Indirubin-3'-monoxime exhibits potent antiviral and anti-inflammatory effects against human adenoviruses in vitro and in vivo.

Human adenovirus (HAdV) infection is a major cause of respiratory disease, yet no antiviral drugs have been approved for its treatment. Herein, we evaluated the antiviral and anti-inflammatory effects of cyclin-dependent protein kinase (CDK) inhibitor indirubin-3'-monoxime (IM) against HAdV infection in cells and a transgenic mouse model. After evaluating its cytotoxicity, cytopathic effect reduction, antiviral replication kinetics, and viral yield reduction assays were performed to assess the anti-HAdV activity of IM. Quantitative real-time polymerase chain reaction (qPCR), quantitative reverse transcription PCR (qRT-PCR), and western blotting were used to assess the effects of IM on HAdV DNA replication, transcription, and protein expression, respectively. IM significantly inhibited HAdV DNA replication as well as E1A and Hexon transcription, in addition to significantly suppressing the phosphorylation of the RNA polymerase II C-terminal domain (CTD). IM mitigated body weight loss, reduced viral burden, and lung injury, decreasing cytokine and chemokine secretion to a greater extent than cidofovir. Altogether, IM inhibits HAdV replication by downregulating CTD phosphorylation to suppress viral infection and corresponding innate immune reactions as a promising therapeutic agent.

Associations of nirmatrelvir-ritonavir treatment with death and clinical improvement in hospitalized patients with COVID-19 during the Omicron wave in Beijing, China: a multicentre, retrospective cohort study.

BACKGROUND: The effectiveness of nirmatrelvir-ritonavir has mainly been shown in non-hospitalized patients with mild-to-moderate coronavirus disease 2019 (COVID-19). The real-world effectiveness of nirmatrelvir-ritonavir urgently needs to be determined using representative in-hospital patients with COVID-19 during the Omicron wave of the pandemic. METHODS: We performed a multicentre, retrospective study in five Chinese PLA General Hospital medical centers in Beijing, China. Patients hospitalized with COVID-19 from 10 December 2022 to 20 February 2023 were eligible for inclusion. A 1:1 propensity score matching was performed between the nirmatrelvir-ritonavir group and the control group. RESULTS: 1010 recipients of nirmatrelvir-ritonavir and 1010 matched controls were finally analyzed after matching. Compared with matched controls, the nirmatrelvir-ritonavir group had a lower incidence rate of all-cause death (4.6/1000 vs. 6.3/1000 person-days, p = 0.013) and a higher incidence rate of clinical improvement (47.6/1000 vs. 45.8/1000 person-days, p = 0.012). Nirmatrelvir-ritonavir was associated with a 22% lower all-cause mortality and a 14% higher incidence of clinical improvement. Initiation of nirmatrelvir-ritonavir within 5 days after symptom onset was associated with a 50% lower mortality and a 26% higher clinical improvement rate. By contrast, no significant associations were identified among patients receiving nirmatrelvir-ritonavir treatment more than 5 days after symptom onset. Nirmatrelvir-ritonavir was also associated with a 50% increase in survival days and a 12% decrease in days to clinical improvement. CONCLUSION: Among hospitalized patients with COVID-19 during the Omicron wave in Beijing, China, the early initiation of nirmatrelvir-ritonavir was associated with clinical benefits of lowering mortality and improving clinical recovery.

Real-world effectiveness of nirmatrelvir-ritonavir versus azvudine in hospitalized patients with COVID-19 during the omicron wave in Beijing: a multicenter retrospective cohort study.

BACKGROUND AND AIM: Two oral antivirals (Nirmatrelvir- ritonavir and Azvudine) are widely used in China practice during the Omicron wave of the pandemic. However, little evidence regarding the real-world effectiveness of these two oral antivirals in in-hospital patients. We aimed to evaluate the clinical effectiveness of nirmatrelvir-ritonavir versus azvudine among adult hospitalized patients with COVID-19. METHODS: This retrospective cohort study used data from three Chinese PLA General Hospital medical centres. Hospitalized patients with COVID-19 treated with azvudine or nirmatrelvir-ritonavir from Dec 10, 2022, to February 20, 2023, and did not require invasive ventilation support on admission were eligible for inclusion. RESULTS: After exclusions and propensity-score matching, the final analysis included 486 azvudine recipients and 486 nirmatrelvir-ritonavir recipients. By 28 days of initiation of the antivirus treatment, the crude incidence rate of all-cause death was similar in both types of antivirus treatment (nirmatrelvir-ritonavir group 2.8 events 1000 person-days [95% CI, 2.1-3.6] vs azvudine group 3.4 events/1000 person-days [95% CI, 2.6-4.3], P = 0.38). Landmark analysis showed that all-cause death was lower in the nirmatrelvir-ritonavir (3.5%) group than the azvudine (6.8%, P = 0.029) within the initial 10-day admission period, while no significant difference was observed for results between 10 and 28 days follow-up. There was no significant difference between the nirmatrelvir-ritonavir group and the azvudine group in cumulative incidence of the composite disease progression event (8.6% with nirmatrelvir-ritonavir vs. 10.1% with azvudine, HR, 1.22; 95% CI 0.80-1.86, P = 0.43). CONCLUSION: Among patients hospitalized with COVID-19 during the omicron wave in Beijing, similar in-hospital clinical outcomes on 28 days were observed between patients receiving nirmatrelvir-ritonavir and azvudine. However, it is worth noticing that nirmatrelvir-ritonavir appears to hold an advantage over azvudine in reducing early mortality. Further randomized controlled trials are needed to verify the efficacy of those two antivirus medications especially in early treatment.

iNOS inhibitor S-methylisothiourea alleviates smoke inhalation-induced acute lung injury by suppressing inflammation and macrophage infiltration.

OBJECTIVE: We investigated the effects of the inducible NO synthase (iNOS) inhibitor, S-methylisothiourea (SMT), in a mouse model of smoke inhalation-induced acute lung injury (ALI) and explored the underlying molecular mechanism. METHODS AND ANALYSIS: A mouse model of smoke inhalation-induced ALI was established. RNA-sequencing (seq) analysis was conducted to identify the differentially expressed genes (DEGs). Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were performed for functional annotation of DEGs. Moreover, an immunofluorescence assay using macrophage marker F4/80 was performed to assess macrophage infiltration. A hypoxia-induced HUVEC model was used to mimic smoke inhalation-induced injury in endothelial cells. Finally, a transwell assay was used to analyze the chemoattractive effects of endothelial cells on macrophages. RESULTS: SMT markedly alleviated the pulmonary pathological symptoms, edema, and inflammatory response in the mouse smoke inhalation-induced ALI model. RNA-seq analysis revealed that SMT may diminish lung injury by regulating the levels of genes associated with inflammatory responses, cell chemokines, and adhesion. In vivo data revealed that the protective effects of SMT against smoke inhalation-induced ALI were partly achieved by inhibiting the production of adhesion molecules and infiltration of macrophages. Furthermore, in vitro data from the hypoxia-induced HUVEC model revealed that SMT reduced macrophage chemotaxis by inhibiting the production of chemokines and adhesion molecules in endothelial cells. CONCLUSION: iNOS inhibitor SMT protects the lungs from smoke inhalation-induced ALI by reducing the production of pro-inflammatory cytokines, adhesion molecules, and chemokines in endothelial cells, thereby inhibiting inflammation and macrophage infiltration.

Towards a photonic integrated all-optical phase regenerator.

All-optical phase regeneration aims at restoring the phase information of coherently encoded data signals directly in the optical domain so as to compensate for phase distortions caused by transceiver imperfections and nonlinear impairments along the transmission link. Although it was proposed two decades ago, all-optical phase regeneration has not been seen in realistic networks to date, mainly because this technique entails complex bulk modules and relies on high-precision phase sensitive nonlinear dynamics, both of which are adverse to field deployment. Here, we demonstrate a new, to the best of our knowledge, architecture to implement all-optical phase regeneration using integrated photonic devices. In particular, we realize quadrature phase quantization by exploring the phase-sensitive parametric wave mixing within on-chip silicon waveguides, while multiple coherent pump laser tones are provided by a chip-scale micro-cavity Kerr frequency comb. Multi-channel all-optical phase regeneration is experimentally demonstrated for 40 Gbps QPSK data, achieving the best SNR improvement of more than 6 dB. Our study showcases a promising avenue to enable the practical implementation of all-optical phase regeneration in realistic long-distance fiber transmission networks.

Comparisons of lymphocytes profiles and inflammatory cytokines levels in blood of patients with differed severity of infection by human adenovirus type 7.

BACKGROUND: Human adenovirus (HAdV) infection outbreak causes community-acquired pneumonia. Cellular immune dysfunction and hypercytokinemia play important roles in the pathogenesis of adenovirus respiratory infection. Some soluble factors in peripheral blood can assist in judging the virus-induced disease severity. The expression levels of inflammatory cytokines differ among patients with different disease severity. However, whether and how HAdV-7 infection influences the composition of blood immune cells and serum cytokine levels in patients at different disease stages, as well as the diagnosis values of these parameters, have rarely been intensively studied. We aimed to investigate lymphocytes profiles and cytokines levels in blood of patients at different disease stages upon human adenovirus type 7 (HAdV-7) infections, and explored the diagnosis values of the investigated parameters. METHODS: Patients from two outbreaks of HAdV-7 in military of China were categorized into upper respiratory infection (URI) group, common pneumonia (CP) group and severe pneumonia (SP) group according to disease severity. Peripheral blood samples were subjected to routine laboratory tests, while flow cytometry and ELISA were used to measure the lymphocyte subsets and cytokines in blood, respectively. The receiver operating characteristic (ROC) curves were performed to examine the diagnostic of these blood parameters. RESULTS: Signs of imbalanced lymphocytes composition and hypercytokinemia were observed in HAdV-7-infected patients. The percentages of CD3+ T cells and NK cells were significantly decreased along with the aggravation of the disease, particularly for NK cells and CD4+ T cells. The neutrophil to lymphocyte ratio (NLR) increased significantly in patients with more severe disease. In addition, the levels of serum CXCL10, IL-2 and TNF-α were positively correlated with disease severity, while reduced levels of IFN-γ and IL-10 were found in SP patients. Furthermore, analysis of ROC showed that multiple parameters including the percentage of blood CD3+ cells and serum CXCL10 level could predict the progression of HAdV-7 infection. CONCLUSION: Imbalance of immune state with hypercytokinemia occurred during HAdV-7 infection. The percentages of blood immune cells such as CD3+ T cells and the levels of serum cytokines such as CXCL10 showed potential diagnosis values in HAdV-7 infection.

Phase noise of Kerr soliton dual microcombs.

Dissipative Kerr soliton microcombs are believed to be a promising technique to build a dual-comb source for applications including precision laser metrology, fast laser spectroscopy, and high-speed optical signal processing. In this Letter, we conduct a detailed experimental investigation on the phase coherence between two on-chip Kerr soliton microcombs, where the underlying physical and technical origins that lead to the mutual phase noise between microcombs are analyzed. Moreover, the techniques of 2-point locking and optical frequency division are explored to enhance the dual-microcomb phase coherence, and we demonstrate the best phase noise down to -50 dBc/Hz at 1-Hz offset, -90 dBc/Hz at 1-kHz offset, and -120 dBc/Hz at 1-MHz offset. Our study provides a basic reference for both fundamental studies and practical applications of Kerr soliton dual microcombs that entail high mutual phase coherence.

Polarization multiplexed dissipative Kerr solitons in an on-chip micro-resonator.

We demonstrate polarization multiplexed dissipative Kerr solitons in an on-chip silicon nitride micro-resonator. In our experiment, TE- and TM-polarized solitons can be individually generated and controlled, thanks to their weak mutual interaction as the result of sufficiently different repetition rates and orthogonal polarization states. Furthermore, we find that TE- and TM-polarized solitons usually exhibit uncorrelated time jitters. Therefore, the frequency and phase coherence between the polarization multiplexed soliton microcombs change dramatically as a function of pump laser parameters, where by optimization, we achieve a narrow dual-microcomb beat note linewidth as small as 4.4 kHz. Potential applications of on-chip polarization multiplexed soliton microcombs include Kerr comb spectral expansion, dual-comb metrology, and measurement of quantum entanglements.

Coherent optical communications using coherence-cloned Kerr soliton microcombs.

Dissipative Kerr soliton microcombs have been recognized as a promising multi-wavelength laser source for fiber optical communications, as their comb lines possess frequency and phase stability far beyond the independent lasers. Especially, for coherent optical communications, a highly beneficial but rarely explored target is to re-generate a Kerr soliton microcomb as the receiver local oscillators that conserve the frequency and phase property of the incoming data carriers, so that to enable coherent detection with minimized optical and electrical compensations. Here, via pump laser conveying and two-point locking, we implement re-generation of a Kerr soliton microcomb that faithfully clones the frequency and phase of another microcomb sent from 50 km away. Moreover, by using the coherence-cloned soliton microcombs as carriers and local oscillators, we demonstrate terabit coherent data interconnect, wherein traditional digital processes for frequency offset estimation are totally dispensed with, and carrier phase estimation is substantially simplified via slowed-down estimation rate per channel and joint estimation among multiple channels. Our work reveals that, in addition to providing a multitude of laser tones, regulating the frequency and phase of Kerr soliton microcombs among transmitters and receivers can significantly improve optical coherent communication in terms of performance, power consumption, and simplicity.

Wavelength-division multiplexing communications using integrated soliton microcomb laser source.

In this Letter, we report an investigation of the feasibility and performance of wavelength-division multiplexed (WDM) optical communications using an integrated perfect soliton crystal as the multi-channel laser source. First, we confirm that perfect soliton crystals pumped directly by a distributed-feedback (DFB) laser self-injection locked to the host microcavity has sufficiently low frequency and amplitude noise to encode advanced data formats. Second, perfect soliton crystals are exploited to boost the power level of each microcomb line, so that it can be directly used for data modulation, excluding preamplification. Third, in a proof-of-concept experiment, we demonstrate seven-channel 16-quadrature amplitude modulation (16-QAM) and 4-level pulse amplitude modulation (PAM4) data transmissions using an integrated perfect soliton crystal as the laser carrier; excellent data receiving performance is obtained for various fiber link distances and amplifier configurations. Our study reveals that fully integrated Kerr soliton microcombs are viable and advantageous for optical data communications.

Research on a Dual-Mode Infrared Liquid-Crystal Device for Simultaneous Electrically Adjusted Filtering and Zooming.

A new dual-mode liquid-crystal (LC) micro-device constructed by incorporating a Fabry⁻Perot (FP) cavity and an arrayed LC micro-lens for performing simultaneous electrically adjusted filtering and zooming in infrared wavelength range is presented in this paper. The main micro-structure is a micro-cavity consisting of two parallel zinc selenide (ZnSe) substrates that are pre-coated with ~20-nm aluminum (Al) layers which served as their high-reflection films and electrodes. In particular, the top electrode of the device is patterned by 44 × 38 circular micro-holes of 120 µm diameter, which also means a 44 × 38 micro-lens array. The micro-cavity with a typical depth of ~12 µm is fully filled by LC materials. The experimental results show that the spectral component with needed frequency or wavelength can be selected effectively from incident micro-beams, and both the transmission spectrum and the point spread function can be adjusted simultaneously by simply varying the root-mean-square value of the signal voltage applied, so as to demonstrate a closely correlated feature of filtering and zooming. In addition, the maximum transmittance is already up to ~20% according the peak-to-valley value of the spectral transmittance curves, which exhibits nearly twice the increment compared with that of the ordinary LC-FP filtering without micro-lenses.