Evaluating neural crest cell migration in a Col4a1 mutant mouse model of ocular anterior segment dysgenesis.

The periocular mesenchyme (POM) is a transient migratory embryonic tissue derived from neural crest cells (NCCs) and paraxial mesoderm that gives rise to most of the structures in front of the eye. Morphogenetic defects of these structures can impair aqueous humor outflow, leading to elevated intraocular pressure and glaucoma. Mutations in collagen type IV alpha 1 (COL4A1) and alpha 2 (COL4A2) cause Gould syndrome - a multisystem disorder often characterized by variable cerebrovascular, ocular, renal, and neuromuscular manifestations. Approximately one-third of individuals with COL4A1 and COL4A2 mutations have ocular anterior segment dysgenesis (ASD), including congenital glaucoma resulting from abnormalities of POM-derived structures. POM differentiation has been a major focus of ASD research, but the underlying cellular mechanisms are still unclear. Moreover, earlier events including NCC migration and survival defects have been implicated in ASD; however, their roles are not as well understood. Vascular defects are among the most common consequences of COL4A1 and COL4A2 mutations and can influence NCC survival and migration. We therefore hypothesized that NCC migration might be impaired by COL4A1 and COL4A2 mutations. In this study, we used 3D confocal microscopy, gross morphology, and quantitative analyses to test NCC migration in Col4a1 mutant mice. We show that homozygous Col4a1 mutant embryos have severe embryonic growth retardation and lethality, and we identified a potential maternal effect on embryo development. Cerebrovascular defects in heterozygous Col4a1 mutant embryos were present as early as E9.0, showing abnormal cerebral vasculature plexus remodeling compared to controls. We detected abnormal NCC migration within the diencephalic stream and the POM in heterozygous Col4a1 mutants whereby mutant NCCs formed smaller diencephalic migratory streams and POMs. In these settings, migratory NCCs within the diencephalic stream and POM localize farther away from the developing vasculature. Our results show for the first time that Col4a1 mutations lead to cranial NCCs migratory defects in the context of early onset defective angiogenesis without affecting cell numbers, possibly impacting the relation between NCCs and the blood vessels during ASD development.

TGFß Signaling Dysregulation May Contribute to COL4A1-Related Glaucomatous Optic Nerve Damage.

Purpose: Mutations in the genes encoding type IV collagen alpha 1 (COL4A1) and alpha 2 (COL4A2) cause a multisystem disorder that includes ocular anterior segment dysgenesis (ASD) and glaucoma. We previously showed that transforming growth factor beta (TGFß) signaling was elevated in developing anterior segments from Col4a1 mutant mice and that reducing TGFß signaling ameliorated ASD, supporting a role for the TGFß pathway in disease pathogenesis. Here, we tested whether altered TGFß signaling also contributes to glaucoma-related phenotypes in Col4a1 mutant mice. Methods: To test the role of TGFß signaling in glaucoma-relevant phenotypes, we genetically reduced TGFß signaling using mice with mutated Tgfbr2, which encodes the common receptor for all TGFß ligands in Col4a1+/G1344D mice. We performed slit-lamp biomicroscopy and optical coherence tomography for qualitative and quantitative analyses of anterior and posterior ocular segments, histological analyses of ocular tissues and optic nerves, and intraocular pressure assessments using rebound tonometry. Results: Col4a1+/G1344D mice showed defects of the ocular drainage structures, including iridocorneal adhesions, and phenotypes consistent with glaucomatous neurodegeneration, including thinning of the nerve fiber layer, retinal ganglion cell loss, optic nerve head excavation, and optic nerve degeneration. We found that reducing TGFß receptor 2 (TGFBR2) was protective for ASD, ameliorated ocular drainage structure defects, and protected against glaucomatous neurodegeneration in Col4a1+/G1344D mice. Conclusions: Our results suggest that elevated TGFß signaling contributes to glaucomatous neurodegeneration in Col4a1 mutant mice.

Microphysiological systems inspired by leaf venation.

Nature-inspired microfluidic networks are revolutionizing microphysiological systems, allowing for the precise emulation of human physiology. This article delves into the fabrication techniques of leaf-venation-inspired (LVI) microfluidic networks and explores their transformative applications in organ-on-a-chip and tissue engineering, showcasing their pivotal role in advancing biomedical research.

Color-Tunable Organic Light-Emitting Diodes with Single Pt (O

Color-tunable organic light-emitting diodes (CT-OLEDs) have a large color-tuning range, high efficiency and operational stability at practical luminance, making them ideal for human-machine interactive terminals of wearable biomedical devices. However, the device operational lifetime of CT-OLEDs is currently far from reaching practical requirements. To address this problem, a tetradentate Pt(II) complex named tetra-Pt-dbf, which can emit efficiently in both monomer and aggregation states, is designed. This emitter has high Td of 508 °C and large intermolecular bonding energy of -52.0 kcal mol⁻1, which improve its thermal/chemical stability. This unique single-emitter CT-OLED essentially avoids the "color-aging issue" and achieves a large color-tuning span (red to yellowish green) and a high external quantum efficiency （EQE） of ≈30% at 1000 cd m-2 as well as an EQE of above 25% at 10000 cd m-2. A superior LT90 operational lifetime of 520,536 h at a functional luminance of 100 cd m-2, which is over 20 times longer than the state-of-the-art CT-OLEDs, is estimated. To demonstrate the potential application of such OLEDs in wearable biomedical devices, a simple electromyography (EMG)-visualization system is fabricated using the CT-OLEDs.

[Research progress in Astragali Radix and its active ingredients in treatment of lung cancer].

Lung cancer is the leading cause of cancer death, and its effective treatment is a difficult medical problem. Lung cancer belongs to the traditional Chinese medicine(TCM) disease categories of lung accumulation, lung amassment, and overstrain cough. Rich theoretical basis and practical experience have been accumulated in the TCM treatment of lung cancer. Astragali Radix is one of the representatives of Qi-tonifying drugs. It mainly treat the lung cancer with the syndrome of Qi deficiency and pathogen stagnation, following the principle of reinforcing healthy Qi and eliminating patgogenic Qi. Astragali Radix exerts a variety of pharmacological activities in the treatment of lung cancer, including inhibiting tumor cell proliferation and promoting tumor cell apoptosis, inhibiting tumor invasion and migration, regulating the tumor microenvironment, suppressing tumor angiogenesis, modulating autophagy, inducing macrophage polarization, enhancing immunity, inhibiting immune escape, and reversing cisplatin resistance. The active ingredients of Astragali Radix in treating lung cancer include polysaccharides, saponins, and flavonoids. This study reviewed the pharmacological activities and active ingredients of Astragali Radix in the treatment of lung cancer, providing a basis for the development and utilization of Astragali Radix resources and active ingredients and the research and development of anti-tumor drugs.

Non-invasive detection of lymphoma with circulating tumor DNA features and protein tumor markers.

Background: According to GLOBOCAN 2020, lymphoma ranked as the 9th most common cancer and the 12th leading cause of cancer-related deaths worldwide. Traditional diagnostic methods rely on the invasive excisional lymph node biopsy, which is an invasive approach with some limitations. Most lymphoma patients are diagnosed at an advanced stage since they are asymptomatic at the beginning, which has significantly impacted treatment efficacy and prognosis of the disease. Method: This study assessed the performance and utility of a newly developed blood-based assay (SeekInCare) for lymphoma early detection. SeekInCare utilized protein tumor markers and a comprehensive set of cancer-associated genomic features, including copy number aberration (CNA), fragment size (FS), end motif, and lymphoma-related virus, which were profiled by shallow WGS of cfDNA. Results: Protein marker CA125 could be used for lymphoma detection independent of gender, and the sensitivity was 27.8% at specificity of 98.0%. After integrating these multi-dimensional features, 77.8% sensitivity was achieved at specificity of 98.0%, while its NPV and PPV were both more than 92% for lymphoma detection. The sensitivity of early-stage (I-II) lymphoma was up to 51.3% (47.4% and 55.0% for stage I and II respectively). After 2 cycles of treatment, the molecular response of SeekInCare was correlated with the clinical outcome. Conclusion: In summary, a blood-based assay can be an alternative to detect lymphoma with adequate performance. This approach becomes particularly valuable in cases where obtaining tissue biopsy is difficult to obtain or inconclusive.

Prevalence and factors associated with dynapenia among middle-aged and elderly people in rural southern China.

To estimate the prevalence of dynapenia and examine potential risk factors for dynapenia using a sample of rural middle-aged and elderly Chinese. A cross-sectional study of 253 Chinese adults aged 50 years and older was conducted from June to August in 2022 in Nanjing. A questionnaire was used to collect data on all socioeconomic variables. Body weight, height, body fat percentage, grip strength, waist circumference, calf circumference, and gait speed were measured. The prevalence of dynapenia was 69.6 %, 62.3 % in men and 72.7 % in women respectively. Binary logistic regressions indicated significant associations between dynapenia and age (odds ratio [OR] = 2.59; 95 % confidence interval [CI] 1.63, 4.12; p < 0.001), educational level (OR = 0.55; 95 % CI 0.38, 0.80; p = 0.002). Dynapenia was prevalent among rural middle-aged and elderly people in southern China. Age and lower education level were both associated with dynapenia. Nutrition and physical activity should be strongly recommended as important strategies to maintain and improve muscle strength.

Tumor mutational burden as a predictive biomarker for non-small cell lung cancer treated with immune checkpoint inhibitors of PD-1/PD-L1.

BACKGROUND: The significant clinical benefits of PD-1/PD-L1 immune checkpoint inhibitors (ICIP) in non-small cell lung cancer (NSCLC) have been widely recognized, emphasizing the urgent need for a reliable biomarker. In this study, we find the remarkable capacity of tumor mutational burden (TMB) to serve as an accessible and streamlined indicator. PATIENTS AND METHODS: We designed a retrospective cohort study, consisting of 600 NSCLC patients treated with ICIP. Association between TMB and overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR) has been explored. RESULTS: A strong positive correlation between TMB levels and OS, PFS rates, clinical benefit has been found when TMB > = 16(TMB > = 16 mutations/megabase (mut/Mb)). However, when TMB < 16, increasing TMB values did not exhibit a gradual stepwise increase in OS and PFS rates. The median months of OS in the TMB > = 16 and < 16 are 35.58, and 10.71 months respectively with average 12.39 months (p < 0.0001). The median months of PFS in the TMB > = 16 and < 16 are not-obtained, and 2.79 months respectively with an average of 3.32 months (p < 0.0001). The DCR in the TMB > = 16 and < 16 are 71.4% and 44.2% respectively with an average of 47.7% (p < 0.0001). The ORR in the TMB > = 16 and < 16 are 49.4% and 20.8% respectively with an average of 24.5% (p < 0.0001). CONCLUSION: The TMB > = 16 shows significantly associated with optimal ICIP treatment outcomes, including higher patient survival rates, delayed disease progression, and significant clinical benefits. These results present the potential of TMB as a promising biomarker candidate for NSCLC patients undergoing ICIP treatment.

Heart-on-a-chip systems with tissue-specific functionalities for physiological, pathological, and pharmacological studies.

Recent advances in heart-on-a-chip systems hold great promise to facilitate cardiac physiological, pathological, and pharmacological studies. This review focuses on the development of heart-on-a-chip systems with tissue-specific functionalities. For one thing, the strategies for developing cardiac microtissues on heart-on-a-chip systems that closely mimic the structures and behaviors of the native heart are analyzed, including the imitation of cardiac structural and functional characteristics. For another, the development of techniques for real-time monitoring of biophysical and biochemical signals from cardiac microtissues on heart-on-a-chip systems is introduced, incorporating cardiac electrophysiological signals, contractile activity, and biomarkers. Furthermore, the applications of heart-on-a-chip systems in intelligent cardiac studies are discussed regarding physiological/pathological research and pharmacological assessment. Finally, the future development of heart-on-a-chip toward a higher level of systematization, integration, and maturation is proposed.

miR­3120/Hsc70 participates in forced swim stress­induced mechanical hyperalgesia in rats in an inflammatory state.

The heat shock cognate 71 kDa protein (Hsc70) is a stress­inducible ATPase that can protect cells against harmful stimuli. Transient receptor potential vanilloid 1 (TRPV1) is a well­documented nociceptor. Notably, Hsc70 can inhibit TRPV1 expression and function, suggesting that Hsc70 may have pain regulation potential. However, the role of Hsc70 in stress­induced hyperalgesia remains unclear. In the present study, the participation of Hsc70 and its regulator microRNA (miR)­3120 were investigated in forced swim (FS) stress­induced mechanical hyperalgesia in rats in an inflammatory state. Complete Freund's adjuvant (CFA) hind paw injection was performed to induce inflammatory pain in rats (CFA rats). Furthermore, in FS + CFA rats, FS stress was performed for 3 days before CFA injection. The levels of Hsc70, miR­3120 and their downstream molecule TRPV1 were measured in the dorsal root ganglion (DRG) with western blotting, immunofluorescence, reverse transcription­quantitative polymerase chain reaction and fluorescence in situ hybridization. The results revealed that FS stress significantly exacerbated CFA­induced mechanical pain. Furthermore, CFA upregulated Hsc70 and TRPV1 expression, which was partially inhibited or further enhanced by FS stress, respectively. In FS + CFA rats, intrathecal injection of a lentiviral vector overexpressing Hsc70 (LV­Hsc70) could decrease TRPV1 expression and improve the mechanical pain. Additionally, the expression levels of miR­3120, a regulator of Hsc70, were markedly upregulated on day 3 following FS stress. Finally, miR­3120 was identified to be colocalized with Hsc70 and expressed in all sizes of DRG neurons. In CFA rats, DRG injection of miR­3120 agomir to induce overexpression of miR­3120 resulted in similar TRPV1 expression and behavioral changes as those caused by FS stress, which were abolished in the presence of LV­Hsc70. These findings suggested that miR­3120/Hsc70 may participate in FS stress­induced mechanical hyperalgesia in rats in an inflammatory state, possibly via disinhibiting TRPV1 expression in the DRG neurons.

Application of whole-genome tiling array at Shanghai port, China: An alternative method for SARS-CoV-2 surveillance.

The ongoing coronavirus disease 2019 (COVID-19) pandemic, driven by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), highlights the critical role of genomic surveillance in tracking rapidly spreading viruses and their evolving lineages. The emergence of the SARS-CoV-2 tiling array, a comprehensive tool capable of capturing the entire viral genome, has presented a promising avenue for variants. This study introduces the SARS-CoV-2 tiling array as a novel method for port inspection. Using next-generation sequencing as a benchmark, 35 positive samples underwent sequencing through both methodologies, including the Alpha variant (B.1.1.7), Delta variants (AY.120, AY.122, AY.23.1), and Omicron variants (BA.1, BA.2, BA.2.75, BA.4, BA.5, BE.1, BF.7, BN.1, BQ.1, XBB.1) within the sample set. The whole-genome tiling array demonstrated successful identification of various sublineages of SARS-CoV-2. The average sequencing coverage rates were 99.22% (96.82%-99.92%) for the whole-genome tiling array and 98.56% (92.81%-99.59%) for Illumina sequencing, respectively. The match rates of these two methods ranged from 92.81%-99.59%, with an average rate of 98.56%. Among the benefits of the whole-genome tiling array are its cost-effectiveness and equipment simplification, making it particularly suitable for identifying SARS-CoV-2 variants in the front-line inspection department. The aforementioned findings provide valuable insights into the surveillance of COVID-19 and present a pragmatic solution for improving quarantine measures at entry points.

Circulating cell-free DNA fragmentation is a stepwise and conserved process linked to apoptosis.

BACKGROUND: Circulating cell-free DNA (cfDNA) is a pool of short DNA fragments mainly released from apoptotic hematopoietic cells. Nevertheless, the precise physiological process governing the DNA fragmentation and molecular profile of cfDNA remains obscure. To dissect the DNA fragmentation process, we use a human leukemia cell line HL60 undergoing apoptosis to analyze the size distribution of DNA fragments by shallow whole-genome sequencing (sWGS). Meanwhile, we also scrutinize the size profile of plasma cfDNA in 901 healthy human subjects and 38 dogs, as well as 438 patients with six common cancer types by sWGS. RESULTS: Distinct size distribution profiles were observed in the HL60 cell pellet and supernatant, suggesting fragmentation is a stepwise process. Meanwhile, C-end preference was seen in both intracellular and extracellular cfDNA fragments. Moreover, the cfDNA profiles are characteristic and conserved across mammals. Compared with healthy subjects, distinct cfDNA profiles with a higher proportion of short fragments and lower C-end preference were found in cancer patients. CONCLUSIONS: Our study provides new insight into fragmentomics of circulating cfDNA processing, which will be useful for early diagnosis of cancer and surveillance during cancer progression.

Ssa1-targeted antibody prevents host invasion by Candida albicans.

Introduction: Candida albicans is a commensal fungus that colonizes most healthy individuals' skin and mucosal surfaces but can also cause life-threatening invasive infections, particularly in immunocompromised patients. Despite antifungal treatment availability, drug resistance is increasing, and mortality rates remain unacceptably high. Heat shock protein Ssa1, a conserved member of the Hsp70 family in yeast, is a novel invasin that binds to host cell cadherins, induces host cell endocytosis, and enables C. albicans to cause maximal damage to host cells and induces disseminated and oropharyngeal disease. Result: Here we discovered a mouse monoclonal antibody (mAb 13F4) that targeting C. albicans Ssa1 with high affinity (EC50 = 39.78 ng/mL). mAb 13F4 prevented C. albicans from adhering to and invading human epithelial cells, displayed antifungal activity, and synergized with fluconazole in proof of concept in vivo studies. mAb 13F4 significantly prolonged the survival rate of the hematogenous disseminated candidiasis mice to 75%. We constructed a mAb 13F4 three-dimensional structure using homology modeling methods and found that the antigen-binding fragment (Fab) interacts with the Ssa1 N-terminus. Discussion: These results suggest that blocking Ssa1 cell surface function may effectively control invasive C. albicans infections and provide a potential new treatment strategy for invasive fungal infections.

Satellite glial cell-secreted exosomes after in-vitro oxaliplatin treatment presents a pro-nociceptive effect for dorsal root ganglion neurons and induce mechanical hypersensitivity in naïve mice.

BACKGROUND: The pathophysiological mechanism underlying chemotherapy-induced neuropathic pain (CINP) remains unclear. Sensory neuronal hypersensitivity in the dorsal root ganglion (DRG) is essential for the onset and maintenance of chronic pain. Satellite glial cells (SGCs) in the DRG potentially affect the function of sensory neurons, possibly by mediating extracellular or paracrine signaling. Exosomes play an essential role in cell-cell communication. However, the role of SGC-secreted exosomes in glia-neuron communication and CINP remains unclear. METHODS: SGCs and sensory neurons were cultured from the DRG of mice. The SGCs were treated with 4 µM oxaliplatin for 24 h. Glial fibrillary acid protein (GFAP) and connexin-43 (Cx-43) expressions in the SGCs were examined with immunocytochemistry (ICC). Enzyme-linked immunosorbent assay (ELISA) detected cytokine release in the SGCs after oxaliplatin treatment. Subsequently, SGC-secreted exosomes were collected using ultracentrifugation and identified by nanoparticle tracking analysis, transmission electron microscopy, and western blotting. Subsequently, DRG neurons were incubated with SGC-secreted exosomes for 24 h. The percentage of reactive oxygen species (ROS)-positive neurons was detected using flow cytometry, and acid-sensing ion channel 3 (ASIC3) and transient receptor potential vanilloid 1 (TRPV1) expression were examined by western blotting. SGC-secreted exosomes were intrathecally injected into naïve mice. The mechanical withdrawal threshold was assessed 24, 48, and 72 h following the injection. TRPV1 expression in the DRG was examined 72 h after intrathecal injection. Furthermore, differentially expressed (DE) miRNAs within the SGC-secreted exosomes were detected using RNA sequencing and bioinformatics analysis. Gene Ontology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG), and Reactome pathway analyses were performed to predict the function of the target genes of DE miRNAs. Finally, the DE miRNAs with pain regulation potential were identified in silico. RESULTS: After in-vitro oxaliplatin treatment, ICC showed an increase in the immunoreactivity of GFAP and Cx-43 in the SGCs. ELISA results suggested an increased release of tumor necrosis factor-α and interleukin (IL)-1ß, but a decreased release of IL-10. Oxaliplatin treatment increased the secretion of exosomes in the SGCs from 4.34 to 5.99 × 1011 (particles/ml). The exosome-specific markers CD9 and TSG101 were positive, whereas calnexin was negative for the obtained exosomes. Additionally, the SGC-secreted exosomes were endocytosed by DRG neurons after co-incubation. Moreover, after incubation with conditioned SGC-secreted exosomes (after 4 µM oxaliplatin treatment), the percentage of ROS-positive DRG neurons increased and ASIC3 and TRPV1 expressions were upregulated. After the intrathecal injection of the conditioned SGC-secreted exosomes, the mice presented with mechanical hypersensitivity and TRPV1 expression upregulation in the DRG. Notably, 25 and 120 significantly upregulated and downregulated miRNAs, respectively, were identified in the conditioned SGC-secreted exosomes. When predicting the function of target genes of DE miRNAs, certain GO terms, such as synapse organization, neurogenesis regulation, histone modification, and pain-related KEGG or Reactome pathways, including vascular endothelial growth factor A-vascular endothelial growth factor receptor 2, mammalian target of rapamycin, and mitogen-activated protein kinase signaling pathways, related to nervous system function were predicted. Finally, 27 pain regulation-related miRNAs, including miR-324-3p, miR-181a-5p, and miR-122-5p, were identified in silico. CONCLUSION: Our study demonstrates that SGC-secreted exosomes after in-vitro oxaliplatin treatment present a pro-nociceptive effect for DRG neurons and induce mechanical hypersensitivity in naïve mice, possibly via the contained miRNA cargo. Identifying the candidate miRNAs and verifying their functions in vivo are required to elucidate the exosomes mediating 'glia-neuron' communication under CINP condition.

Mechanism of Action for an All-in-One Monoclonal Antibody Against Staphylococcus aureus Infection.

Staphylococcus aureus is a major human pathogen associated with high mortality rates. The extensive use of antibiotics is associated with the rise of drug resistance, and exotoxins are not targeted by antibiotics. Therefore, monoclonal antibody (mAb) therapy has emerged as a promising solution to solve the clinical problems caused by refractory S aureus. Recent research suggests that the synergistic effects of several cytotoxins, including bicomponent toxins, are critical to the pathogenesis of S aureus. By comparing the amino acid sequences, researchers found that α-toxin and bicomponent toxins have high homology. Therefore, we aimed to screen an antibody, designated an all-in-one mAb, that could neutralize α-toxin and bicomponent toxins through hybridoma fusion. We found that this mAb has a significant pharmacodynamic effect within in vivo mouse models and in vitro experiments.

A panel of seven protein tumour markers for effective and affordable multi-cancer early detection by artificial intelligence: a large-scale and multicentre case-control study.

Background: Early detection of cancer aims to reduce cancer deaths. Unfortunately, many established cancer screening technologies are not suitable for use in low- and middle-income countries (LMICs) due to cost, complexity, and dependency on extensive medical infrastructure. We aimed to assess the performance and robustness of a protein assay (OncoSeek) for multi-cancer early detection (MCED) that is likely to be more practical in LMICs. Methods: This observational study comprises a retrospective analysis on the data generated from the routine clinical testings at SeekIn and Sun Yat-sen Memorial Hospital. 7565 participants (954 with cancer and 6611 without) from the two sites were divided into training and independent validation cohort. The second validation cohort (1005 with cancer and 812 without) was from Johns Hopkins University School of Medicine. Patients with cancer prior to therapy were eligible for inclusion in the study. Individuals with no history of cancer were enrolled from the participating sites as the non-cancer group. One tube of peripheral blood was collected from each participant and quantified a panel of seven selected protein tumour markers (PTMs) by a common clinical electrochemiluminescence immunoassay analyser. An algorithm named OncoSeek was established using artificial intelligence (AI) to distinguish patients with cancer from those without cancer by calculating the probability of cancer (POC) index based on the quantification results of the seven PTMs and clinical information including sex and age of the individuals and to predict the possible affected tissue of origin (TOO) for those who have been detected with cancer signals in blood. Findings: Between November 2012 and May 2022, 7565 participants were enrolled at SeekIn and Sun Yat-sen Memorial Hospital. The conventional clinical method, which relies only on a single threshold for each PTM, would suffer from a high false positive rate that accumulates as the number of markers increased. OncoSeek was empowered by AI technology to significantly reduce the false positive rate, increasing the specificity from 56.9% (95% confidence interval [CI]: 55.8-58.0) to 92.9% (92.3-93.5). In all cancer types, the overall sensitivity of OncoSeek was 51.7% (49.4-53.9), resulting in 84.3% (83.5-85.0) accuracy. The performance was generally consistent in the training and the two validation cohorts. The sensitivities ranged from 37.1% to 77.6% for the detection of the nine common cancer types (breast, colorectum, liver, lung, lymphoma, oesophagus, ovary, pancreas, and stomach), which account for ∼59.2% of global cancer deaths annually. Furthermore, it has shown excellent sensitivity in several high-mortality cancer types for which routine screening tests are lacking in the clinic, such as the sensitivity of pancreatic cancer which was 77.6% (69.3-84.6). The overall accuracy of TOO prediction in the true positives was 66.8%, which could assist the clinical diagnostic workup. Interpretation: OncoSeek significantly outperforms the conventional clinical method, representing a novel blood-based test for MCED which is non-invasive, easy, efficient, and robust. Moreover, the accuracy of TOO facilitates the follow-up diagnostic workup. Funding: The National Key Research and Development Programme of China.

[Analysis of the use status of internet outpatient in stomatological departments based on AI follow-up].

PURPOSE: To analyze the use status and satisfaction of the follow-up patients, and explore the construction of internet medical service model and platform in stomatology. METHODS: Patients who visited the internet clinic of stomatology from January to June, 2021 were selected. After diagnosis and treatment, they were followed up by AI intelligent voice with self-designed questionnaire. SPSS 21.0 software was used for statistical analysis. RESULTS: A total of 372 valid questionnaires were collected. The male-to-female ratio of oral patients was 1.25:1, with an average age of 35.96 years. Most of them had a bachelor's degree or above, and the patients were mainly from the Yangtze River Delta. 53.76% of patients needed doctors to prescribe drugs. 81.72% of the dental patients believed that the consultation process of internet clinic was convenient, and 79.83% of patients perceived that the system operation of internet clinic was convenient. Binary logistic regression showed that digital literacy, convenience of medical treatment process were significantly related to the satisfaction of internet outpatient service, while gender, education level, online medical treatment duration and convenience of system operation were not related. CONCLUSIONS: Internet medical treatment in stomatology is feasible, but it is still necessary to break through limitations and further innovate service function. Internet outpatients are mainly young and middle-aged, but it is still necessary to care for the special group of the elderly. It is necessary to further optimize the process, upgrade the system and innovate management, strengthen policy support and incentive mechanism, and promote the transformation of medical service mode in stomatology.

The effect of triethylamine on dye-sensitized upconversion luminescence and its application in nanoprobes and photostability.

Triethylamine (TEA) is an effective medium for inhibiting dye aggregation and improving the luminescence of dye-sensitized lanthanide-doped upconversion nanoparticles (UCNPs). However, excessive TEA will cause quenching of upconversion luminescence. In this paper, the possible mechanism of TEA affecting upconversion luminescence is discussed. It is found that TEA can enhance the nucleophilicity of the solvent, leading to dye shedding from the nanoparticles. Reducing the dielectric constant of the solvent can make TEA play a more positive role in upconversion luminescence and photostability of dye-sensitized UCNPs. When heptanol is selected as the solvent for CyBSO-sensitized ß-NaYF4:20%Yb3+,2%Er3+ (UNs), TEA can increase the upconversion luminescence by 6.0 times relative to that in methanol. More importantly, the optimal content of TEA in heptanol is 3700 times more than that in methanol. Under the action of large amounts of TEA in heptanol, a novel upconversion nanoprobe for detecting ascorbic acid is developed with a limit of detection of 0.103 µM and high selectivity over potential interfering species. Meanwhile, the high concentration of TEA in heptanol can improve the photostability of CyBSO-sensitized UNs by 10.4 times, which is of paramount importance for the practical application of dye-sensitized UCNPs.

Leaf-venation-directed cellular alignment for macroscale cardiac constructs with tissue-like functionalities.

Recapitulating the complex structural, mechanical, and electrophysiological properties of native myocardium is crucial to engineering functional cardiac tissues. Here, we report a leaf-venation-directed strategy that enables the compaction and remodeling of cell-hydrogel hybrids into highly aligned and densely packed organizations in predetermined patterns. This strategy contributes to interconnected tubular structures with cell alignment along the hierarchical channels. Compared to randomly-distributed cells, the engineered leaf-venation-directed-cardiac tissues from neonatal rat cardiomyocytes manifest advanced maturation and functionality as evidenced by detectable electrophysiological activity, macroscopically synchronous contractions, and upregulated maturation genes. As a demonstration, human induced pluripotent stem cell-derived leaf-venation-directed-cardiac tissues are engineered with evident structural and functional improvement over time. With the elastic scaffolds, leaf-venation-directed tissues are assembled into 3D centimeter-scale cardiac constructs with programmed mechanical properties, which can be delivered through tubing without affecting cell viability. The present strategy may generate cardiac constructs with multifaceted functionalities to meet clinical demands.

Elevated TGFß signaling contributes to cerebral small vessel disease in mouse models of Gould syndrome.

Cerebral small vessel disease (CSVD) is a leading cause of stroke and vascular cognitive impairment and dementia. Studying monogenic CSVD can reveal pathways that are dysregulated in common sporadic forms of the disease and may represent therapeutic targets. Mutations in collagen type IV alpha 1 (COL4A1) and alpha 2 (COL4A2) cause highly penetrant CSVD as part of a multisystem disorder referred to as Gould syndrome. COL4A1 and COL4A2 form heterotrimers [a1α1α2(IV)] that are fundamental constituents of basement membranes. However, their functions are poorly understood and the mechanism(s) by which COL4A1 and COL4A2 mutations cause CSVD are unknown. We used histological, molecular, genetic, pharmacological, and in vivo imaging approaches to characterize central nervous system (CNS) vascular pathologies in Col4a1 mutant mouse models of monogenic CSVD to provide insight into underlying pathogenic mechanisms. We describe developmental CNS angiogenesis abnormalities characterized by impaired retinal vascular outgrowth and patterning, increased numbers of mural cells with abnormal morphologies, altered contractile protein expression in vascular smooth muscle cells (VSMCs) and age-related loss of arteriolar VSMCs in Col4a1 mutant mice. Importantly, we identified elevated TGFß signaling as a pathogenic consequence of Col4a1 mutations and show that genetically suppressing TGFß signaling ameliorated CNS vascular pathologies, including partial rescue of retinal vascular patterning defects, prevention of VSMC loss, and significant reduction of intracerebral hemorrhages in Col4a1 mutant mice aged up to 8 months. This study identifies a novel biological role for collagen α1α1α2(IV) as a regulator of TGFß signaling and demonstrates that elevated TGFß signaling contributes to CNS vascular pathologies caused by Col4a1 mutations. Our findings suggest that pharmacologically suppressing TGFß signaling could reduce the severity of CSVD, and potentially other manifestations associated with Gould syndrome and have important translational implications that could extend to idiopathic forms of CSVD.