations.

Perfluoroalkyl substances (PFAS) are persistent and pose a risk to human health. High throughput screening (HTS) cell-based bioassays may inform risk assessment of PFAS provided that quantitative in vitro to in vivo extrapolation (QIVIVE) can be developed. The QIVIVE ratio is the ratio of nominal (Cnom) or freely dissolved concentration (Cfree) in human blood to Cnom or Cfree in the bioassays. Considering that the concentrations of PFAS in human plasma and in vitro bioassays may vary by orders of magnitude, we tested the hypothesis that anionic PFAS bind to proteins concentration-dependently and therefore the binding differs substantially between human plasma and bioassays, which has an impact on QIVIVE. Solid phase microextraction (SPME) with C18-coated fibers served to quantify the Cfree of four anionic PFAS (perfluorobutanoate (PFBA), perfluorooctanoate (PFOA), perfluorohexane sulfonate (PFHxS) and perfluorooctane sulfonate (PFOS)) in the presence of proteins and lipid, medium components, cells and human plasma over five orders of magnitude in concentrations. The C18-SPME method was used to quantify the non-linear binding to proteins, human plasma and medium, and the partition constants to cells. These binding parameters were used to predict Cfree of PFAS in cell bioassays and human plasma by a concentration-dependent mass balance model (MBM). The approach was illustrated with a reporter gene assay indicating activation of the peroxisome proliferator-activated receptor gamma (PPARγ-GeneBLAzer). Blood plasma levels were collected from literature for occupational exposure and the general population. The QIVIVEnom ratios were higher than the QIVIVEfree ratios due to the strong affinity to proteins and large differences in protein contents between human blood and bioassays. For human health risk assessment, the QIVIVEfree ratios of many in vitro assays need to be combined to cover all health relevant endpoints. If Cfree cannot be measured, they can be estimated with the MBM and concentration-dependent distribution ratios.

(S + C)-band polymer waveguide amplifier based on Tm3+ and Er3+ layer-doped core-shell nanoparticles.

Optical waveguide amplifiers are essential devices in integrated optical systems. Their gain bandwidths directly determine the operating wavelength of optical circuits. Due to the difficulty of developing wideband gain media, it has been a challenge to fabricate devices with broadband amplification capability, resulting in few reports on multi-band polymer waveguide amplifiers. Here, a polymer waveguide amplifier is demonstrated, which achieves loss compensation covering the whole (S + C) band by using NaYF4:Tm,Yb@NaYF4@NaYF4:Er nanoparticles (NPs)-doped SU-8 as the gain medium. The NPs with a layer-doped core-multishell structure not only provided two emitters required for (S + C)-band amplification, but also reduced the energy transfer (ET) between them. Under 980-nm excitation, the full width at half maximum (FWHM) of the emission peak of NPs reached 119 nm, and the relative gain in the (S + C) band was about 6-8 dB, successfully expanding the operating wavelength from single-band to multi-band.

Self-reported sleep disturbance is significantly associated with depression, anxiety, self-efficacy, and stigma in Chinese patients with rheumatoid arthritis.

The objective of this article is to assess self-reported sleep disturbance and identify psychological, clinical, and sociodemographic factors that might influence sleep disturbance in patients with rheumatoid arthritis (RA). The study included 141 patients with confirmed RA (84.4% women, mean age 56.87 years). The Pittsburgh Sleep Quality Index, the Chinese version of rheumatoid arthritis self-efficacy scale, the Chinese version of Anxiety Depression Distress Inventory-27, the Chinese version of Stigma Scale for Chronic Illness, Visual Analogue Scale-Pain, disease activity index were used. Sleep disturbance was positively correlated with age, pain, disease activity, depression and anxiety, and stigma, while self-efficacy was correlated negatively with sleep disturbance. Multiple linear regression analysis revealed that depression, anxiety, self-efficacy, and stigma explained 77.4% of sleep quality variance. The data has demonstrated a suggestive relationship between low sleep quality and anxiety, depression, self-efficacy, and stigma. Patients reporting poor sleep, fatigue, and pain might have particular psychological intervention needs focusing on distress or anxiety symptoms, low self-efficacy, and high stigma.

Thulium-doped fluorotellurite glass fibers for broadband S-band amplifiers.

We demonstrated broadband S-band (1460-1530 nm) amplification in Tm3+-doped fluorotellurite glass fibers (TDFTFs) by using a 1400/1570 nm dual-wavelength pump technique. TDFTFs based on TeO2-BaF2-Y2O3 (TBY) glass were fabricated by using a rod-in-tube method. For an input signal power of 0 dBm (or 1 mW), a broadband positive net gain ranging from <1440 nm to 1546 nm was achieved in a 1.55-m-long TDFTF with a Tm3+ doping concentration of ∼4000 ppm, as the pump powers of the 1400 nm and 1570 nm lasers were 1.7 W and 0.14 W, respectively. The corresponding bandwidth for a net gain of >20 dB was ∼66 nm (1458-1524 nm), and the measured saturated output power was ∼24.84 dBm at 1490 nm. In addition, numerical simulation was performed by using the parameters of the TDFTFs and the pump lasers, and the noise figure was calculated to be <5.6 dB in the S band. Our results showed that the TDFTFs were promising gain media for constructing efficient broadband S-band fiber amplifiers.

Peripheral and cognitive benefits of physical exercise in a mouse model of midlife metabolic syndrome.

Despite national and international efforts for the prevention of metabolic syndrome and its underlying diseases/disorders, its prevalence is still rising, especially in the middle-aged population. In this study, we explore the effect of high fat diet on the development of metabolic syndrome in middle-aged mice and to evaluate the potential benefits of voluntary physical exercise on the periphery as well as brain cognitive function, and to explore the potential mechanisms. We found that metabolic syndrome developed at middle age significantly impairs cognitive function and the impairment is associated with gene dysregulation in metabolic pathways that are largely affecting astrocytes in the brain. Eight-week voluntary wheel running at a frequency of three times a week, not only improves peripheral glucose control but also significantly improves learning and memory. The improvement of cognitive function is associated with restoration of gene expression involved in energy metabolism in the brain. Our study suggests that voluntary physical exercise is beneficial for metabolic syndrome-induced peripheral as well as cognitive dysfunction and can be recommended as therapeutic intervention for metabolic syndrome and associated diseases.

Third-order cascaded Raman shift in all-solid fluorotellurite fiber pumped at 1550†nm.

In this Letter, we demonstrate a third-order cascaded Raman shift in an all-solid fluorotellurite fiber pumped by a 1550 nm nanosecond laser. The fluorotellurite glass with a composition of TeO2-BaF2-Y2O3 (TBY) has a usable Raman shift of ∼785 cm-1 and a Raman gain coefficient of ∼1.65 × 10-12 m/W at 1550 nm, which is approximately 25.4 times larger than that of silica glass. By using a 5.38 m fluorotellurite fiber as the Raman gain medium and a 1550 nm nanosecond laser as the pump light, a third-order cascaded Raman shift is obtained via spontaneous cascaded Raman amplification in the fluorotellurite fiber, causing the generation of the first-, second-, and third-order Stokes emissions that peak at 1765, 2049, and 2438 nm, respectively. For an average pump power of ∼491.5 mW, the output power of the generated first-, second-, and third-order Stokes light is approximately 14.1, 67.4, and 31.6 mW, respectively. The corresponding conversion efficiency is approximately 2.87%, 13.70%, and 6.43%, respectively. Our results show that fluorotellurite fibers are promising Raman gain media for constructing cascaded Raman fiber lasers with a wide range of wavelengths.

Exposure to perfluorooctane sulfonate reduced cell viability and insulin release capacity of ß cells.

Per- and polyfluoroalkyl substances (PFAS) are found to have multiple adverse outcomes on human health. Recently, epidemiological and toxicological studies showed that exposure to PFAS had adverse impacts on pancreas and showed association with insulin abnormalities. To explore how PFAS may contribute to diabetes, we studied impacts of perfluorooctane sulfonate (PFOS) on cell viability and insulin release capacity of pancreatic ß cells by using in vivo and in vitro methods. We found that 28-day administration with PFOS (10 mg/(kg body weight•day)) caused reductions of pancreas weight and islet size in male mice. PFOS administration also led to lower serum insulin level both in fasting state and after glucose infusion among male mice. For cell-based in vitro bioassay, we used mouse ß-TC-6 cancer cells and found 48-hr exposure to PFOS decreased the cell viability at 50 µmol/L. By measuring insulin content in supernatant, 48-hr pretreatment of PFOS (100 µmol/L) decreased the insulin release capacity of ß-TC-6 cells after glucose stimulation. Although these concentrations were higher than the environmental concentration of PFOS, it might be reasonable for high concentration of PFOS to exert observable toxic effects in mice considering mice had a faster removal efficiency of PFOS than human. PFOS exposure (50 µmol/L) to ß-TC-6 cells induced intracellular accumulation of reactive oxidative specie (ROS). Excessive ROS induced the reactive toxicity of cells, which eventually invoke apoptosis and necrosis. Results in this study provide evidence for the possible causal link of exposure to PFOS and diabetes risk.

Polymer-based S-band waveguide amplifier using NaYF4:Yb,Tm-PMMA nanocomposite as gain medium.

Optical waveguide amplifiers are essential to improve the performance of integrated communication systems. Previous research has mainly focused on C- and L-bands amplification, but there are few reports on S-band waveguide amplifiers. Here, we introduce a polymer-based waveguide amplifier that uses a NaYF4:Yb3+,Tm3+ nanoparticles-PMMA nanocomposite as gain medium, which can provide loss compensation in the S-band. To obtain the strongest emission luminescence at 1480 nm, we optimized the doping concentration of Yb3+ and Tm3+ to 20% and 1%, respectively. By copolymerizing the nanoparticles and methyl methacrylate monomers, the nanocomposite was synthesized and used as the gain medium to fabricate S-band waveguide amplifiers. A relative gain of 5.6 dB/cm was observed at 1480 nm under the excitation of a 980-nm pump laser. To the best of our knowledge, this is the first time that S-band amplification has been observed in a polymer-based waveguide amplifier. This result is expected to extend the waveband of polymer-based waveguide amplifiers to the S-band.