Background
Coronavirus disease 2019 (COVID-19) has been demonstrated to be the cause of pneumonia. Nevertheless, it has not been reported as the cause of acute myocarditis or fulminant myocarditis.
...Case presentation
A 63-year-old male was admitted with pneumonia and cardiac symptoms. He was genetically confirmed as having COVID-19 according to sputum testing on the day of admission. He also had elevated troponin I (Trop I) level (up to 11.37 g/L) and diffuse myocardial dyskinesia along with a decreased left ventricular ejection fraction (LVEF) on echocardiography. The highest level of interleukin-6 was 272.40 pg/ml. Bedside chest radiographs showed typical ground-glass changes indicative of viral pneumonia. Laboratory test results for viruses that cause myocarditis were all negative. The patient conformed to the diagnostic criteria of the Chinese expert consensus statement for fulminant myocarditis. After receiving antiviral therapy and mechanical life support, Trop I was reduced to 0.10 g/L, and interleukin-6 was reduced to 7.63 pg/mL. Moreover, the LVEF of the patient gradually recovered to 68%. The patient died of aggravation of secondary infection on the 33rd day of hospitalization.
Conclusion
COVID-19 patients may develop severe cardiac complications such as myocarditis and heart failure. This is the first report of COVID-19 complicated with fulminant myocarditis. The mechanism of cardiac pathology caused by COVID-19 needs further study.
Coronaviruses are pathogens of humans and animals that cause widespread and costly diseases. The development of effective strategies to combat the threat of coronaviruses is therefore a top priority. ...The conserved coronavirus octamer motif 5'GGAAGAGC3' exists in the 3' untranslated region of all identified coronaviruses. In the current study, we aimed to examine whether targeting the coronavirus octamer motif GGAAGAGC is a promising approach to develop coronavirus vaccine.
Plaque assays were used to determine the titers of mouse hepatitis virus (MHV)-A59 octamer mutant (MHVoctm) and wild-type (wt) MHV-A59 (MHVwt). Western blotting was used for the determination of translation efficiency of MHVoctm and MHVwt. Plaque assays and RT-qPCR were employed to examine whether MHVoctm was more sensitive to interferon treatment than MHVwt. Weight loss, clinical signs, survival rate, viral RNA detection and histopathological examination were used to evaluate whether MHVoctm was a vaccine candidate against MHVwt infection in BALB/c mice.
In this study, we showed that (i) the MHVoctm with mutation of coronavirus octamer was able to grow to high titers but attenuated in mice, (ii) with the reduced multiplicity of infection (MOI), the difference in gene expression between MHVoctm and MHVwt became more evident in cultured cells, (iii) MHVoctm was more sensitive to interferon treatment than MHVwt and (iv) mice inoculated with MHVoctm were protected from MHVwt infection.
Based on the results obtained from cultured cells, it was suggested that the synergistic effects of octamer mutation, multiplicity of infection and immune response may be a mechanism explaining the distinct phenotypes of octamer-mutated coronavirus in cell culture and mice. In addition, targeting the conserved coronavirus octamer motif is a strategy for development of coronavirus vaccine. Since the conserved octamer exists in all coronaviruses, this strategy of targeting the conserved octamer motif can also be applied to other human and animal coronaviruses for the development of coronavirus vaccines, especially the emergence of novel coronaviruses such as SARS-CoV-2, saving time and cost for vaccine development and disease control.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The conventional cascode structure for driving depletion-mode (D-mode) gallium nitride (GaN) high electron mobility transistors (HEMTs) raises reliability concerns. This is because of the possibility ...of the gate to source voltage of the GaN HEMT surging to a negative voltage during the turn off transition. The existing solutions for this problem in the literature produce additional drawbacks such as reducing the switching frequency or introducing many additional components. These drawbacks may outweigh the advantages of using a GaN HEMT over its silicon (Si) alternative. This paper proposes two innovative gate drive circuits for D-mode GaN HEMTs—namely the GaN-switching based cascode GaN HEMT and the modified GaN-switching based cascode GaN HEMT. In these schemes, the Si MOSFET in series with the D-mode GaN HEMT is always turned on during regular operation. The GaN HEMT is then switched on and off by using a charge pump based circuit and a conventional gate driver. Since the GaN HEMT is driven independently, the highly negative gate-to-source voltage surge during turn off is avoided, and in addition, high switching frequency operation is made possible. Only two diodes and one capacitor are used in each of the schemes. The application of the proposed circuits is experimentally demonstrated in a high voltage flyback converter, where more than 96% efficiency is obtained for 60 W output load.
It remains controversial whether entecavir (ETV) and tenofovir disoproxil fumarate (TDF) is associated with different clinical outcomes for chronic hepatitis B (CHB). This study aimed to compare the ...long-term risk of ETV versus TDF on hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) in CHB patients from a large multi-institutional database in Taiwan. From 2011 to 2018, a total of 21,222 CHB patients receiving ETV or TDF were screened for eligibility. Patients with coinfection, preexisting cancer and less than 6 months of follow-up were excluded. Finally, 7248 patients (5348 and 1900 in the ETV and TDF groups, respectively) were linked to the National Cancer Registry database for the development of HCC or ICC. Propensity score matching (PSM) (2:1) analysis was used to adjust for baseline differences. The HCC incidence between two groups was not different in the entire population (hazard ratio HR 0.82; 95% confidence interval CI 0.66-1.02, p = 0.078) and in the PSM population (HR 0.83; 95% CI 0.65-1.06, p = 0.129). Among decompensated cirrhotic patients, a lower risk of HCC was observed in TDF group than in ETV group (HR 0.54; 95% CI 0.30-0.98, p = 0.043, PSM model). There were no differences between ETV and TDF groups in the ICC incidence (HR 1.84; 95% CI 0.54-6.29, p = 0.330 in the entire population and HR 1.04; 95% CI 0.31-3.52, p = 0.954 in the PSM population, respectively). In conclusion, treatment with ETV and TDF showed a comparable long-term risk of HCC and ICC in CHB patients.
Abstract
We have successfully fabricated high quality single crystalline La
0.7
Sr
0.3
MnO
3
(LSMO) film in the freestanding form that can be transferred onto silicon wafer and copper mesh support. ...Using soft x-ray absorption (XAS) and resonant inelastic x-ray scattering (RIXS) spectroscopy in transmission and reflection geometries, we demonstrate that the x-ray emission from Mn 3
s
-2
p
core-to-core transition (3
s
PFY) seen in the RIXS maps can represent the bulk-like absorption signal with minimal self-absorption effect around the Mn
L
3
-edge. Similar measurements were also performed on a reference LSMO film grown on the SrTiO
3
substrate and the agreement between measurements substantiates the claim that the bulk electronic structures can be preserved even after the freestanding treatment process. The 3
s
PFY spectrum obtained from analyzing the RIXS maps offers a powerful way to probe the bulk electronic structures in thin films and heterostructures when recording the XAS spectra in the transmission mode is not available.
Background Radiotherapy (RT) following breast-conserving surgery (BCS) is mainly used to decrease the rate of ipsilateral breast tumor recurrence (IBTR) in women with breast ductal carcinoma in situ ...(DCIS). Recent studies have demonstrated that low-dose tamoxifen significantly reduces IBTR in breast DCIS. Here, we aim to determine whether the administration of low-dose tamoxifen is non-inferior to RT in preventing IBTR in patients with low-risk characteristics of breast DCIS. Methods/design This is a prospective, international, open-label, randomized, non-inferiority trial. Patients with low-risk clinicopathologic features (> 40 years old, low risk of breast cancer susceptibility gene (BRCA) 1 and BRCA2 mutations, mammographically detected unicentric and non-mass lesions, low- or intermediate-grade without comedo or necrosis, measuring < 2.5 cm with margins greater than or equal to 3 mm, and estrogen receptor-positive status) of DCIS who underwent BCS will be randomized at a 1:1 ratio to either receive tamoxifen (5 mg/day) for 5 years or undergo RT with conventional fractions (50 Gy in 25 fractions) or hypofractionations (40.05 Gy in 15 fractions). Randomization will be stratified by the Taiwan Breast Cancer Consortium. As approximately 5% of patients cannot tolerate the side effects of low-dose tamoxifen and will receive RT, we estimate that 405 patients will be randomized to a low-dose tamoxifen arm and 405 patients to the RT arm, according to a non-inferiority margin within 5% of IBTR difference and 90% beta-power noticing non-inferiority. The primary endpoints are breast tumor recurrence, including ipsilateral, regional, contralateral, and distant recurrence of breast DCIS or invasive cancer. The secondary endpoints are overall survival and adverse effects of RT and tamoxifen. Translational studies will also be conducted for this trial. Discussion This is the first non-inferiority trial on breast DCIS. This study will provide an important recommendation for clinical physicians on whether to use low-dose adjuvant tamoxifen for patients with low-risk breast DCIS who do not want to receive adjuvant RT. Trial registration ClinicalTrials.gov, ID: NCT04046159, Registered on April 30, 2019. Keywords: Ductal carcinoma in situ, Breast, Tamoxifen, Radiotherapy, Low-risk
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We have developed a manufacturing-friendly spin-orbit torque magnetic random access memory (SOT-MRAM) technology in CMOS compatible 8-inch fab process. The proposed SOT-MRAM process technology ...resolves etching non-uniformity and reduction of high resistivity heavy-metal nanowire resistance issues. Besides, we present device size-dependent switching current threshold in the proposed SOT-MRAM cell structure. To realize the potential of our fabricated SOT-MRAM, wafer-level uniformity, cycling and temperature dependence SOT switching have been comprehensively investigated. Furthermore, the thermal stability factor (<inline-formula> <tex-math notation="LaTeX">{\Delta } </tex-math></inline-formula>) was calculated from temperature-dependence SOT switching to fulfill the thermal stability criteria, i.e., > 10 years of this emerging SOT-MRAM technology.
Feline infectious peritonitis (FIP) is a fatal illness caused by a mutated feline coronavirus (FCoV). This disease is characterized by its complexity, resulting from systemic infection, ...antibody-dependent enhancement (ADE), and challenges in accessing effective therapeutics. Extract derived from
(L.) R. Wilczek (VRE) exhibits various pharmacological effects, including antiviral activity. This study aimed to investigate the antiviral potential of VRE against FCoV, addressing the urgent need to advance the treatment of FIP. We explored the anti-FCoV activity, antiviral mechanism, and combinational application of VRE by means of
antiviral assays. Our findings reveal that VRE effectively inhibited the cytopathic effect induced by FCoV, reduced viral proliferation, and downregulated spike protein expression. Moreover, VRE blocked FCoV in the early and late infection stages and was effective under
ADE infection. Notably, when combined with VRE, the polymerase inhibitor GS-441524 or protease inhibitor GC376 suppressed FCoV more effectively than monotherapy. In conclusion, this study characterizes the antiviral property of VRE against FCoV
, and VRE possesses therapeutic potential for FCoV treatment.
Differentiated cardiomyocytes (CMs) must undergo diverse morphological and functional changes during postnatal development. However, the mechanisms underlying initiation and coordination of these ...changes remain unclear. Here, we delineate an integrated, time-ordered transcriptional network that begins with expression of genes for cell-cell connections and leads to a sequence of structural, cell-cycle, functional, and metabolic transitions in mouse postnatal hearts. Depletion of histone H2B ubiquitin ligase RNF20 disrupts this gene network and impairs CM polarization. Subsequently, assay for transposase-accessible chromatin using sequencing (ATAC-seq) analysis confirmed that RNF20 contributes to chromatin accessibility in this context. As such, RNF20 is likely to facilitate binding of transcription factors at the promoters of genes involved in cell-cell connections and actin organization, which are crucial for CM polarization and functional integration. These results suggest that CM polarization is one of the earliest events during postnatal heart development and provide insights into how RNF20 regulates CM polarity and the postnatal gene program.
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•Epigenetic regulator RNF20 regulates a time-ordered gene network in postnatal heart•CM polarization is one of the earliest events during postnatal heart development•RNF20-mediated chromatin remodeling is pivotal for postnatal transcription and CM polarization
Lin et al. delineate a time-ordered gene network in postnatal hearts that initiates with expression of cell-cell connection-related genes. Loss of RNF20 disrupts this network and affects cardiomyocyte (CM) polarization. Further evidence suggests that RNF20 modulates chromatin accessibility and facilitates transcription factor binding to genetically regulate CM polarization within the postnatal heart.
Palbociclib, a CDK4/6 inhibitor, has recently been approved for hormone receptor‐positive breast cancer patients. The effects of palbociclib as a treatment for other malignancies, including ...hepatocellular carcinoma (HCC), are of great clinical interest and are under active investigation. Here, we report the effects and a novel mechanism of action of palbociclib in HCC. We found that palbociclib induced both autophagy and apoptosis in HCC cells through a mechanism involving 5′ AMP‐activated protein kinase (AMPK) activation and protein phosphatase 5 (PP5) inhibition. Blockade of AMPK signals or ectopic expression of PP5 counteracted the effect of palbociclib, confirming the involvement of the PP5/AMPK axis in palbociclib‐mediated HCC cell death. However, CDK4/6 inhibition by lentivirus‐mediated shRNA expression did not reproduce the effect of palbociclib‐treated cells, suggesting that the anti‐HCC effect of palbociclib is independent of CDK4/6. Moreover, two other CDK4/6 inhibitors (ribociclib and abemaciclib) had minimal effects on HCC cell viability and the PP5/AMPK axis. Palbociclib also demonstrated significant tumor‐suppressive activity in a HCC xenograft model, which was associated with upregulation of pAMPK and PP5 inhibition. Finally, we analyzed 153 HCC clinical samples and found that PP5 expression was highly tumor specific and was associated with poor clinical features. Taken together, we conclude that palbociclib exerted antitumor activity against HCC through the PP5/AMPK axis independent of CDK4/6. Our findings provide a novel mechanistic basis for palbociclib and reveal the therapeutic potential of targeting PP5/AMPK signaling with a PP5 inhibitor for the treatment of hepatocellular carcinoma.
Palbociclib is known as a CDK4/6 inhibitor and approved for the treatment of hormone receptor‐positive breast cancer. Here, we show that palbociclib exerts antitumor activity against hepatocellular carcinoma (HCC), but through a novel mechanism, inhibiting PP5 phosphatase and thus activating AMPK. PP5 expression in patients with HCC is associated with aggressive clinical features and thus might be a therapeutic target for HCC treatment.
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