Modulation of plasmacytoid dendritic cells response in inflammation and autoimmunity.

The discovery of toll-like receptors (TLRs) and the subsequent recognition that endogenous nucleic acids (NAs) could serve as TLR ligands have led to essential insights into mechanisms of healthy immune responses as well as pathogenic mechanisms relevant to systemic autoimmune and inflammatory diseases. In systemic lupus erythematosus, systemic sclerosis, and rheumatoid arthritis, NA-containing immune complexes serve as TLR ligands, with distinct implications depending on the additional immune stimuli available. Plasmacytoid dendritic cells (pDCs), the robust producers of type I interferon (IFN-I), are providing critical insights relevant to TLR-mediated healthy immune responses and tissue repair, as well as generation of inflammation, autoimmunity and fibrosis, processes central to the pathogenesis of many autoimmune diseases. In this review, we describe recent data characterizing the role of platelets and NA-binding chemokines in modulation of TLR signaling in pDCs, as well as implications for how the IFN-I products of pDCs contribute to the generation of inflammation and wound healing responses by monocyte/macrophages. Chemokine modulators of TLR-mediated B cell tolerance mechanisms and interactions between TLR signaling and metabolic pathways are also considered. The modulators of TLR signaling and their contribution to the pathogenesis of systemic autoimmune diseases suggest new opportunities for identification of novel therapeutic targets.

Enhanced Selective Ion Transport in Highly Charged Bacterial Cellulose/Boron Nitride Composite Membranes for Thermo-Osmotic Energy Harvesting.

Significant untapped energy exists within low-grade heat sources and salinity gradients. Traditional nanofluidic membranes exhibit inherent limitations, including low ion selectivity, high internal resistance, reliance on nonrenewable resources, and instability in aqueous solutions, invariably constraining their practical application. Here, an innovative composite membrane-based nanofluidic system is reported, involving the strategy of integrating tailor-modified bacterial nanofibers with boron nitride nanosheets, enabling high surface charge densities while maintaining a delicate balance between ion selectivity and permeability, ultimately facilitating effective thermo-osmotic energy harvesting. The device exhibits an impressive output power density of 10 W m-2 with artificial seawater and river water at a 50 K temperature gradient. Furthermore, it demonstrates robust power density stability under prolonged exposure to salinity gradients or even at elevated temperatures. This work opens new avenues for the development of nanofluidic systems utilizing composite materials and presents promising solutions for low-grade heat recovery and osmotic energy harvesting.

Faslpr gene dosage tunes the extent of lymphoproliferation and T cell differentiation in lupus.

Sle1 and Faslpr are two lupus susceptibility loci that lead to manifestations of systemic lupus erythematosus. To evaluate the dosage effects of Faslpr in determining cellular and serological phenotypes associated with lupus, we developed a new C57BL/6 (B6) congenic lupus strain, B6.Sle1/Sle1.Faslpr/+ (Sle1homo.lprhet) and compared it with B6.Faslpr/lpr (lprhomo), B6.Sle1/Sle1 (Sle1homo), and B6.Sle1/Sle1.Faslpr/lpr (Sle1homo.lprhomo) strains. Whereas Sle1homo.lprhomo mice exhibited profound lymphoproliferation and early mortality, Sle1homo.lprhet mice had a lifespan comparable to B6 mice, with no evidence of splenomegaly or lymphadenopathy. Compared to B6 monogenic lupus strains, Sle1homo.lprhet mice exhibited significantly elevated serum ANA antibodies and increased proteinuria. Additionally, Sle1homo.lprhet T cells had an increased propensity to differentiate into Th1 cells. Gene dose effects of Faslpr were noted in upregulating serum IL-1⍺, IL-2, and IL-27. Taken together, Sle1homo.lprhet strain is a new C57BL/6-based model of lupus, ideal for genetic studies, autoantibody repertoire investigation, and for exploring Th1 effector cell skewing without early-age lymphoproliferative autoimmunity.

Therapeutic efficacy of an alpha-particle emitter labeled anti-GD2 humanized antibody against osteosarcoma-a proof of concept study.

PURPOSE: Current treatments for osteosarcoma (OS) have a poor prognosis, particularly for patients with metastasis and recurrence, underscoring an urgent need for new targeted therapies to improve survival. Targeted alpha-particle therapy selectively delivers cytotoxic payloads to tumors with radiolabeled molecules that recognize tumor-associated antigens. We have recently demonstrated the potential of an FDA approved, humanized anti-GD2 antibody, hu3F8, as a targeted delivery vector for radiopharmaceutical imaging of OS. The current study aims to advance this system for alpha-particle therapy of OS. METHODS: The hu3F8 antibody was radiolabeled with actinium-225, and the safety and therapeutic efficacy of the [225Ac]Ac-DOTA-hu3F8 were evaluated in both orthotopic murine xenografts of OS and spontaneously occurring OS in canines. RESULTS: Significant antitumor activity was proven in both cases, leading to improved overall survival. In the murine xenograft's case, tumor growth was delayed by 16-18 days compared to the untreated cohort as demonstrated by bioluminescence imaging. The results were further validated with magnetic resonance imaging at 33 days after treatment, and microcomputed tomography and planar microradiography post-mortem. Histological evaluations revealed radiation-induced renal toxicity, manifested as epithelial cell karyomegaly and suggestive polyploidy in the kidneys, suggesting rapid recovery of renal function after radiation damage. Treatment of the two canine patients delayed the progression of metastatic spread, with an overall survival time of 211 and 437 days and survival beyond documented metastasis of 111 and 84 days, respectively. CONCLUSION: This study highlights the potential of hu3F8-based alpha-particle therapy as a promising treatment strategy for OS.

Sialic Acid-Modified O-GlcNAc Transferase Inhibitor Liposome Presents Antitumor Effect in Hepatocellular Carcinoma.

O-linked-N-acetylglucosaminylation (O-GlcNAcylation) plays a key role in hepatocellular carcinoma (HCC) development, and the inhibition of O-GlcNAcylation has therapeutic potential. To decrease the systemic adverse events and increase targeting, we used sialic acid (SA)-decorated liposomes loaded with OSMI-1, an inhibitor of the O-GlcNAcylation, to further improve the anti-HCC effect. Fifty pairs of HCC tissue samples and the cancer genome atlas database were used to analyze the expression of O-GlcNAc transferase (OGT) and its effects on prognosis and immune cell infiltration. OSMI-1 cells were treated with SA and liposomes. Western blotting, immunofluorescence, cell proliferation assay, flow cytometry, enzyme-linked immunosorbent assay, immunohistochemistry, and tumorigenicity assays were used to investigate the antitumor effect of SA-modified OSMI-1 liposomes in vitro and in vivo. OGT was highly expressed in HCC tissues, negatively correlated with the degree of tumor infiltration of CD8+ and CD4+T cells and prognosis, and positively correlated with the degree of Treg cell infiltration. SA-modified OSMI-1 liposome (OSMI-1-SAL) was synthesized with stable hydrodynamic size distribution. Both in vitro and in vivo, OSMI-1-SAL exhibited satisfactory biosafety and rapid uptake by HCC cells. Compared to free OSMI-1, OSMI-1-SAL had a stronger capacity for suppressing the proliferation and promoting the apoptosis of HCC cells. Moreover, OSMI-1-SAL effectively inhibited tumor initiation and development in mice. OSMI-1-SAL also promoted the release of damage-associated molecular patterns, including anticalreticulin, high-mobility-group protein B1, and adenosine triphosphate, from HCC cells and further promoted the activation and proliferation of the CD8+ and CD4+T cells. In conclusion, the OSMI-1-SAL synthesized in this study can target HCC cells, inhibit tumor proliferation, induce tumor immunogenic cell death, enhance tumor immunogenicity, and promote antitumor immune responses, which has the potential for clinical application in the future.

The value of baseline 18F-sodium fluoride and 18F-choline PET activity for identifying responders to radium-223 treatment in castration-resistant prostate cancer bone metastases.

OBJECTIVES: To investigate whether baseline 18F-sodium fluoride (NaF) and 18F-choline PET activity is associated with metastatic castration-resistant prostate cancer (mCRPC) global and individual bone metastases' DWI MR imaging response to radium-223 treatment. METHODS: Thirty-six bone-only mCRPC patients were prospectively recruited from three centers. Whole-body (WB)-MRI with DWI and 18F-NaF and 18F-choline PET/CT were performed at therapy baseline and 8-week intervals. In each patient, bone disease median global (g)ADC change between baseline and follow-up was calculated. Additionally, up to five bone target lesions per patient were delineated and individual median ADC change recorded. An ADC increase > 30% defined response per-patient and per-lesion. For the same targets, baseline 18F-NaF and 18F-choline PET SUVmax were recorded. Mean SUVmax across patient targets was correlated with gADC change and lesion SUVmax with per-lesion ADC change. RESULTS: A total of 133 lesions in 36 patients (14 responders) were analyzed. 18F-NaF PET per-patient mean SUVmax was significantly higher in responders (median = 56.0 versus 38.7 in non-responders; p = 0.008), with positive correlation between SUVmax and gADC increase (rho = 0.42; p = 0.015). A 48.7 SUVmax threshold identified responders with 77% sensitivity and 75% specificity. Baseline 18F-NaF PET per-lesion SUVmax was higher in responding metastases (median = 51.6 versus 31.8 in non-responding metastases; p = 0.001), with positive correlation between baseline lesion SUVmax and ADC increase (rho = 0.39; p < 0.001). A 36.8 SUVmax threshold yielded 72% sensitivity and 63% specificity. No significant association was found between baseline 18F-choline PET SUVmax and ADC response on a per-patient (p = 0.164) or per-lesion basis (p = 0.921). CONCLUSION: 18F-NaF PET baseline SUVmax of target mCRPC bone disease showed significant association with response to radium-223 defined by ADC change. CLINICAL RELEVANCE STATEMENT: 18F-sodium fluoride PET/CT baseline maximum SUV of castration-resistant prostate cancer bone metastases could be used as a predictive biomarker for response to radium-223 therapy. KEY POINTS: • 18F-sodium fluoride PET baseline SUVmax of castration-resistant prostate cancer bone metastases showed significant association with response to radium-223. • Baseline 18F-sodium fluoride PET can improve patient selection for radium-223 therapy. • Change in whole-body DWI parameters can be used for response correlation with baseline 18F-sodium fluoride PET SUVmax in castration-resistant prostate cancer bone metastases.

Prognostic Differences Between Surveillance and Active Treatment After Initial Orchiectomy in Patients With Stage I Mixed Germ Cell Tumors of the Testis: A Propensity Score Matching Analysis.

INTRODUCTION: The prognosis and optimal treatment approach for stage I mixed germ cell cancers of the testis are not well-established. This study aimed to assess contemporary treatment rates and their correlation with the cancer-specific mortality (CSM) and other-cause mortality (OCM) in patients with stage I testicular mixed germ cell tumors (TMGCT) who underwent orchiectomy, comparing surveillance with active treatment, including chemotherapy (CHT) and retroperitoneal lymph node dissection (RPLND). METHODS: Retrospective analysis of clinical data from stage I TMGCT patients who underwent orchiectomy was conducted using the Surveillance, Epidemiology, and End Results database from 2004 to 2019. The annual percentage change (APC) in the use of surveillance, postoperative CHT, and RPLND was examined. Propensity score matching (PSM) and cumulative incidence, analyses were employed to compare differences in CSM and OCM between surveillance and active treatment, as well as between CHT and RPLND. Multivariate competing-risks regression models were utilized to investigate independent factors affecting CSM and OCM among stage I TMGCT patients. RESULTS: The study included 5743 individuals with stage I TMGCT that underwent surveillance (61.6%), CHT(27.2%), or RPLND (11.2%). Among them, 82 deaths were attributed to TMGCT, and 82 deaths resulted from other causes. Surveillance rates increased over time (APC: 0.635%, P = 0.008), as did CHT rates (APC: 0.863%, P < 0.001), while RPLND rates declined (APC: -0.96%, P < 0.001). After PSM, multivariate competing-risks regression analysis showed that, active treatment, compared to surveillance, was not an independent factor for CSM and OCM. In contrast, when compared to CHT, RPLND was an independent factor associated with lower CSM (hazard ratio = 0.247, 95% confidence interval: 0.08-0.761; P = 0.015), but not OCM (hazard ratio = 0.946, 95% confidence interval: 0.377-2.37; P = 0.91). CONCLUSIONS: Surveillance and CHT rates have increased over time for patients with stage I TMGCT following initial orchiectomy, while RPLND utilization has decreased. There was no significant difference in CSM between surveillance and active treatment groups, but RPLND demonstrated significantly lower CSM than CHT in active treatment. Our findings suggest that the usage of RPLND in patients with stage I TMGCT should be reconsidered.

Understanding the electrochemical properties of Mg-doped Li2MnO3: first-principles calculations.

Non-transition metal doping, especially for Mg, has been gradually employed to optimize the electrochemical performance of Li-rich cathode material Li2MnO3. However, the effects of Mg doping on the electrochemical behavior of Li2MnO3 have not been studied extensively. In this work, we investigate the effect of Mg doping at both the 2b (in the Li/Mn mixed layer) and 4h (in the Li layer) Li sites on the electrochemical properties of Li2MnO3 through first-principles calculations and ab initio molecular dynamics simulations. The local lattice structure, electronic density of states, Bader charge, delithiation voltage, lattice oxygen stability and Li diffusion kinetics are examined. Electronic structure analysis shows that Mg can activate the electrochemical activity of surrounding Mn by charge transfer, making Mn participate in charge compensation at the initial delithiation stage. Mg doping can also cause an increase in the average oxygen vacancy formation energy and hence depress the oxygen release during the delithiation process. Molecular dynamics simulations show that the diffusion kinetics of Li ions in Mg2b-Li2MnO3 is enhanced with respect to the undoped one, whereas Mg doped at the 4h site cannot improve the diffusion kinetics of Li ions. Further studies found that Mg doped at the 2b site results in a decrease in the energy barrier for the intra-layer diffusion and an increase in the energy barrier for the inter-layer diffusion of the nearby Li vacancies.

Preparation and epitope analysis of monoclonal antibodies against African swine fever virus DP96R protein.

BACKGROUND: Many proteins of African swine fever virus (ASFV, such as p72, p54, p30, CD2v, K205R) have been successfully expressed and characterized. However, there are few reports on the DP96R protein of ASFV, which is the virulence protein of ASFV and plays an important role in the process of host infection and invasion of ASFV. RESULTS: Firstly, the prokaryotic expression vector of DP96R gene was constructed, the prokaryotic system was used to induce the expression of DP96R protein, and monoclonal antibody was prepared by immunizing mice. Four monoclonal cells of DP96R protein were obtained by three ELISA screening and two sub-cloning; the titer of ascites antibody was up to 1:500,000, and the monoclonal antibody could specifically recognize DP96R protein. Finally, the subtypes of the four strains of monoclonal antibodies were identified and the minimum epitopes recognized by them were determined. CONCLUSION: Monoclonal antibody against ASFV DP96R protein was successfully prepared and identified, which lays a foundation for further exploration of the structure and function of DP96R protein and ASFV diagnostic technology.

Linewidth compression of a single longitudinal mode ytterbium-doped fiber laser based on femtosecond laser fabricated fiber Bragg gratings.

We demonstrate a single longitudinal mode distributed Bragg reflection (DBR) fiber laser by directly fabricating fiber Bragg gratings (FBGs) on an ytterbium-doped fiber (YDF) using a femtosecond laser. A simple optical self-injection feedback method was used to effectively compress the linewidth and reduce relative intensity noise (RIN) of a single longitudinal mode DBR fiber laser. Further, we investigated the effect of self-injection feedback cavity length and reflectivity on linewidth compression and determined that the linewidth tends to decrease with the increase of the external cavity photon lifetime. By a self-injection feedback, the laser linewidth was compressed from 31.8 kHz to 1.4 kHz. Meanwhile, the relaxation oscillation peak from -103.2d B/H z at 1.51 MHz was suppressed to -122.3d B/H z at 0.16 MHz. This low-noise narrow linewidth single longitudinal mode fiber laser is expected to be a promising candidate for applications such as active detection of neutral atmosphere and distributed fiber sensing.

Intersectional analysis of social disparities in type 2 diabetes risk among adults in Germany: results from a nationwide population-based survey.

BACKGROUND: Differences in type 2 diabetes risk have been reported for several sociodemographic determinants including sex/gender or socioeconomic status. From an intersectional perspective, it is important to not only consider the role of social dimensions individually, but also their intersections. This allows for a deeper understanding of diabetes risk and preventive needs among diverse population groups. METHODS: As an intersectionality-informed approach, multilevel analysis of individual heterogeneity and discriminatory accuracy (MAIHDA) was used in a population-based sample of adults without known diabetes in Germany from the cross-sectional survey "Disease knowledge and information needs- Diabetes mellitus (2017)". Diabetes risk was assessed by the German Diabetes Risk Score (GDRS, range 0-122 points), estimating the individual risk of developing type 2 diabetes within the next 5 years based on established self-reported risk factors. Nesting individuals in 12 intersectional strata defined by combining sex/gender, educational level, and history of migration, we calculated measures to quantify the extent to which individual differences in diabetes risk were explained at strata level, and how much this was due to additive or multiplicative intersectional effects of social determinants. RESULTS: Drawing on data of 2,253 participants, we found good discriminatory accuracy of intersectional strata (variance partition coefficient = 14.00% in the simple intersectional model). Model-predicted GDRS means varied between 29.97 (corresponding to a "low risk" of < 2%) in women with high educational level and a history of migration, and 52.73 ("still low risk" of 2-5%) in men with low educational level without a history of migration. Variance in GDRS between strata was mainly explained by additive effects of social determinants (proportional change in variance to intersectional interaction model = 77.95%) with being male and having low educational level being associated with higher GDRS. There was no evidence of multiplicative effects in individual strata. CONCLUSIONS: Type 2 diabetes risk differed between intersectional strata and can to some extent be explained at strata level. The role of intersectional effects was minor and needs to be further investigated. Findings suggest a need for specific preventive measures targeted at large groups with increased diabetes risk, such as men and persons with low educational level.

[Subjective health in the early phase of the COVID-19 pandemic-a comparison of socio-demographic groups and pandemic-related risk factors]. / Subjektive Gesundheit in der Frühphase der COVID-19-Pandemie ­ ein Vergleich von soziodemografischen Gruppen und pandemiebezogenen Risikofaktoren.

BACKGROUND: In the early stages of the COVID-19 pandemic in 2020, daily life was significantly restricted due to the containment measures of the initial lockdown while SARS-CoV­2 incidences remained relatively low. This study analyses socio-demographic and socio-economic groups in terms of changes in their subjective health during this phase. METHODS: Data from the Socio-Economic Panel (n = 14,856, March-July 2020) were used to estimate the relative frequency of self-reported good health, great worries about one's own health, and high life satisfaction of men and women stratified by age, education, income, migration history, pre-existing medical conditions, and high-risk occupation. The results were mutually adjusted using logistic regression, displayed on a monthly basis, and compared with the pre-pandemic period. RESULTS: Individuals of higher age, with lower education or income, and with pre-existing medical conditions reported positive health outcomes less frequently and worries more often. The differences between the subgroups remained largely stable compared to the pre-pandemic period. During the period of strongest restrictions due to infection-control measures, good health was reported less frequently by individuals with lower education or income compared to individuals with higher education or income. DISCUSSION: The impact of the early phase of the pandemic on subjective health and life satisfaction was low for the majority of the examined groups. Relative impairments were only identified for women in low socio-economic positions.

A Possibilistic Formulation of Autonomous Search for Targets.

Autonomous search is an ongoing cycle of sensing, statistical estimation, and motion control with the objective to find and localise targets in a designated search area. Traditionally, the theoretical framework for autonomous search combines sequential Bayesian estimation with information theoretic motion control. This paper formulates autonomous search in the framework of possibility theory. Although the possibilistic formulation is slightly more involved than the traditional method, it provides a means for quantitative modelling and reasoning in the presence of epistemic uncertainty. This feature is demonstrated in the paper in the context of partially known probability of detection, expressed as an interval value. The paper presents an elegant Bayes-like solution to sequential estimation, with the reward function for motion control defined to take into account the epistemic uncertainty. The advantages of the proposed search algorithm are demonstrated by numerical simulations.

CellTrackVis: interactive browser-based visualization for analyzing cell trajectories and lineages.

BACKGROUND: Automatic cell tracking methods enable practitioners to analyze cell behaviors efficiently. Notwithstanding the continuous development of relevant software, user-friendly visualization tools have room for further improvements. Typical visualization mostly comes with main cell tracking tools as a simple plug-in, or relies on specific software/platforms. Although some tools are standalone, limited visual interactivity is provided, or otherwise cell tracking outputs are partially visualized. RESULTS: This paper proposes a self-reliant visualization system, CellTrackVis, to support quick and easy analysis of cell behaviors. Interconnected views help users discover meaningful patterns of cell motions and divisions in common web browsers. Specifically, cell trajectory, lineage, and quantified information are respectively visualized in a coordinated interface. In particular, immediate interactions among modules enable the study of cell tracking outputs to be more effective, and also each component is highly customizable for various biological tasks. CONCLUSIONS: CellTrackVis is a standalone browser-based visualization tool. Source codes and data sets are freely available at http://github.com/scbeom/celltrackvis with the tutorial at http://scbeom.github.io/ctv_tutorial .

Design and Construction of Carbon-Coated Fe3 O4 /Cr2 O3 Heterostructures Nanoparticles as High-Performance Anodes for Lithium Storage.

Transition metal oxides, highly motivated anodes for lithium-ion batteries due to high theoretical capacity, typically afflict by inferior conductivity and significant volume variation. Architecting heterogeneous structures with distinctive interfacial features can effectively regulate the electronic structure to favor electrochemical properties. Herein, an engineered carbon-coated nanosized Fe3 O4 /Cr2 O3 heterostructure with multiple interfaces is synthesized by a facile sol-gel method and subsequent heat treatment. Such ingenious components and structural design deliver rapid Li+ migration and facilitate charge transfer at the heterogeneous interface. Simultaneously, the strong coupling synergistic interactions between Fe3 O4 , Cr2 O3 , and carbon layers establish multiple interface structures and built-in electric fields, which accelerate ion/electron transport and effectively eliminate volume expansion. As a result, the multi-interface heterostructure, as a lithium-ion battery anode, exhibits superior cycling stability maintaining a reversible capacity of 651.2 mAh g-1 for 600 cycles at 2 C. The density functionaltheory calculations not only unravel the electronic structure of the modulation but also illustrate favorable lithium-ion adsorption kinetics. This multi-interface heterostructure strategy offers a pathway for the development of advanced alkali metal-ion batteries.

Perceived Chronic Stress Is Associated With the German Diabetes Risk Score Among Adults Without Known Diabetes in Germany.

OBJECTIVE: There is evidence that psychological distress increases the risk of type 2 diabetes (T2D), but implications for prevention remain elusive. We examined the association between chronic stress and the German Diabetes Risk Score (GDRS) among adults without diabetes in Germany. METHODS: The study population consisted of 4654 persons aged 18 to 64 years without known diabetes drawn from the German Health Interview and Examination Survey for Adults (2008-2011). The predicted 5-year T2D risk (in percent) was estimated using the GDRS. Perceived chronic stress was assessed by the Screening Scale of the Trier Inventory for the Assessment of Chronic Stress and categorized into "up to average," "above average," and "high." The cross-sectional association of chronic stress with log-transformed GDRS (expressed as geometric mean ratio [GMR]) was analyzed in multivariable linear regression models. Covariables included age, sex, community size, region, educational level, living alone, social support, depression, and alcohol use. RESULTS: The mean predicted 5-year T2D risk rates were 2.7%, 2.9%, and 3.0% for chronic stress up to average, above average, and high chronic stress, respectively. Adjusted mean predicted 5-year risk was significantly higher among persons with chronic stress above average (GMR = 1.10, 95% confidence interval = 1.02-1.19) and high stress (GMR = 1.21, 95% CI = 1.06-1.39) compared with persons with chronic stress up to average. No interactions with sex or other covariables were found. CONCLUSIONS: Perceived chronic stress is independently associated with an increased predicted T2D risk in cross-sectional analysis and should be considered as T2D risk factor in longitudinal studies.

Slit2 suppresses endotoxin-induced uveitis by inhibiting the PI3K/Akt/IKK/NF-κB pathway.

Uveitis is a devastating intraocular inflammatory disease. The secreted leucine-rich repeat protein slit homologue 2 (Slit2) has been found to be an essential regulator of inflammation. This study aimed to analyse the anti-inflammatory effects and the underlying mechanisms of Slit2 in an endotoxin-induced uveitis (EIU) rat model. In this study, rats with EIU pretreated recombinant human Slit2 (rhSlit2) or a control vehicle by intravitreal injection. The clinical scores were graded under a slit lamp. The protein concentrations and total number of cells in the aqueous humour (AqH) were examined, and the retinal expression of various inflammatory mediators was detected. The levels of nuclear factor-kappa B (NF-κB), phosphorylated NF-κB, IkappaB-a (IκB-a), phosphorylated IκB-a, IKK, phosphorylated IKK, PI3Kp85, phosphorylated PI3Kp85, Akt and phosphorylated Akt were evaluated by western blotting. Treatment with rhSlit2 dramatically diminished the clinical scores of EIU, with significant decreases in inflammatory cell infiltration, protein concentrations, cellulose-like exudates, the production of ICAM-1, MCP-1, TNF-α and IL-6 in the AqH; and adhesion of leucocytes. The PI3K/Akt/IKK/NF-κB pathway was found to be activated in EIU. However, the pre-treatment of rhSlit2 significantly inhibited the production of ICAM-1, MCP-1, TNF-α, and IL-6, and inhibited leucocyte adhesion by modulating the PI3K/Akt/IKK/NF-κB pathway. In conclusion, the intravitreal injection of rhSlit2 alleviated EIU-related inflammation in Sprague-Dawley rats by reducing the proinflammatory cytokines and leucocyte adhesion; in particular, rhSlit2 may inhibit LPS-induced inflammation by inhibiting the activation of PI3K/Akt/IKK/NF-κB signalling pathway. Therefore, rhSlit2 shows significant potential for effectively alleviating immune inflammatory responses in vivo.

First-in-human imaging using [11C]MDTC: a radiotracer targeting the cannabinoid receptor type 2.

PURPOSE: We report findings from the first-in-human study of [11C]MDTC, a radiotracer developed to image the cannabinoid receptor type 2 (CB2R) with positron emission tomography (PET). METHODS: Ten healthy adults were imaged according to a 90-min dynamic PET protocol after bolus intravenous injection of [11C]MDTC. Five participants also completed a second [11C]MDTC PET scan to assess test-retest reproducibility of receptor-binding outcomes. The kinetic behavior of [11C]MDTC in human brain was evaluated using tissue compartmental modeling. Four additional healthy adults completed whole-body [11C]MDTC PET/CT to calculate organ doses and the whole-body effective dose. RESULTS: [11C]MDTC brain PET and [11C]MDTC whole-body PET/CT was well-tolerated. A murine study found evidence of brain-penetrant radiometabolites. The model of choice for fitting the time activity curves (TACs) across brain regions of interest was a three-tissue compartment model that includes a separate input function and compartment for the brain-penetrant metabolites. Regional distribution volume (VT) values were low, indicating low CB2R expression in the brain. Test-retest reliability of VT demonstrated a mean absolute variability of 9.91%. The measured effective dose of [11C]MDTC was 5.29 µSv/MBq. CONCLUSION: These data demonstrate the safety and pharmacokinetic behavior of [11C]MDTC with PET in healthy human brain. Future studies identifying radiometabolites of [11C]MDTC are recommended before applying [11C]MDTC PET to assess the high expression of the CB2R by activated microglia in human brain.

[18F]FNDP PET neuroimaging test-retest repeatability and whole-body dosimetry in humans.

PURPOSE: Soluble epoxide hydrolase (sEH) is an enzyme that shapes immune signaling through its role in maintaining the homeostasis of polyunsaturated fatty acids and their related byproducts. [18F]FNDP is a radiotracer developed for use with positron emission tomography (PET) to image sEH, which has been applied to imaging sEH in the brains of healthy individuals. Here, we report the test-retest repeatability of [18F]FNDP brain PET binding and [18F]FNDP whole-body dosimetry in healthy individuals. METHODS: Seven healthy adults (4 men, 3 women, ages 40.1 ± 4.6 years) completed [18F]FNDP brain PET on two occasions within a period of 14 days in a test-retest study design. [18F]FNDP regional total distribution volume (VT) values were derived from modeling time-activity data with a metabolite-corrected arterial input function. Test-retest variability, mean absolute deviation, and intraclass correlation coefficient (ICC) were investigated. Six other healthy adults (3 men, 3 women, ages 46.0 ± 7.0 years) underwent [18F]FNDP PET/CT for whole-body dosimetry, which was acquired over 4.5 h, starting immediately after radiotracer administration. Organ-absorbed doses and the effective dose were then estimated. RESULTS: The mean test-retest difference in regional VT (ΔVT) was 0.82 ± 5.17%. The mean absolute difference in regional VT was 4.01 ± 3.33%. The ICC across different brain regions ranged from 0.92 to 0.99. The organs with the greatest radiation-absorbed doses included the gallbladder (0.081 ± 0.024 mSv/MBq), followed by liver (0.077 ± 0.018 mSv/MBq) and kidneys (0.063 ± 0.006 mSv/MBq). The effective dose was 0.020 ± 0.003 mSv/MBq. CONCLUSION: These data support a favorable test-retest repeatability of [18F]FNDP brain PET regional VT. The radiation dose to humans from each [18F]FNDP PET scan is similar to that of other 18F-based PET radiotracers.

Nanodrug Delivery Strategies to Signaling Pathways in Alopecia.

Over 50% of the global population suffers from hair loss. The mixed results in the treatment of hair loss reveal the limitations of conventional commercial topical drugs. One the one hand, the definite pathogenesis of hair loss is still an enigma. On the other hand, targeted drug carriers ensure the drug therapeutic effect and low side effects. This review highlights the organization and overview of nine crucial signaling pathways associated with hair loss, as well as the development of nanobased topical delivery systems loading the clinical drugs, which will fuel emerging hair loss treatment strategies.