This paper presents a mixed-signal ASIC for triple-chamber pacemakers. The ASIC performs four major functionalities: 1) sensing of heartbeat signals; 2) measuring the heart resistance of three chambers independently to diagnose the attachment status of the electrodes and provide additional information about the pathological status of the patient's heart; 3) generating stimulus pulses with programmable magnitude and pulse width; 4) receiving commands and configuration data from MCU, and transferring register data to MCU through the SPI interface. The ASIC is fabricated in a 0.35-μm BCD technology with a chip area of 3.8×3.8 mm2. Measurement results show that the magnitude of the stimulus pulses can be programmed from 0. 1 to 7.4 V with 0.1-V step. Almost linear heart resistance measuring is achieved in the resistance range of 250 to 4000 Q. Average current consumption is 4 μA from a 2.8-V supply.
The value of radiomics features from the adrenal gland and periadrenal fat CT images for predicting disease progression in patients with COVID-19 has not been studied extensively. We assess the value of radiomics features from the adrenal gland and periadrenal fat CT images in predicting COVID-19 disease exacerbation.A total of 1,245 patients (685 moderate and 560 severe patients) were enrolled in a retrospective study. We proposed a 3D V-net to segment adrenal glands in onset CT images automatically, and periadrenal fat was obtained using inflation operation around the adrenal gland. Next, we built a clinical model (CM), three radiomics models (adrenal gland model [AM], periadrenal fat model [PM], and fusion of adrenal gland and periadrenal fat model [FM]), and radiomics nomogram (RN) after radiomics features extracted.The auto-segmentation framework yielded a dice value 0.79 in the training set. CM, AM, PM, FM, and RN obtained AUCs of 0.717, 0.716, 0.736, 0.760, and 0.833 in the validation set. FM and RN had better predictive efficacy than CM (P < 0.0001) in the training set. RN showed that there was no significant difference in the validation set (mean absolute error [MAE] = 0.04) and test set (MAE = 0.075) between predictive and actual results. Decision curve analysis showed that if the threshold probability was between 0.4 and 0.8 in the validation set or between 0.3 and 0.7 in the test set, it could gain more net benefits using RN than FM and CM.Radiomics features extracted from the adrenal gland and periadrenal fat CT images are related to disease exacerbation in patients with COVID-19.
There is a lack of an HSV-2 vaccine, in part as the result of various factors that limit robust and long-term memory immune responses at the mucosal portals of viral entry. We previously demonstrated that chemokine CCL19 augmented mucosal and systemic immune responses to HIV-1 envelope glycoprotein. Whether such enhanced immunity can protect animals against virus infection remains to be addressed. We hypothesized that using CCL19 in a fusion form to direct an immunogen to responsive immunocytes might have an advantage over CCL19 being used in combination with an immunogen. We designed two fusion constructs, plasmid (p)gBIZCCL19 and pCCL19IZgB, by fusing CCL19 to the C- or N-terminal end of the extracellular HSV-2 glycoprotein B (gB) with a linker containing two (Gly4Ser)2 repeats and a GCN4-based isoleucine zipper motif for self-oligomerization. Following immunization in mice, pgBIZCCL19 and pCCL19IZgB induced strong gB-specific IgG and IgA in sera and vaginal fluids. The enhanced systemic and mucosal Abs showed increased neutralizing activity against HSV-2 in vitro. Measurement of gB-specific cytokines demonstrated that gB-CCL19 fusion constructs induced balanced Th1 and Th2 cellular immune responses. Moreover, mice vaccinated with fusion constructs were well protected from intravaginal lethal challenge with HSV-2. Compared with pgB and pCCL19 coimmunization, fusion constructs increased mucosal surface IgA(+) cells, as well as CCL19-responsive immunocytes in spleen and mesenteric lymph nodes. Our findings indicate that enhanced humoral and cellular immune responses can be achieved by immunization with an immunogen fused to a chemokine, providing information for the design of vaccines against mucosal infection by HSV-2 and other sexually transmitted viruses.
Zika virus (ZIKV) infections can cause microcephaly and neurological disorders. However, the early infection events of ZIKV in neural cells remain to be characterized. Here by using a combination of pharmacological and molecular approaches and the human glioblastoma cells T98G as a model, we first observed that ZIKV infection was inhibited by chloroquine and NH4Cl, indicating a requirement of low intracellular pH. We further showed that dynamin is required as ZIKV entry was affected by the specific inhibitor dynasore, siRNA knockdown of dynamin or by expressing the dominant negative K44A mutant. Moreover, ZIKV entry was significantly inhibited by chlorpromazine, pitstop2, or siRNA knockdown of clathrin heavy chain, indicating an involvement of clathrin-mediated endocytosis. In addition, genistein treatment, siRNA knockdown of caveolin-1 or overexpression of a dominant negative caveolin mutant impacted ZIKV entry, with ZIKV particles being observed to colocalize with caveolin-1, implying that caveola endocytosis can also be involved. Furthermore, we found that endocytosis of ZIKV is dependent on membrane cholesterol, microtubules and actin cytoskeleton. Importantly, ZIKV infection was inhibited by silencing of Rab5 and Rab7, while confocal microscopy showed that ZIKV particles localized in Rab5- and Rab7-postive endosomes. These results indicated that, after internalization, ZIKV likely moves to Rab5-positive early endosome and Rab7-positive late endosomes before delivering its RNA into the cytoplasm. Taken together, our study for the first time described the early infection events of ZIKV in human glioblastoma cells T98G.
Herpes simplex virus type 2 (HSV-2) is the main cause of genital herpes and its infection is common in the lower genital tract. Although neuronal and immune cells can be infected, epithelial cells and keratinocytes are the primary HSV-2 target cells. HSV-2 establishes latency by evading the host immune system and its infection can also increase the risk of HIV-1 sexual transmission. Our pervious study found that HSV-2 immediate early protein ICP22 inhibited IFN-β production by interfering with the IRF3 pathway. However, ICP22-null HSV-2 did not completely loss the capability in suppressing IFN-β induction, suggesting the involvement of other viral components in the process. In this study, by using an ex vivo cervical explant model, we first demonstrated that HSV-2 can indeed inhibit IFN-β induction in human mucosal tissues. We further identified HSV-2 immediate early protein ICP27 as a potent IFN-β antagonist. ICP27 significantly suppresses Sendai virus or polyinosinic-polycytidylic acid-induced IFN-β production in human mucosal epithelial cells, showing that ICP27 inhibits IFN-β promoter activation and IFN-β production at both mRNA and protein levels. Additional studies revealed that ICP27 directly associates with IRF3 and inhibits its phosphorylation and nuclear translocation, resulting in the inhibition of IFN-β induction. Our findings provide insights into the molecular mechanism underlying HSV-2 mucosal immune evasion and information for the design of HSV-2 mucosal vaccines.
Herpes simplex virus type 2 (HSV-2) is a sexually transmitted virus, the cause of genital herpes, and its infection can increase the risk of HIV-1 infection. After initial infection, HSV-2 can establish lifelong latency within the nervous system, which is likely associated with the virus-mediated immune evasion. In this study, we found that HSV-2 UL24 significantly inhibited the activation of the IFN-β promoter and the production of IFN-β at both mRNA and protein levels. Of importance, the inhibitory effect of HSV-2 on IFN-β production was significantly impaired in the context of HSV-2 infection when UL24 was knocked down. Additional studies revealed that, although the full-length HSV-2 UL24 affected cell cycle and viability to some extent, its N-terminal 1-202AA domain showed no obvious cytotoxicity while its C-terminal 201-281 AA domain had a minimal impact on cell viability. Further studies showed that the N-terminal 1-202 AA domain of HSV-2 UL24 (HSV-2 UL24-N) was the main functional region responsible for the inhibition of IFN-β production mediated by HSV-2 UL24. This domain significantly suppressed the activity of RIG-IN, MAVS, TBK-1, IKK-ε, or the IRF-3/5D-activated IFN-β promoter. Mechanistically, HSV-2 UL24-N suppressed IRF-3 phosphorylation, resulting in the inhibition of IFN-β production. The findings of this study highlight the significance of HSV-2 UL24 in inhibiting IFN-β production, revealing two potential roles of UL24 during HSV-2 infection: facilitating immune evasion and inducing cell cycle arrest.
(Patterns 1, 100092-1--100092-9; October 9, 2020) In the originally published version of this article, the formulas for Sensitivity, Specificity, and F1 weighted in Table S3, shown below, were incorrect.Tabled 1MetricsDefinitionSensitivityTPTP+FPSpecificityTPTN+FPF1 weighted1TP+FP∗2TPTP+FN+1+1TN+FN∗2TNTN+FP+1 Open table in a new tab The correct formulas are:Tabled 1MetricsDefinitionSensitivityTPTP+FNSpecificityTNTN+FPF1 weighted2TP2TP+FN+FP∗TP+FNTP+FN+FP+TN+2TN2TN+FP+FN∗TN+FPTP+FN+FP+TN Open table in a new tab The article has been corrected online, and the authors apologize for any confusion this error may have caused. A Learning-Based Model to Evaluate Hospitalization Priority in COVID-19 PandemicsZheng et al.PatternsAugust 3, 2020In BriefThe authors propose a learning-based model to assist clinicians in quick and efficient triage of patients in places where medical resources are limited in COVID-19 pandemics. This model used four easily accessible biomarkers to assess the severity of COVID-19 and was found to be effective in identifying the risk of severe COVID-19. It enables healthcare administrators to distribute hospitalization resources where they are most needed. Full-Text PDF Open Access
Human norovirus (HuNoV) is the leading cause of acute gastroenteritis (AGE) worldwide, which is highly stable and contagious, with a few virus particles being sufficient to establish infection. Although the World Health Organization in 2016 stated that it should be an absolute priority to develop a HuNoV vaccine, unfortunately, there is currently no licensed HuNoV vaccine available. The major barrier to the development of an effective HuNoV vaccine is the lack of a robust and reproducible in vitro cultivation system. To develop a HuNoV vaccine, HuNoV immunogen alone or in combination with other viral immunogens have been designed to assess whether they can simultaneously induce protective immune responses against different viruses. Additionally, monovalent and multivalent vaccines from different HuNoV genotypes, including GI and GII HuNoV virus-like particles (VLPs), have been assessed in order to induce broad protection. Although there are several HuNoV vaccine candidates based on VLPs that are being tested in clinical trials, the challenges to develop effective HuNoV vaccines remain largely unresolved. In this review, we summarize the advances of the HuNoV cultivation system and HuNoV vaccine research and discuss current challenges and future perspectives in HuNoV vaccine development.
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