IL-27 disturbs lipid metabolism and restrains mitochondrial activity to inhibit γδ T17 cell-mediated skin inflammation.

IL-17+ γδ T cells (γδ T17) are kick-starters of inflammation due to their strict immunosurveillance of xenobiotics or cellular damages and rapid response to pro-inflammatory stimulators. IL-27 is a well-recognized pleiotropic immune regulator with potent inhibitory effects on type 17 immune responses. However, its actions on γδ T17 mediated inflammation and the underlying mechanisms are less well understood. Here we find that IL-27 inhibits the production of IL-17 from γδ T cells. Mechanistically, IL-27 promotes lipolysis while inhibits lipogenesis, thus reduces the accumulation of lipids and subsequent membrane phospholipids, which leads to mitochondrial deactivation and ensuing reduction of IL-17. More importantly, Il27ra deficient γδ T cells are more pathogenic in an imiquimod-induced murine psoriasis model, while intracutaneous injection of rmIL-27 ameliorates psoriatic inflammation. In summary, this work uncovered the metabolic basis for the immune regulatory activity of IL-27 in restraining γδ T17 mediated inflammation, which provides novel insights into IL-27/IL-27Ra signaling, γδ T17 biology and the pathogenesis of psoriasis.

Nano-laponite encapsulated coaxial fiber scaffold promotes endochondral osteogenesis.

Osteoinductive supplements without side effects stand out from the growth factors and drugs widely used in bone tissue engineering. Lithium magnesium sodium silicate hydrate (laponite) nanoflake is a promising bioactive component for bone regeneration, attributed to its inherent biosafety and effective osteoinductivity. Up to now, the in vivo osteogenic potential and mechanisms of laponite-encapsulated fibrous membranes remain largely unexplored. This study presents a unique method for homogeneously integrating high concentrations of laponite RDS into a polycaprolactone (PCL) matrix by dispersing laponite RDS sol into the polymer solution. Subsequently, a core-shell fibrous membrane (10RP-PG), embedding laponite-loaded PCL in its core, was crafted using coaxial electrospinning. The PCL core's slow degradation and the shell's gradient degradation enabled the sustained release of bioactive ions (Si and Mg) from laponite. In vivo studies on a critical-sized calvarial bone defect model demonstrated that the 10RP-PG membrane markedly enhanced bone formation and remodeling by accelerating the process of endochondral ossification. Further transcriptome analysis suggested that osteogenesis in the 10RP-PG membrane is driven by Mg and Si from endocytosed laponite, activating pathways related to ossification and endochondral ossification, including Hippo, Wnt and Notch. The fabricated nanocomposite fibrous membranes hold great promise in the fields of critical-sized bone defect repair.

Preliminary investigation of nitric oxide release from upconverted nanoparticles excited at 808 nm near-infrared for brain tumors.

Upconverted UCNPs@mSiO2-NH2 nanoparticles were synthesized via thermal decomposition while employing the energy resonance transfer principle and the excellent near-infrared (NIR) light conversion property of up-conversion. The 808 nm NIR-excited photocontrolled nitric oxide (NO) release platform was successfully developed by electrostatically loading photosensitive NO donor Roussin's black salt (RBS) onto UCNPs@mSiO2-NH2, enabling the temporal, spatial, and dosimetric regulation of NO release for biological applications of NO. The release of NO ranged from 0.015⁓0.099 mM under the conditions of 2.0 W NIR excitation power, 20 min of irradiation time, and UCNPs@mSiO2-NH2&RBS concentration of 0.25⁓1.25 mg/mL. Therefore, this NO release platform has an anti-tumor effect. In vitro experiments showed that under the NIR light, at concentrations of 0.3 mg/mL and 0.8 mg/mL of UCNPs@mSiO2-NH2&RBS, the activity of glioma (U87) and chordoma (U-CH1) cells, as measured by CCK8 assay, was reduced to 50 %. Cell flow cytometry and Western Blot experiments showed that NO released from UCNPs@mSiO2-NH2&RBS under NIR light induced apoptosis in brain tumor cells. In vivo experiments employing glioma and chordoma xenograft mouse models revealed significant inhibition of tumor growth in the NIR and UCNPs@mSiO2-NH2&RBS group, with no observed significant side effects in the mice. Therefore, NO released by UCNPs@mSiO2-NH2&RBS under NIR irradiation can be used as a highly effective and safe strategy for brain tumor therapy.

Accelerated Degradation of DiXyl-α,ε-Lys-ARP via Interaction between Extra-Added Xylose and Monosubstituted Lys-ARPs during Maillard Reaction.

Lysine (Lys) is capable of forming a di-substituted Amadori rearrangement product (ARP) with xylose (Xyl), designated as diXyl-α,ε-Lys-ARP. DiXyl-α,ε-Lys-ARP degradation was characterized by two steps: Initially, Xyl-α- and Xyl-ε-Lys-ARP were formed through elimination or hydrolysis at specific Nα/Nε positions of the corresponding enol and imine intermediates, which were then further degraded to dicarbonyl compounds and regenerated Lys. Xyl-α- or Xyl-ε-Lys-ARP had a reactive free amino group (ε-NH2 or α-NH2), both of which were still highly reactive and able to undergo further reactions with Xyl. Therefore, the diXyl-α,ε-Lys-ARP/Xyl model system was established to explore the impact of extra-added Xyl on diXyl-α,ε-Lys-ARP degradation behavior. Extra-added Xyl remarkably affected the degradation pathway of diXyl-α,ε-Lys-ARP by capturing the Xyl-α- and Xyl-ε-Lys-ARP to regenerate diXyl-α,ε-Lys-ARP. This interaction between Xyl and mono-substituted Lys-ARPs promoted the shift of chemical equilibrium toward the degradation of diXyl-α,ε-Lys-ARP, thereby accelerating its degradation rate. This degradation was markedly facilitated by the elevated temperature and pH values. Interestingly, the yield of Xyl-α- and Xyl-ε-Lys-ARP was particularly dependent on the pH during diXyl-α,ε-Lys-ARP degradation. Xyl-ε-Lys-ARP was the dominant product at pH 5.5-7.5 while Xyl-α-Lys-ARP possessed a relatively higher content under weak alkaline conditions, which was related to the reactivities of the Nα/Nε positions under various reaction conditions.

Preparation and Performance Evaluation of a New Type of Polyethylene-vinyl Acetate/Polystyrene Microsphere Composite Pour Point Depressant for Waxy Crude Oil.

Polymer/inorganic nanocomposite pour point depressant (PPD) is a research hotspot in the field of waxy crude oil pipelining. However, the inorganic nanoparticles need to be organically modified to improve their organic compatibility, and the inorganic nanoparticles are harmful to crude oil refining. In this work, organic PSMS with an average size of 1.4 µm was first synthesized by dispersion polymerization. Then, a new type of EVA/PSMS composite PPD was prepared by melt blending. The effects of the PSMS, EVA PPD, and composite PPD on the pour point, rheological properties, and wax precipitating properties of a specific waxy crude oil were investigated. It was found that adding 50-200 ppm of PSMS alone slightly improves the crude oil rheology through a spatial hindrance effect, while adding 20 ppm of EVA PPD greatly improves the crude oil rheology by modifying the wax crystal morphology. Compared with EVA PPD, adding 20 ppm composite PPD improves the crude oil rheology further, and the rheological improving ability first enhances and then weakens with increasing the PSMS content in the composite PPD (0-10 wt %). At the PSMS content in the composite PPD 5 wt %, the EVA/PSMS 5% composite PPD makes the wax crystal aggregates more compact, thus showing the strongest rheological improving ability. The EVA molecules could adsorb on the PSMS and form the composite particles, which further regulate the wax crystal morphology and then improve the crude oil rheology further.

Small Scale, Big Impact: Nanotechnology-Enhanced Drug Delivery for Brain Diseases.

Central nervous system (CNS) diseases, ranging from brain cancers to neurodegenerative disorders like dementia and acute conditions such as strokes, have been heavily burdening healthcare and have a direct impact on patient quality of life. A significant hurdle in developing effective treatments is the presence of the blood-brain barrier (BBB), a highly selective barrier that prevents most drugs from reaching the brain. The tight junctions and adherens junctions between the endothelial cells and various receptors expressed on the cells make the BBB form a nonfenestrated and highly selective structure that is crucial for brain homeostasis but complicates drug delivery. Nanotechnology offers a novel pathway to circumvent this barrier, with nanoparticles engineered to ferry drugs across the BBB, protect drugs from degradation, and deliver medications to the designated area. After years of development, nanoparticle optimization, including sizes, shapes, surface modifications, and targeting ligands, can enable nanomaterials tailored to specific brain drug delivery settings. Moreover, smart nano drug delivery systems can respond to endogenous and exogenous stimuli that control subsequent drug release. Here, we address the importance of the BBB in brain disease treatment, summarize different delivery routes for brain drug delivery, discuss the cutting-edge nanotechnology-based strategies for brain drug delivery, and further offer valuable insights into how these innovations in nanoparticle technology could revolutionize the treatment of CNS diseases, presenting a promising avenue for noninvasive, targeted therapeutic interventions.

Antibiotic feeding changes the bacterial community of Chilo suppressalis and thereby affects its pesticide tolerance.

BACKGROUND: Owing to the widespread use of chemical pesticides to control agricultural pests, pesticide tolerance has become a serious problem. In recent years, it has been found that symbiotic bacteria are related to pesticides tolerance. To investigate the potential role of microorganisms in the pesticide tolerance of Chilo suppressalis, this study was conducted. RESULTS: The insect was fed with tetracycline and cefixime as the treatment group (TET and CFM, respectively), and did not add antibiotics in the control groups (CK). The 16S rDNA sequencing results showed that antibiotics reduced the diversity of C. suppressalis symbiotic microorganisms but did not affect their growth and development. In bioassays of the three C. suppressalis groups (TET, CFM, and CK), a 72 h LC50 fitting curve was calculated to determine whether long-term antibiotic feeding leads to a decrease in pesticide resistance. The CK group of C. suppressalis was used to determine the direct effect of antibiotics on pesticide tolerance using a mixture of antibiotics and pesticides. Indirect evidence suggests that antibiotics themselves did not affect the pesticide tolerance of C. suppressalis. The results confirmed that feeding C. suppressalis cefixime led to a decrease in the expression of potential tolerance genes to chlorantraniliprole. CONCLUSIONS: This study reveals the impact of antibiotic induced changes in symbiotic microorganisms on the pesticide tolerance of C. suppressalis, laying the foundation for studying the interaction between C. suppressalis and microorganisms, and also providing new ideas for the prevention and control of C. suppressalis and the creation of new pesticides.

Discordance between Remnant Cholesterol and Low-density Lipoprotein Cholesterol Predicts Cardiovascular Disease: the Kailuan Prospective Cohort Study.

BACKGROUND: Previous studies have shown that remnant cholesterol (RC) was associated with cardiovascular disease (CVD). The study aim to identify the association of RC and the discordance between RC and lipoprotein cholesterol (LDL-C) with CVD. METHODS: Data was obtained from the Kailuan study. RC was calculated as the non high-density lipoprotein cholesterol minus LDL-C. Discordant RC and LDL-C were defined by percentile difference and clinical cutoff points. Cox proportional hazard models were used to explore the association of RC and the discordance between RC and LDL-C with CVD. RESULTS: Total of 96,769 participants were inclued, with the median age of 51.61 years, 79.56% of male. There was a significant association between RC levels and the risk of CVD, with an HR of 1.10 (95% CI, 1.08-1.13) in the continuous analysis. The discordantly high RC group had a significant increase in CVD, MI, and stroke risk, with HRs of 1.18 (95%CI, 1.10-1.26), 1.23 (1.06-1.43), and 1.15 (1.07-1.24), respectively. Compared to the group with low LDL-C and low RC, the group with low LDL-C and high RC had significantly higher incidences of CVD (HR, 1.33 [95% CI, 1.26-1.40]), MI (HR, 1.59 [95% CI, 1.41-1.80]), and stroke (HR, 1.28 [95% CI, 1.20-1.35]). CONCLUSIONS: Elevated levels of RC and discordantly high RC with LDL-C both were associated with the risk of CVD, MI, and stroke. These findings demonstrate the clinical significance of identifying residual risk related to RC.

Nitrogen deficiency modulates carbon allocation to promote nodule nitrogen fixation capacity in soybean.

Previously, the effect of soil mineral N deficiency on nodule nitrogen fixation capacity (NFC) is unclear. In this study, we found that N deficiency would enhance sucrose allocation to nodules and PEP allocation to bacteroid to promote nodule NFC. Our findings provide new insights into the design of leguminous crops with improved adaptation to fluctuating N levels in the soil.

Effects of the motor cortical theta-burst transcranial-focused ultrasound stimulation on the contralateral motor cortex.

Theta-burst transcranial ultrasound stimulation (tbTUS) increases primary motor cortex (M1) excitability for at least 30 min. However, the remote effects of focal M1 tbTUS on the excitability of other cortical areas are unknown. Here, we examined the effects of left M1 tbTUS on right M1 excitability. An 80 s train of active or sham tbTUS was delivered to the left M1 in 20 healthy subjects. Before and after the tbTUS, we measured: (1) corticospinal excitability using motor-evoked potential (MEP) amplitudes from single-pulse transcranial magnetic stimulation (TMS) of left and right M1; (2) interhemispheric inhibition (IHI) from left to right M1 and from right to left M1 using a dual-site paired-pulse TMS paradigm; and (3) intracortical circuits of the right M1 with short-interval intracortical inhibition and intracortical facilitation (ICF) using paired-pulse TMS. Left M1 tbTUS decreased right M1 excitability as shown by decreased MEP amplitudes, increased right M1 ICF and decreased short-interval IHI from left to right hemisphere at interstimulus interval (ISI) of 10 ms but not long-interval IHI at interstimulus interval of 40 ms. The study showed that left M1 tbTUS can change the excitability of remote cortical areas with decreased right M1 excitability and interhemispheric inhibition. The remote effects of tbTUS should be considered when it is used in neuroscience research and as a potential neuromodulation treatment for brain disorders. KEY POINTS: Transcranial ultrasound stimulation (TUS) is a novel non-invasive brain stimulation technique for neuromodulation with the advantages of being able to achieve high spatial resolution and target deep brain structures. A repetitive TUS protocol, with an 80 s train of theta burst patterned TUS (tbTUS), has been shown to increase primary motor cortex (M1) excitability, as well as increase alpha and beta movement-related spectral power in distinct brain regions. In this study, we examined on the effects of the motor cortical tbTUS on the excitability of contralateral M1 measured with MEPs elicited by transcranial magnetic stimulation. We showed that left M1 tbTUS decreased right M1 excitability and left-to-right M1 interhemispheric inhibition, and increased intracortical facilitation of right M1. These results lead to better understand the effects of tbTUS and can help the development of tbTUS for the treatment of neurological and psychiatric disorders and in neuroscience research.

Association of triglyceride-glucose index and its related parameters with atherosclerotic cardiovascular disease: evidence from a 15-year follow-up of Kailuan cohort.

BACKGROUND: Triglyceride glucose (TyG) index and its related parameters have been introduced as cost-effective surrogate indicators of insulin resistance, while prospective evidence of their effects on atherosclerotic cardiovascular disease (ASCVD) remained scattered and inconsistent. We aimed to evaluate the association of TyG and its related parameters with new-onset ASCVD, and the predictive capacity were further compared. METHOD: A total of 95,342 ASCVD-free participants were enrolled from the Kailuan study. TyG and its related parameters were defined by fasting blood glucose, triglyceride, body mass index (BMI), waist circumstance (WC) and waist-to-height ratio (WHtR). The primary outcome was incident ASCVD, comprising myocardial infarction (MI) and ischemic stroke (IS). Cox proportional hazard models and restricted cubic spline (RCS) analyses were adopted to investigate the association between each index and ASCVD. The C-index, integrated discrimination improvement (IDI), and net reclassification improvement (NRI) were used for comparison of their predictive value for ASCVD. RESULTS: During a median follow-up of 15.0 years, 8,031 new cases of ASCVD were identified. The incidence rate of ASCVD increased along with elevated levels of each index, and the relationships were found to be nonlinear in the RCS analyses. The hazard ratio (HR) and 95% confidence interval (95% CI) for ASCVD was 1.39 (1.35, 1.43), 1.46 (1.41, 1.50), 1.50 (1.46, 1.55), and 1.52 (1.48, 1.57) per 1 IQR increase of baseline TyG, TyG-BMI, TyG-WC, and TyG-WHtR, respectively, and the association were more pronounced for females and younger individuals aged < 60 years (Pfor interaction<0.05). Using the updated mean or time-varying measurements instead of baseline indicators did not significantly alter the primary findings. Additionally, TyG-WC and TyG-WHtR showed better performance in predicting risk of ASCVD than TyG, with the IDI (95% CI) of 0.004 (0.001, 0.004) and 0.004 (0.001, 0.004) and the category-free NRI (95% CI) of 0.120 (0.025, 0.138) and 0.143 (0.032, 0.166), respectively. Similar findings were observed for MI and IS. CONCLUSIONS: Both the TyG index and its related parameters were significantly and positively associated with ASCVD. TyG-WC and TyG-WHtR had better performance in predicting incident ASCVD than TyG, which might be more suitable indices for risk stratification and enhance the primary prevention of ASCVD.

Preparation, Optimization, and Anti-Pulmonary Infection Activity of Casein-Based Chrysin Nanoparticles.

Introduction: Chrysin has a wide range of biological activities, but its poor bioavailability greatly limits its use. Here, we attempted to prepare casein (cas)-based nanoparticles to promote the biotransfer of chrysin, which demonstrated better bioavailability and anti-infection activity compared to free chrysin. Methods: Cas-based chrysin nanoparticles were prepared and characterized, and most of the preparation process was optimized. Then, the in vitro and in vivo release characteristics were studied, and anti-pulmonary infection activity was evaluated. Results: The constructed chrysin-cas nanoparticles exhibited nearly spherical morphology with particle size and ζ potential of 225.3 nm and -33 mV, respectively. These nanoparticles showed high encapsulation efficiency and drug-loading capacity of 79.84% ± 1.81% and 11.56% ± 0.28%, respectively. In vitro release studies highlighted a significant improvement in the release profile of the chrysin-cas nanoparticles (CCPs). In vivo experiments revealed that the relative oral bioavailability of CCPs was approximately 2.01 times higher than that of the free chrysin suspension. Further investigations indicated that CCPs effectively attenuated pulmonary infections caused by Acinetobacter baumannii by mitigating oxidative stress and reducing pro-inflammatory cytokines levels, and the efficacy was better than that of the free chrysin suspension. Conclusion: The findings underscore the advantageous bioavailability of CCPs and their protective effects against pulmonary infections. Such advancements position CCPs as a promising pharmaceutical agent and candidate for future therapeutic drug innovations.

An Early Accumulation of Serum Uric Acid Confers More Risk of Heart Failure: A 10-year Prospective Cohort Study.

BACKGROUND: Evidence on the longitudinal association of serum uric acid (SUA) with the risk of heart failure (HF) was limited and controversial. This study aimed to investigate the associations of cumulative SUA (cumSUA), incorporating its time course of accumulation, with the risk of HF. METHODS: This prospective study enrolled 54,606 participants from the Kailuan study. The magnitude of SUA accumulation was expressed as cumSUA, exposure duration, and cumulative burden from baseline to the third survey, with cumSUA, calculated by multiplying mean values between consecutive examinations by time intervals between visits, as the primary exposure. RESULTS: During a median follow-up of 10.00 years, 1,260 cases of incident HF occurred. A higher risk of HF was observed in participants with the highest versus the lowest quartile of cumSUA (adjusted hazard ratio [aHR], 1.54; 95% confidence interval [CI], 1.29-1.84), 6-years (6 years) versus 0-year exposure duration (aHR, 1.87; 95% CI, 1.43-2.45), cumulative burden >0 versus =0 (aHR, 1.55; 95 CI, 1.29-1.86), and those with a negative versus positive SUA slope (aHR, 1.12; 95% CI, 1.02-1.25). When cumSUA was incorporated with its time course, those with cumSUA≥median and a negative SUA slope had the highest risk of HF (aHR, 1.55; 95% CI, 1.29-1.86). CONCLUSIONS: Incident HF risk was associated with the magnitude and time course of cumSUA accumulation. Early accumulation resulted in a greater risk of HF than later accumulation, indicating the importance of optimal SUA control earlier in life.

In situ comparison of osteogenic effects of polymer-based scaffolds with different degradability by integrated scaffold model.

Polymer-based scaffolds with different degradability have been investigated to screen the matrix whose degradation rate is more closely matched with the bone regeneration rate. However, these comparisons are inclined to be compromised by the animal individual differences. In this study, we constructed an integrated scaffold model comprising four parts with different degradability and bioactivity to achieve an in situ comparison of bone regeneration ability of different scaffolds. Slow-degradable polycaprolactone (PCL), fast-degradable poly (lactic-co-glycolic acid) (PLGA), and silica-coated PCL and PLGA scaffolds were assembled into a round sheet to form a hydroxyapatite (HA)-free integrated scaffold. HA-doped PCL, PLGA, and silica-coated PCL and PLGA scaffolds were assembled to create an HA-incorporated integrated scaffold. The in vivo experimental results demonstrated that the local acid microenvironment caused by the rapid degradation of PLGA interfered with the osteogenic process promoted by PCL-based scaffolds in defect areas implanted with HA-free integrated scaffolds. Since the incorporation of HA alleviated the acidic microenvironment to some extent, each scaffold in HA-incorporated scaffolds exhibited its expected bone regeneration capacity. Consequently, it is feasible to construct an integrated structure for comparing the osteogenic effects of various scaffolds in situ, when there is no mutual interference between the materials. The strategy presented in this study inspired the structure design of biomaterials to enable in situ comparison of bone regeneration capacity of scaffolds.

Cumulative remnant cholesterol burden increases the risk of cardiovascular disease among young adults.

BACKGROUND: Previous studies have shown that remnant cholesterol (RC) was associated with cardiovascular disease (CVD) among middle-aged or older adults. However, lack of evidence on long-term exposures to RC and their role in CVD risk among young adults. We thus aimed to explore the association between cumulative RC burden and CVD in young adults. METHODS: We enrolled participants younger than 45 years free of CVD history in the Kailuan Study who completed the first three health examinations from 2006 to 2010. Cumulative RC burden included cumulative RC burden score, time-weighted cumulative RC, exposure duration of high RC, and time course of RC accumulation. The outcome was the incidence of CVD. Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) between cumulative RC burden and CVD risk. RESULTS: A total of 15,219 participants were included (73.70% male, median age 39.13 years). During a median follow-up duration of 8.71 years (interquartile range: 8.4-9.15 years), 502 individuals developed CVD. After adjustment for traditional cardiovascular risk factors, highest risk of CVD was observed in participants with the highest cumulative RC burden score (HR, 1.66; 95% CI, 1.29-2.12), the highest quartile time-weighted cumulative RC (HR,1.50; 95% CI, 1.15-1.96), the longest exposure duration of high RC (HR, 1.71; 95% CI, 1.21-2.42), and those with cumulative RC burden and positive slope (HR, 1.79; 95% CI, 1.35-2.36). CONCLUSIONS: Cumulative RC burden increased the risk of CVD among young adults, suggesting that maintaining low RC levels throughout young adulthood may minimize CVD risk.

Hematoporphyrin derivative-mediated photodynamic techniques for the diagnosis and treatment of chordoma.

BACKGROUND: Chordoma is a rare congenital low-grade malignant tumor characterized by infiltrative growth. It often tends to compress important intracranial nerves and blood vessels, making its surgical treatment extremely difficult. Besides, the efficacy of radiotherapy and chemotherapy is limited. The photosensitizer hematoporphyrin derivative (HPD) can emit red fluorescence under 405 nm excitation and produce reactive oxygen species for tumor therapy under 630 nm excitation. Herein, we investigated the effects of the photosensitizer hematoporphyrin derivative (HPD) on different cell lines of chordoma and xenograft tumors under 405 nm and 630 nm excitation. METHODS: The photosensitizer hematoporphyrin derivative (HPD) and Two different chordoma cell lines (U-CH1, JHC7) were used for the test. The in vitro experiments were as follows: (1) the fluorescence intensity emitted by chordoma cells excited by different 405 nm light intensities was observed under a confocal microscope; (2) the Cell Counting Kit-8 (CCK-8) assay was performed to detect the effects of different photosensitizer concentrations and 630 nm light energy densities on the activity of chordoma cells. In the in vivo experiments, (3) Fluorescence visualization of chordoma xenograft tumors injected with photosensitizer via tail vein under 405 nm excitation; (4) Impact of 630 nm excitation of photosensitizer on the growth of chordoma xenograft tumors. RESULTS: (1) The photosensitizers in chordoma cells and chordoma xenografts of nude mice were excited by 405 nm to emit red fluorescence; (2) 630 nm excitation photosensitizer reduces chordoma cell activity and inhibits chordoma xenograft tumor growth in chordoma nude mice. CONCLUSION: Photodynamic techniques mediated by the photosensitizer hematoporphyrin derivatives can be used for the diagnosis and treatment of chordoma.

Bio-Nano Toolbox for Precision Alzheimer's Disease Gene Therapy.

Alzheimer's disease (AD) is the most burdensome aging-associated neurodegenerative disorder, and its treatment encounters numerous failures during drug development. Although there are newly approved in-market ß-amyloid targeting antibody solutions, pathological heterogeneity among patient populations still challenges the treatment outcome. Emerging advances in gene therapies offer opportunities for more precise personalized medicine; while, major obstacles including the pathological heterogeneity among patient populations, the puzzled mechanism for druggable target development, and the precision delivery of functional therapeutic elements across the blood-brain barrier remain and limit the use of gene therapy for central neuronal diseases. Aiming for "precision delivery" challenges, nanomedicine provides versatile platforms that may overcome the targeted delivery challenges for AD gene therapy. In this perspective, to picture a toolbox for AD gene therapy strategy development, the most recent advances from benchtop to clinics are highlighted, possibly available gene therapy targets, tools, and delivery platforms are outlined, their challenges as well as rational design elements are addressed, and perspectives in this promising research field are discussed.

Efficient Biosynthesis of Salidroside via Artificial in Vivo enhanced UDP-Glucose System Using Cheap Sucrose as Substrate.

Salidroside, a valuable phenylethanoid glycoside, is obtained from plants belonging to the Rhodiola genus, known for its diverse biological properties. At present, salidroside is still far from large-scale industrial production due to its lower titer and higher process cost. In this study, we have for the first time increased salidroside production by enhancing UDP-glucose supply in situ. We constructed an in vivo UDP-glucose regeneration system that works in conjunction with UDP-glucose transferase from Rhodiola innovatively to improve UDP-glucose availability. And a coculture was formed in order to enable de novo salidroside synthesis. Confronted with the influence of tyrosol on strain growth, an adaptive laboratory evolution strategy was implemented to enhance the strain's tolerance. Similarly, salidroside production was optimized through refinement of the fermentation medium, the inoculation ratio of the two microbes, and the inoculation size. The final salidroside titer reached 3.8 g/L. This was the highest titer achieved at the shake flask level in the existing reports. And this marked the first successful synthesis of salidroside in an in situ enhanced UDP-glucose system using sucrose. The cost was reduced by 93% due to the use of inexpensive substrates. This accomplishment laid a robust foundation for further investigations into the synthesis of other notable glycosides and natural compounds.

A sequential macrophage activation strategy for bone regeneration: A micro/nano strontium-releasing composite scaffold loaded with lipopolysaccharide.

Effective tissue repair relies on the orchestration of different macrophage phenotypes, both the M2 phenotype (promotes tissue repair) and M1 phenotype (pro-inflammatory) deserve attention. In this study, we propose a sequential immune activation strategy to mediate bone regeneration, by loading lipopolysaccharide (LPS) onto the surface of a strontium (Sr) ions -contained composite scaffold, which was fabricated by combining Sr-doped micro/nano-hydroxyapatite (HA) and dual degradable matrices of polycaprolactone (PCL) and poly (lactic-co-glycolic acid) (PLGA). Our strategy involves the sequential release of LPS to promote macrophage homing and induce the expression of the pro-inflammatory M1 phenotype, followed by the release of Sr ions to suppress inflammation. In vitro and in vivo experiments demonstrated that, the appropriate pro-inflammatory effects at the initial stage of implantation, along with the anti-inflammatory effects at the later stage, as well as the structural stability of the scaffolds conferred by the composition, can synergistically promote the regeneration and repair of bone defects.

The trial-by-trial fluctuations in primary motor cortex excitability during attentional bias among smokers: A transcranial magnetic stimulation study.

Background: A relatively new computational approach called trial-level bias score (TL-BS) has shown that attentional bias to smoking-related stimuli in smokers fluctuates temporally, trial by trial, during attention tasks. Here, we investigated the reliability of using TL-BS values to assess attentional bias and the electrophysiology mechanisms undergirding fluctuations in attentional bias among smokers. Method: In total, 26 male smokers and 26 male non-smokers performed a dot-probe task in Experiment 1. In Experiment 2, an additional 23 male smokers and 23 male non-smokers performed the same task while undergoing single-pulse transcranial magnetic stimulation, which was used to investigate corticospinal excitability. Results: It showed that assessing TL-BS parameters for reaction time (RT) was more reliable than calculating the traditional mean attentional bias score; however, this superior reliability was no longer apparent after controlling for general RT variability. There was a significant difference between smokers and non-smokers in TL-BS parameters calculated for both RT and motor-evoked potential (MEP) amplitude. However, TL-BS parameters for RT and MEP amplitude were strongly correlated with general RT variability and general MEP variability, respectively. Conclusions: Our findings indicated that TL-BS parameters may not be ideal for measuring attentional bias at either the behavioral or electrophysiology level; however, larger general RT and MEP amplitude variabilities in non-smokers may indicate dysregulation of cognitive processing in smokers.