Since mid-December of 2019, coronavirus disease 2019 (COVID-19) has been spreading from Wuhan, China. The confirmed COVID-19 patients in South Korea are those who came from or visited China. As ...secondary transmissions have occurred and the speed of transmission is accelerating, there are rising concerns about community infections. The 54-year old male is the third patient diagnosed with COVID-19 in Korea. He is a worker for a clothing business and had mild respiratory symptoms and intermittent fever in the beginning of hospitalization, and pneumonia symptoms on chest computerized tomography scan on day 6 of admission. This patient caused one case of secondary transmission and three cases of tertiary transmission. Hereby, we report the clinical findings of the index patient who was the first to cause tertiary transmission outside China. Interestingly, after lopinavir/ritonavir (Kaletra, AbbVie) was administered, β-coronavirus viral loads significantly decreased and no or little coronavirus titers were observed.
Activation of YAP, a Hippo pathway effector, is an important resistance mechanism to BRAF inhibitor (BRAFi) in melanoma. Emerging evidence also suggests that YAP is involved in suppression of the ...antitumor immune response. However, the potential direct impact of YAP activity on cytotoxic T-cell immune responses has not been explored yet. Here, we show that BRAFi-resistant melanoma cells evade CD8
T-cell immune responses in a PD-L1-dependent manner by activating YAP, which synchronously supports melanoma cell survival upon BRAF inhibition. PD-L1 expression is elevated in BRAFi-resistant melanoma cells, in which YAP is robustly activated, and YAP knockdown decreases PD-L1 expression. In addition, constitutively active YAP (YAP-5SA) increases PD-L1 expression by binding to an upstream enhancer of the PD-L1 gene and potentiating its transcription. Both BRAFi-resistant and YAP-5SA-expressing melanoma cells suppress the cytotoxic function and cytokine production of Melan-A-specific CD8
T cells, whereas anti-PD-1 antibody reverses the YAP-mediated T-cell suppression. Moreover, nuclear enrichment of YAP in clinical melanoma samples correlates with increased PD-L1 expression. Our findings show that YAP directly mediates evasion of cytotoxic T-cell immune responses in BRAFi-resistant melanoma cells by upregulating PD-L1, and targeting of YAP-mediated immune evasion may improve prognosis of melanoma patients.
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Navigation of nanoparticles to target sites of blood flow disturbance markedly upgrades the diagnostic paradigm in vascular medicine. The theranostic treatment of pre‐stenotic vessels can prevent the ...irreversible occlusion process effectively. Here, these nanotheranostic functions are established by displaying CDK9(cyclin‐dependent kinase 9)‐targeting peptide (P.) onto nanovesicles (NV) and liposomes using the navigation function and subsequent binding‐on signaling of P. as a game‐changer. When rabbit vessels are allografted with injecting contrast‐loaded P. liposomes, the case‐dependent stenotic degree after 2–6 weeks can be diagnosed accurately within 2–4 days via computed tomography imaging with cross‐validation in a mouse model of partial carotid ligation. Furthermore, the anti‐CDK9 signaling of P. NV is activated post‐targeting and effectively prevents vascular stenosis by suppressing inflammation and lipotoxicity in the vessels, serum, and/or liver. CDK9 targeting is confirmed using computer, in vitro, and in vivo models. This study demonstrates an unprecedented nanotheranostic function for future clinical applications.
The disturbed flow‐sensing peptide plays a game‐changer role in guiding diagnosis and treatment of pre‐stenotic vessels as a theranostic navigator. Displaying the peptide on nanoparticles enables accurate prediction of vascular stenosis with subsequent prevention of vascular remodeling through multi‐organ targeting. The results from rabbit, mouse, and in vitro models validates an unprecedented nanotheranostic function for the future medicine.
We report a flexible hydrogen sensing platform based on a single-strand yarn consisting of high-density electrospun nanofibers, on which nanograined Pd or Pd@Pt is coated via yarn spinning followed ...by sputter deposition. In general, Pd undergoes a phase transition to PdH x (α-PdH x at H2 < 1% and β-PdH x at H2 > 2%), in which H atoms act as electron scattering centers, thus increasing the resistance. In our system, the sensors exhibit switchable H2 sensing behaviors, that is, (i) ΔR/R 0 > 0 at H2 > 1% by the active electron scattering and (ii) ΔR/R 0 < 0 at H2 < 1% derived from nanograined Pd effects. Due to high mechanical stability stemming from nanogranular morphologies of Pd, which is essential for enduring a huge volume expansion upon exposure to high-concentration H2, we could obtain a wide concentration range (4–0.0001%) H2 detection resolution. Moreover, an ultrathin Pt overlayer coated on Pd offers an accelerated H2 detection capability based on effective gas dissociation and activation properties. Furthermore, by virtue of the core (thread)–shell (nanofiber yarn) scaffold, long cycling reliability and flexibility were achieved. This facile and low-cost yarn fabrication method offers the development of single-strand thread-type wearable chemiresistors that possess a high surface area and open porosity, facilitating gas diffusion and reaction.
This study investigates the unsteady aerodynamic characteristics of the cambered wings of a flapping-wing micro air vehicle (FW-MAV) in hover. A three-dimensional fluid–structure interaction solver ...is developed for a realistic modeling of large-deforming wing structure and geometry. Cross-validation is conducted against the experimental results obtained also in the present study to establish more accurate analyses of cambered wings. An investigation is carried out on the unsteady vortex structures around the wings caused by the passive twisting motion. A parametric study is then conducted to evaluate the aerodynamic performance with respect to the camber angle at three different flapping frequencies including normal operating conditions. The camber angles producing the largest thrust and highest propulsive efficiency are estimated at each flapping frequency, and their effects on aerodynamic performance are analyzed in terms of the stroke phase. The timing and magnitude of the passive twisting motion, which are dependent on the camber angle at the operating frequency, greatly affects the unsteady vortex structure. Consequently, the camber angle designed at the operating frequency plays a key role in enhancing the aerodynamic performance of FW-MAVs.
Hydrogen sulfide has emerged as an exciting endogenous gasotransmitter in addition to nitric oxide and carbon dioxide. Noninvasive detection methods for hydrogen sulfide thus become indispensable ...tools for studying its diverse roles in biological systems. Accordingly, fluorescent probes for hydrogen sulfide have received great attention in recent years. A practically useful fluorescent probe for bioimaging of hydrogen sulfide should be selective, sensitive, fast-responsive, biocompatible, observable in the biological optical window, and capable of deep-tissue imaging. These sensing properties, however, are extremely difficult to achieve at the same time. Disclosed here is the two-photon fluorescent probe that meets all of these criteria. The probe belongs to a Michael acceptor system, which raised a serious selectivity issue over the competing biothiols such as cysteine and glutathione. We have addressed the selectivity issue by optimizing the electronic and steric interactions between biothiols and the probe, in addition to achieving very high sensitivity, fast-response, and biocompatibility. Also, the sensing mechanism suggested in the literature was revised. The probe thus enables us to image the endogenously produced hydrogen sulfide with negligible interference from other biothiols in live cells. The excellent sensing properties of the probe combined with its capability of bioimaging thus make it a practically useful tool for further studying biological roles of hydrogen sulfide.
Background
Islet transplantation is an effective therapy for selected patients with type 1 diabetes with labile glycemic control and hypoglycemic unawareness, but donor organs are limited. Islet ...xenotransplantation using porcine islets will potentially solve this problem. Although successful proof of concept studies using clinically inapplicable anti‐CD154 monoclonal antibody (mAb) in pig‐to‐non‐human primate (NHP) islet xenotransplantation has been demonstrated by several groups worldwide, potentially clinically applicable anti‐CD40 (2C10R4) mAb‐based studies have not been reported.
Methods
Nine streptozotocin (STZ)‐induced diabetic rhesus monkeys were transplanted with adult porcine islets isolated from designated pathogen‐free (DPF) miniature pigs. They were treated with anti‐CD40 mAb‐based immunosuppressive regimen and were divided into 3 groups: anti‐CD40 only group (n = 2), belatacept group (anti‐CD40 mAb+belatacept, n = 2), and tacrolimus group (anti‐CD40 mAb+tacrolimus, n = 5). All monkeys received anti‐thymocyte globulin (ATG), cobra venom factor (CVF), adalimumab, and sirolimus. Blood glucose levels (BGL) and serum porcine C‐peptide concentrations were measured. Humoral and cellular immune responses were assessed by ELISA and ELISPOT, respectively. Liver biopsy and subsequent immunohistochemistry were conducted.
Results
All animals restored normoglycemia immediately after porcine islet transplantation and finished the follow‐up without any severe adverse effects except for one animal (R092). Most animals maintained their body weight. Median survival, as defined by a serum porcine C‐peptide concentration of >0.15 ng/mL, was 31, 27, and 60 days for anti‐CD40 only, belatacept, and tacrolimus groups, respectively. Anti‐αGal IgG levels in serum and the number of interferon‐γ secreting T cells in peripheral blood mononuclear cells did not increase in most animals.
Conclusion
These results showed that anti‐CD40 mAb combined with tacrolimus was effective in prolonging porcine islet graft survival, but anti‐CD40 mAb was not as effective as anti‐CD154 mAb in terms of preventing early islet loss.
During cancer immunoediting, loss of major histocompatibility complex class I (MHC-I) in neoplasm contributes to the evasion of tumours from host immune system. Recent studies have demonstrated that ...most natural killer (NK) cells that are found in advanced cancers are defective, releasing the malignant MHC-I-deficient tumours from NK-cell-dependent immune control. Here, we show that a natural killer T (NKT)-cell-ligand-loaded tumour-antigen expressing antigen-presenting cell (APC)-based vaccine effectively eradicates these advanced tumours. During this process, we find that the co-expression of Tim-3 and PD-1 marks functionally exhausted NK cells in advanced tumours and that MHC-I downregulation in tumours is closely associated with the induction of NK-cell exhaustion in both tumour-bearing mice and cancer patients. Furthermore, the recovery of NK-cell function by IL-21 is critical for the anti-tumour effects of the vaccine against advanced tumours. These results reveal the process involved in the induction of NK-cell dysfunction in advanced cancers and provide a guidance for the development of strategies for cancer immunotherapy.
Among colorectal cancers (CRCs), high-frequency microsatellite instability (MSI-H) is associated with a better prognosis, compared with low-frequency MSI or microsatellite stability (MSI-L/MSS). ...However, it is unclear whether MSI affects the prognosis of recurrent CRCs.
This study included 2940 patients with stage I-III CRC who underwent complete resection. The associations of MSI status with recurrence patterns, disease-free survival (DFS), overall survival from diagnosis to death (OS1), and overall survival from recurrence to death (OS2) were analysed.
A total of 261 patients (8.9%) had MSI-H CRC. Patients with MSI-H CRC had better DFS, compared to patients with MSI-L/MSS CRC (hazard ratio (HR): 0.619, P<0.001). High-frequency microsatellite instability CRC was associated with more frequent local recurrence (30.0% vs 12.0%, P=0.032) or peritoneal metastasis (40.0% vs 12.3%, P=0.003), and less frequent lung (10.0% vs 42.5%, P=0.004) or liver metastases (15.0% vs 44.7%, P=0.01). Recurrent MSI-H CRC was associated with worse OS1 (HR: 1.363, P=0.035) and OS2 (HR: 2.667, P<0.001). An analysis of patients with colon cancer yielded similar results.
Recurrence patterns differed between MSI-H CRC and MSI-L/MSS CRC, and recurrent MSI-H CRCs had a worse prognosis.
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