Solution for the External Contour Changes in Cone Beam Computed Tomography-Guided On-demand Online Adaptive Radiotherapy for a Patient With Very Advanced Head and Neck Cancer: A Technical Case Report.

This article presents a case of a patient with advanced head and neck cancer, characterized by a large and protruding tumor. The patient was treated with an innovative on-demand online adaptive radiotherapy (ART) technology, guided by cone beam computed tomography (CBCT), on the Ethos adaptive radiotherapy platform (version 1.0, Varian Medical Systems, Palo Alto, CA). A solution was provided for this special case to address the issue where part of the target volume could not participate in the optimization due to exceeding the external contour boundary during online adaptive radiotherapy. The treatment outcome was satisfactory in terms of tumor regression, while only grade 1 radiodermatitis and grade 2 oral mucositis at the end of radiotherapy. This article discusses the clinical diagnosis, treatment process, and follow-up of this case, aiming to provide clinical references for a broader application of this technology.

A Competition for the Diagnosis of Myopic Maculopathy by Artificial Intelligence Algorithms.

Importance: Myopic maculopathy (MM) is a major cause of vision impairment globally. Artificial intelligence (AI) and deep learning (DL) algorithms for detecting MM from fundus images could potentially improve diagnosis and assist screening in a variety of health care settings. Objectives: To evaluate DL algorithms for MM classification and segmentation and compare their performance with that of ophthalmologists. Design, Setting, and Participants: The Myopic Maculopathy Analysis Challenge (MMAC) was an international competition to develop automated solutions for 3 tasks: (1) MM classification, (2) segmentation of MM plus lesions, and (3) spherical equivalent (SE) prediction. Participants were provided 3 subdatasets containing 2306, 294, and 2003 fundus images, respectively, with which to build algorithms. A group of 5 ophthalmologists evaluated the same test sets for tasks 1 and 2 to ascertain performance. Results from model ensembles, which combined outcomes from multiple algorithms submitted by MMAC participants, were compared with each individual submitted algorithm. This study was conducted from March 1, 2023, to March 30, 2024, and data were analyzed from January 15, 2024, to March 30, 2024. Exposure: DL algorithms submitted as part of the MMAC competition or ophthalmologist interpretation. Main Outcomes and Measures: MM classification was evaluated by quadratic-weighted κ (QWK), F1 score, sensitivity, and specificity. MM plus lesions segmentation was evaluated by dice similarity coefficient (DSC), and SE prediction was evaluated by R2 and mean absolute error (MAE). Results: The 3 tasks were completed by 7, 4, and 4 teams, respectively. MM classification algorithms achieved a QWK range of 0.866 to 0.901, an F1 score range of 0.675 to 0.781, a sensitivity range of 0.667 to 0.778, and a specificity range of 0.931 to 0.945. MM plus lesions segmentation algorithms achieved a DSC range of 0.664 to 0.687 for lacquer cracks (LC), 0.579 to 0.673 for choroidal neovascularization, and 0.768 to 0.841 for Fuchs spot (FS). SE prediction algorithms achieved an R2 range of 0.791 to 0.874 and an MAE range of 0.708 to 0.943. Model ensemble results achieved the best performance compared to each submitted algorithms, and the model ensemble outperformed ophthalmologists at MM classification in sensitivity (0.801; 95% CI, 0.764-0.840 vs 0.727; 95% CI, 0.684-0.768; P = .006) and specificity (0.946; 95% CI, 0.939-0.954 vs 0.933; 95% CI, 0.925-0.941; P = .009), LC segmentation (DSC, 0.698; 95% CI, 0.649-0.745 vs DSC, 0.570; 95% CI, 0.515-0.625; P < .001), and FS segmentation (DSC, 0.863; 95% CI, 0.831-0.888 vs DSC, 0.790; 95% CI, 0.742-0.830; P < .001). Conclusions and Relevance: In this diagnostic study, 15 AI models for MM classification and segmentation on a public dataset made available for the MMAC competition were validated and evaluated, with some models achieving better diagnostic performance than ophthalmologists.

Quickly diagnosing Bietti crystalline dystrophy with deep learning.

Bietti crystalline dystrophy (BCD) is an autosomal recessive inherited retinal disease (IRD) and its early precise diagnosis is much challenging. This study aims to diagnose BCD and classify the clinical stage based on ultra-wide-field (UWF) color fundus photographs (CFPs) via deep learning (DL). All CFPs were labeled as BCD, retinitis pigmentosa (RP) or normal, and the BCD patients were further divided into three stages. DL models ResNeXt, Wide ResNet, and ResNeSt were developed, and model performance was evaluated using accuracy and confusion matrix. Then the diagnostic interpretability was verified by the heatmaps. The models achieved good classification results. Our study established the largest BCD database of Chinese population. We developed a quick diagnosing method for BCD and evaluated the potential efficacy of an automatic diagnosis and grading DL algorithm based on UWF fundus photography in a Chinese cohort of BCD patients.

The actin cytoskeleton is important for pseudorabies virus infection.

Viruses are dependent on the host factors for their replication and survival. Therefore, identification of host factors that druggable for antiviral development is crucial. The actin cytoskeleton plays an important role in the virus infection. The dynamics change of actin and its function are regulated by multiple actin-associated proteins (AAPs). However, the role and mechanism of various AAPs in the life cycle of virus are still enigmatic. In this study, we analyzed the roles of actin and AAPs in the replication of pseudorabies virus (PRV). Using a library of compounds targeting AAPs, our data found that multiple AAPs, such as Rho-GTPases, Rock, Myosin and Formin were involved in PRV infection. Besides, our result demonstrated that the actin-binding protein Drebrin was also participated in PRV infection. Further studies are necessary to elucidate the molecular mechanism of AAPs in the virus life cycle, in the hope of mining host factors for antiviral developments.

Dosimetric comparison of ZAP-X, Gamma Knife, and CyberKnife stereotactic radiosurgery for single brain metastasis.

PURPOSE: To evaluate the dosimetric characteristics of ZAP-X stereotactic radiosurgery (SRS) for single brain metastasis by comparing with two mature SRS platforms. METHODS: Thirteen patients with single brain metastasis treated with CyberKnife (CK) G4 were selected retrospectively. The prescription dose for the planning target volume (PTV) was 18-24 Gy for 1-3 fractions. The PTV volume ranged from 0.44 to 11.52 cc.Treatment plans of thirteen patients were replanned using the ZAP-X plan system and the Gamma Knife (GK) ICON plan system with the same prescription dose and organs at risk (OARs) constraints. The prescription dose of PTV was normalized to 70% for both ZAP-X and CK, while it was 50% for GK. The dosimetric parameters of three groups included the plan characteristics (CI, GI, GSI, beams, MUs, treatment time), PTV (D2, D95, D98, Dmin, Dmean, Coverage), brain tissue (volume of 100%-10% prescription dose irradiation V100%-V10%, Dmean) and other OARs (Dmax, Dmean),all of these were compared and evaluated. All data were read and analyzed with MIM Maestro. One-way ANOVA or a multisample Friedman rank sum test was performed, where p < 0.05 indicated significant differences. RESULTS: The CI of GK was significantly lower than that of ZAP-X and CK. Regarding the mean value, ZAP-X had a lower GI and higher GSI, but there was no significant difference among the three groups. The MUs of ZAP-X were significantly lower than those of CK, and the mean value of the treatment time of ZAP-X was significantly shorter than that of CK. For PTV, the D95, D98, and target coverage of CK were higher, while the mean of Dmin of GK was significantly lower than that of CK and ZAP-X. For brain tissue, ZAP-X showed a smaller volume from V100% to V20%; the statistical results of V60% and V50% showed a difference between ZAP-X and GK, while the V40% and V30% showed a significant difference between ZAP-X and the other two groups; V10% and Dmean indicated that GK was better. Excluding the Dmax of the brainstem, right optic nerve and optic chiasm, the mean value of all other OARs was less than 1 Gy. For the brainstem, GK and ZAP-X had better protection, especially at the maximum dose. CONCLUSION: For the SRS treating single brain metastasis, all three treatment devices, ZAP-X system, CyberKnife G4 system, and GammaKnife system, could meet clinical treatment requirements. The newly platform ZAP-X could provide a high-quality plan equivalent to or even better than CyberKnife and Gamma Knife, with ZAP-X presenting a certain dose advantage, especially with a more conformal dose distribution and better protection for brain tissue. As the ZAP-X systems get continuous improvements and upgrades, they may become a new SRS platform for the treatment of brain metastasis.

Biodegradable Persistent Luminescence Nanoparticles as Pyroptosis Inducer for High-Efficiency Tumor Immunotherapy.

Pyroptosis possesses potent antitumor immune activity, making pyroptosis inducer development a promising direction for tumor immunotherapy. Persistent luminescence nanoparticles (PLNPs) are highly sensitive optical probes extensively employed in tumor diagnosis and therapy. However, a pyroptosis inducer based on PLNPs has not been reported yet. Herein, polyethylene glycol-poly lactic acid-co-glycolic acid (PEG-PLGA: PP) modified biodegradable CaS:Eu2+ (CSE@PP) PLNPs are synthesized as a pyroptosis inducer for tumor immunotherapy for the first time. The synthesized CSE@PP possesses biowindow persistent luminescence (PersL) and pH-responsive degradation properties, allowing it to remain stable under neutral pH but degrade when exposed to weak acid (pH < 6.5). During degradation within the tumor, CSE@PP constantly releases H2S and Ca2+ while its PersL gradually fades away. Thus, the PersL signal can self-monitor H2S and Ca2+ release. Furthermore, the released H2S and Ca2+ result in mitochondrial dysfunction and the inactivation of reactive oxygen species scavenging enzymes, synergistic facilitating intracellular oxidative stress, which induces caspase-1/GSDM-D dependent pyroptosis and subsequent antitumor immune responses. In a word, it is confirmed that CSE@PP can self-monitor H2S and Ca2+ release and pyroptosis-mediated tumor Immunotherapy. This work will facilitate biomedical applications of PLNPs and inspire pyroptosis-induced tumor immunotherapy.

Coverage Analysis for High-Speed Railway Communications with Narrow-Strip-Shaped Cells over Suzuki Fading Channels.

Unlike circular cell coverage in public land mobile communications, narrow-strip-shaped cell coverage should be considered in high-speed railway (HSR) communications. Moreover, for the coverage analysis in HSR communications, most works ignore the effect of small-scale fading, which results in an inaccurate coverage performance evaluation. In this paper, we focus on the coverage analysis for HSR communications with narrow-strip-shaped cells over the Suzuki fading channel, where the composite channel fading includes path loss, lognormal shadowing, and Rayleigh-distributed small-scale fading. Based on the channel model, we first analyze the statistical characteristic of the received signal-to-noise ratio. Then, we derive analytical expressions of the edge coverage probability (ECP) and the percentage of cell coverage area (CCA). To link the edge coverage performance and the average coverage performance of a cell, we express the percentage of CCA as a summation of the ECP and a positive increment. As special cases, we also obtain the coverage performance expressions for the systems without small-scale fading. Through Monte Carlo simulations, the accuracy of the derived expressions is verified. Numerical results also show that the small-scale fading has a strong effect on coverage performance and cannot be ignored. In addition, the effects of key parameters are also discussed.

Effect of Humanin and MOTS-c on ameliorating reproductive damage induced by prepubertal cyclophosphamide chemotherapy in male mice.

Male patients who undergo prepubertal chemotherapy face the dual problems of fertility preservation in adulthood, including low testosterone, hypersexual function, and infertility. Humanin, as a small polypeptide coded within the mitochondrial DNA, with the mitochondrial short open reading frame named MOTS-c, both was believed to regulate mitochondrial homeostasis, be anti-inflammatory, improve metabolism, anti-apoptosis, and multiple pharmacological effects. However, there exists little evidence that reported Humanin and MOTS-c 's effects on moderating male spermatogenic function of patients after prepubertal chemotherapy. Here, we found that in vivo, mitochondrial polypeptides Humanin analog (HNG) and MOTS-c efficaciously protected the testicular spermatogenic function from reproductive injury. Moreover, transcriptomic sequencing analysis was performed to verify the differentially expressed genes such as Piwil2, AGT (angiotensinogen), and PTGDS (glycoprotein prostaglandin D2 synthase), which are related to the regulation of male reproductive function of male mice induced by prepubertal chemotherapy. Collectively, our data revealed that both Humanin analogs HNG and MOTS-c are the feasible approaches attached to the protective effect on the male reproductive function damaged by prepubertal chemotherapy.

Enhanced 3D dose prediction for hypofractionated SRS (gamma knife radiosurgery) in brain tumor using cascaded-deep-supervised convolutional neural network.

Gamma Knife radiosurgery (GKRS) is a well-established technique in radiation therapy (RT) for treating small-size brain tumors. It administers highly concentrated doses during each treatment fraction, with even minor dose errors posing a significant risk of causing severe damage to healthy tissues. It underscores the critical need for precise and meticulous precision in GKRS. However, the planning process for GKRS is complex and time-consuming, heavily reliant on the expertise of medical physicists. Incorporating deep learning approaches for GKRS dose prediction can reduce this dependency, improve planning efficiency and homogeneity, streamline clinical workflows, and reduce patient lagging times. Despite this, precise Gamma Knife plan dose distribution prediction using existing models remains a significant challenge. The complexity stems from the intricate nature of dose distributions, subtle contrasts in CT scans, and the interdependence of dosimetric metrics. To overcome these challenges, we have developed a "Cascaded-Deep-Supervised" Convolutional Neural Network (CDS-CNN) that employs a hybrid-weighted optimization scheme. Our innovative method incorporates multi-level deep supervision and a strategic sequential multi-network training approach. It enables the extraction of intra-slice and inter-slice features, leading to more realistic dose predictions with additional contextual information. CDS-CNN was trained and evaluated using data from 105 brain cancer patients who underwent GKRS treatment, with 85 cases used for training and 20 for testing. Quantitative assessments and statistical analyses demonstrated high consistency between the predicted dose distributions and the reference doses from the treatment planning system (TPS). The 3D overall gamma passing rates (GPRs) reached 97.15% ± 1.36% (3 mm/3%, 10% threshold), surpassing the previous best performance by 2.53% using the 3D Dense U-Net model. When evaluated against more stringent criteria (2 mm/3%, 10% threshold, and 1 mm/3%, 10% threshold), the overall GPRs still achieved 96.53% ± 1.08% and 95.03% ± 1.18%. Furthermore, the average target coverage (TC) was 98.33% ± 1.16%, dose selectivity (DS) was 0.57 ± 0.10, gradient index (GI) was 2.69 ± 0.30, and homogeneity index (HI) was 1.79 ± 0.09. Compared to the 3D Dense U-Net, CDS-CNN predictions demonstrated a 3.5% improvement in TC, and CDS-CNN's dose prediction yielded better outcomes than the 3D Dense U-Net across all evaluation criteria. The experimental results demonstrated that the proposed CDS-CNN model outperformed other models in predicting GKRS dose distributions, with predictions closely matching the TPS doses.

A Hybrid Handover Scheme for Vehicular VLC/RF Communication Networks.

Visible light communication (VLC) is a promising complementary technology to its radio frequency (RF) counterpart to satisfy the high quality-of-service (QoS) requirements of intelligent vehicular communications by reusing LED street lights. In this paper, a hybrid handover scheme for vehicular VLC/RF communication networks is proposed to balance QoS and handover costs by considering the vertical handover and horizontal handover together judging from the mobile state of the vehicle. A Markov decision process (MDP) is formulated to describe this hybrid handover problem, with a cost function balancing the handover consumption, delay, and reliability. A value iteration algorithm was applied to solve the optimal handover policy. The simulation results demonstrated the performance of the proposed hybrid handover scheme in comparison to other benchmark schemes.

Promoted oxygen adsorption on porous CeO2 cubes with abundant oxygen vacancies for efficient gaseous formaldehyde removal.

Photocatalytic degradation stands as a promising method for eliminating gas-phase pollutants, with the efficiency largely hinging on the capture of photogenerated electrons by oxygen. In this work, we synthesized a porous CeO2 single crystal cube with abundant oxygen vacancies as photocatalyst, employing urea as a pore-forming agent and for gas-phase formaldehyde degradation. Compared with the CeO2 cubes without pores, the porous ones were superior in specific surface area, akin to conventional CeO2 nanoparticles. The photocatalytic degradation for gas-phase formaldehyde on porous CeO2 cubes was significantly accelerated, of which degradation rate is 3.3 times and 2.1 times that of CeO2 cubes without pores and CeO2 nanoparticles, respectively. Photoelectric tests and DFT calculations revealed that this enhancement stemmed from facilitated oxygen adsorption due to pronounced oxygen vacancies. Consequently, the capture of photoelectrons by oxygen was promoted and its recombination with holes was suppressed, along with an accelerated generation of curial free radicals such as ·OH. This work reveals the pivotal role of surface oxygen vacancies in promoting adsorbed oxygen, proposing a viable strategy to enhance the photocatalytic degradation efficiency for gas-phase pollutants.

X-ray activated near-infrared persistent luminescence nanoparticles for trimodality in vivo imaging.

As promising luminescence nanoparticles, near-infrared (NIR) persistent luminescence nanoparticles (PLNPs) have received extensive attention in the field of high-sensitivity bioimaging in recent years. However, NIR PLNPs face problems such as short excitation wavelengths and single imaging modes, which limit their applications in in vivo reactivated imaging and multimodal imaging. Here, we report for the first time novel Gd2GaTaO7:Cr3+,Yb3+ (GGTO) NIR PLNPs that integrate X-ray activated NIR persistent luminescence (PersL), high X-ray attenuation and excellent magnetic properties into a single nanoparticle (NP). In this case, Cr3+ is used as the luminescence center. The co-doped Yb3+ and coating effectively enhance the X-ray activated NIR PersL. At the same time, the presence of the high-Z element Ta also makes the GGTO NPs exhibit high X-ray attenuation performance, which can be used as a CT contrast agent to achieve in vivo CT imaging. In addition, since the matrix contains a large amount of Gd, the GGTO NPs show remarkable magnetic properties, which can realize in vivo MR imaging. GGTO NPs combine the trimodal benefits of X-ray reactivated PersL, CT and MR imaging and are suitable for single or combined applications that require high sensitivity and spatial resolution imaging.

Borneol acts as an adjuvant agent to enhance the oral absorption of Panax notoginseng saponins in rats: Effect of optical configuration and compatibility ratios.

ETHNOPHARMACOLOGICAL RELEVANCE: Panax notoginseng saponins (PNS), as the main active component of Panax notoginseng, shows broad pharmacological effects but with low oral bioavailability. Borneol (BO) is commonly used as an adjuvant drug in the field of traditional Chinese medicine, which has been proven to facilitate the absorption of ginsenosides such as Rg1 and Rb1 in vivo. The presence of chiral carbons has resulted in three optical isomers of BO commercially available in the market, all of which are documented by national standards. AIM OF THE STUDY: This study aimed to investigate the role of BO in promoting the oral absorption of PNS from the perspective of optical configuration and compatibility ratios. MATERIALS AND METHODS: In this study, an ultra-performance liquid chromatography coupled with triple quadrupole-linear ion trap tandem mass spectrometry (UPLC-QTRAP-MS/MS) method was validated and applied to determine the concentrations of five main saponins in PNS in rat plasma. The kinetic characteristics of PNS were compared when co-administered with BO based on optical isomerism and different compatibility ratios. RESULTS: The results showed that BO promoted the exposure of PNS in rats. Three forms of BO, namely d-borneol (DB), l-borneol (LB), and synthetic borneol (SB), exhibited different promotion strengths. SB elevated PNS exposure in rats more than DB or LB. It is also interesting to note that under different compatibility ratios, SB can exert a strong promoting effect only when PNS and BO were combined in a 1:1 ratio (PNS 75 mg/kg; BO 75 mg/kg). As a pharmacokinetic booster, the dosage of BO is worthy of consideration and should follow the traditional medication principles of Chinese medicine. CONCLUSIONS: This study shed new light on the compatible use of PNS and BO from the perspective of "configuration-dose-influence" of BO. The results provide important basis for the clinical application and selection of BO.

Gene replacement therapy in Bietti crystalline corneoretinal dystrophy: an open-label, single-arm, exploratory trial.

Bietti crystalline corneoretinal dystrophy is an inherited retinal disease caused by mutations in CYP4V2, which results in blindness in the working-age population, and there is currently no available treatment. Here, we report the results of the first-in-human clinical trial (NCT04722107) of gene therapy for Bietti crystalline corneoretinal dystrophy, including 12 participants who were followed up for 180-365 days. This open-label, single-arm exploratory trial aimed to assess the safety and efficacy of a recombinant adeno-associated-virus-serotype-2/8 vector encoding the human CYP4V2 protein (rAAV2/8-hCYP4V2). Participants received a single unilateral subretinal injection of 7.5 × 1010 vector genomes of rAAV2/8-hCYP4V2. Overall, 73 treatment-emergent adverse events were reported, with the majority (98.6%) being of mild or moderate intensity and considered to be procedure- or corticosteroid-related; no treatment-related serious adverse events or local/systemic immune toxicities were observed. Compared with that measured at baseline, 77.8% of the treated eyes showed improvement in best-corrected visual acuity (BCVA) on day 180, with a mean ± standard deviation increase of 9.0 ± 10.8 letters in the 9 eyes analyzed (p = 0.021). By day 365, 80% of the treated eyes showed an increase in BCVA, with a mean increase of 11.0 ± 10.6 letters in the 5 eyes assessed (p = 0.125). Importantly, the patients' improvement observed using multifocal electroretinogram, microperimetry, and Visual Function Questionnaire-25 further supported the beneficial effects of the treatment. We conclude that the favorable safety profile and visual improvements identified in this trial encourage the continued development of rAAV2/8-hCYP4V2 (named ZVS101e).

Functional Green-Emitting Mn2+-doped Zinc Germanate Persistent Luminescent Nanoparticles for Dual-Mode Immunochromatographic Detection.

Immunochromatography is a commonly used immediate detection technique, using signal labels to generate detection signals for rapid medical diagnosis. However, its detection sensitivity is affected by background fluorescence caused by the excitation light source. We have developed an immunochromatographic test strip using Zn2GeO4:Mn2+ (ZGM) persistent luminescent nanoparticles (PLNPs) for immediate fluorescence detection and highly sensitive persistent luminescence (PersL) detection without background fluorescence interference. ZGM emits a strong green light when exposed to ultraviolet (UV) excitation, and its green PersL can persist for over 30 min after the excitation light is turned off. We modified the surface of ZGM with heparin-binding protein (HBP) antibodies to create immunochromatographic test strips for the detection of HBP as the target analyte. Under UV excitation, the chromatography test paper can be visually observed at concentrations as low as 25 ng/mL. After the excitation light source is switched off, PersL can achieve a detection limit of 4.7 ng/mL without background interference. This dual-mode immunochromatographic detection, based on ZGM, shows great potential for in vitro diagnostic applications.

[Phenotypic and genetic analysis of a Chinese pedigree affected with Hereditary antithrombin deficiency due to a novel variant of SERPINC1 gene].

OBJECTIVE: To analyze the clinical phenotype and genetic characteristics of a Chinese pedigree affected with Hereditary antithrombin deficiency. METHODS: A pedigree diagnosed at the the Second Affiliated Hospital of Wenzhou Medical University, Yuying Children's Hospital in June, 2020 was selected as the study subject. Plasma prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (FIB), and thrombin time (TT) of the probands and their pedigree members were determined using a STA-R automatic coagulation analyzer. Antithrombin activity (AT: A) and antithrombin antigen (AT: Ag) in plasma were determined with chromogenic substrate and immunonephelometry assays. All exons and flanking sequences of the anticoagulant protein gene SERPINC1 were amplified by PCR and subjected to Sanger sequencing. Candidate variants were verified with bioinformatic tools (PolyPhen-2, SIFT, Mutation Taster and PYMOL) to explore their effect on the function and structural conformation of the protein. RESULTS: The probands (II-2, II-10), their brother (II-5) and sons (III-1, III-8) had shown normal PT, APTT, FIB, and TT, but significantly decreased AT: A and AT: Ag, with their levels being 34%, 57%, 56%, 48%, 53% and 13.51 mg/dL, 13.44 mg/dL, 18.39 mg/dL, 17.36 mg/dL, 17.71 mg/dL, respectively. The remaining pedigree members had normal values. Sanger sequencing revealed that the probands and all affected pedigree members had harbored a heterozygous c.851T>C (p.Met284Thr) missense variant in exon 5 of the SERPINC1 gene. Bioinformatic analysis and simulation suggested that the variant has resulted in alteration of hydrogen bonds at the c.851 position, which may affect the structure of the protein. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was classified as pathogenic (PS1+PM1+PM5+PP1+PP4). CONCLUSION: The probands and other affected members were all diagnosed with type I hereditary AT deficiency, for which the c.851T>C (p.Met284Thr) variant of the SERPINC1 gene may be accountable.

Near-Infrared Persistent Luminescence Nanoprobe for Early Detection of Atherosclerotic Plaque.

Atherosclerosis (AS) is a crucial contributor to various cardiovascular diseases (CVDs), which seriously threaten human life and health. Early and accurate recognition of AS plaques is essential for the prevention and treatment of CVD. Herein, we introduce an AS-targeting nanoprobe based on near-infrared (NIR) persistent luminescence nanoparticles (PLNPs), developing a highly sensitive NIR persistent luminescence (PersL) AS plaque imaging technique and successfully realizing early AS plaque detection. The nanoprobe exhibits good monodispersity and regular spherical morphology and also owns exceptional NIR PersL performance upon repetitive irradiation by biological window light. The surface-conjugated antibody (anti-osteopontin) endowed nanoprobe excellent targeting ability to foam cells within plaques. After intravenously injected nanoprobe into AS model mice, the highly sensitive PersL imaging technique can accurately detect AS plaques prior to ultrasonography (US) and magnetic resonance imaging (MRI). Specifically, the NIR PersL imaging reveals AS plaques at the earliest within 2 weeks, with higher signal-to-background ratio (SBR) up to 5.72. Based on this technique, the nanoprobe has great potential for applications in the prevention and treatment of CVD, the study of AS pathogenesis, and the screening of anti-AS drugs.

Myeloid and lymphoid expression of C9orf72 regulates IL-17A signaling in mice.

A mutation in C9ORF72 is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Patients with ALS or FTD often develop autoimmunity and inflammation that precedes or coincides with the onset of neurological symptoms, but the underlying mechanisms are poorly understood. Here, we knocked out murine C9orf72 in seven hematopoietic progenitor compartments by conditional mutagenesis and found that myeloid lineage C9orf72 prevents splenomegaly, loss of tolerance, and premature mortality. Furthermore, we demonstrated that C9orf72 plays a role in lymphoid cells to prevent interleukin-17A (IL-17A) production and neutrophilia. Mass cytometry identified early and sustained elevation of the costimulatory molecule CD80 expressed on C9orf72-deficient mouse macrophages, monocytes, and microglia. Enrichment of CD80 was similarly observed in human spinal cord microglia from patients with C9ORF72-mediated ALS compared with non-ALS controls. Single-cell RNA sequencing of murine spinal cord, brain cortex, and spleen demonstrated coordinated induction of gene modules related to antigen processing and presentation and antiviral immunity in C9orf72-deficient endothelial cells, microglia, and macrophages. Mechanistically, C9ORF72 repressed the trafficking of CD80 to the cell surface in response to Toll-like receptor agonists, interferon-γ, and IL-17A. Deletion of Il17a in C9orf72-deficient mice prevented CD80 enrichment in the spinal cord, reduced neutrophilia, and reduced gut T helper type 17 cells. Last, systemic delivery of an IL-17A neutralizing antibody augmented motor performance and suppressed neuroinflammation in C9orf72-deficient mice. Altogether, we show that C9orf72 orchestrates myeloid costimulatory potency and provide support for IL-17A as a therapeutic target for neuroinflammation associated with ALS or FTD.