Effect of pre-hospitalization use of oral antiviral agents on reducing critical illness and mortality for patients with COVID-19 pneumonia.

OBJECTIVES: This study aimed to evaluate the effect of administering nirmatrelvir/ritonavir and molnupiravir before hospitalisation on subsequent critical illness among patients with COVID-19 pneumonia. METHODS: This retrospective cohort study included patients with COVID-19 pneumonia who required hospitalisation between 1 January 1 2022 and 31 August 2022. The primary outcomes were the development of critical illness, including intensive care unit admission, use of mechanical ventilation, or mortality. A multivariate logistic regression analysis was conducted to assess the varying risks of critical illness and mortality. A total of 1,011 COVID-19 patients were analysed. Among them, 304 (30.1%) received molnupiravir and 131 (13.0%) received nirmatrelvir/ritonavir before hospitalisation. RESULTS: There were significant reductions for critical illness (adjusted odds ratio 0.29, 95% confidence interval 0.21-0.39, P < 0.001) and mortality (adjusted odds ratio 0.40, 95% confidence interval 0.27-0.59, P < 0.001) in patients receiving oral antivirals compared with those who did not. No significant differences in critical illness were observed between molnupiravir and nirmatrelvir/ritonavir. The combination of COVID-19 vaccines and oral antivirals can further reduce the risk of critical illness in high-risk populations. CONCLUSION: Administering molnupiravir and nirmatrelvir/ritonavir before hospitalisation reduced the risk of COVID-19 patients with moderate to severe pneumonia progressing to critical illness and mortality.

Imiquimod Accelerated Antitumor Response by Targeting Lysosome Adaptation in Skin Cancer Cells.

Lysosomal adaptation is a cellular physiological process in which the number and function of lysosomes are regulated at the transcriptional and post-transcriptional levels in response to extracellular and/or intracellular cues or lysosomal damage. Imiquimod (IMQ), a synthetic toll-like receptor 7 ligand with hydrophobic and weak basic properties, exhibits both antitumor and antiviral activity against various skin malignancies as a clinical treatment. Interestingly, IMQ has been suggested to be highly concentrated in the lysosomes of plasmacytoid dendritic cells, indicating that IMQ could modulate lysosome function after sequestration in the lysosome. In this study, we found that IMQ not only induced lysosomal membrane permeabilization and dysfunction but also increased lysosome biogenesis to achieve lysosomal adaptation in cancer cells. IMQ-induced ROS production but not lysosomal sequestration of IMQ was the major cause of lysosomal adaptation. Moreover, IMQ-induced lysosomal adaptation occurred through lysosomal calcium ion release and activation of the calcineurin/TFEB axis to promote lysosome biogenesis. Finally, depletion of TFEB sensitized skin cancer cells to IMQ-induced apoptosis in vitro and in vivo. In summary, a disruption of lysosomal adaptation might represent a therapeutic strategy for synergistically enhancing the cytotoxicity of IMQ in skin cancer cells.

Dual-acting antibacterial porous chitosan film embedded with a photosensitizer.

This study proposes to develop a dual-acting antibacterial film of porous chitosan (Cs) embedded with small molecular compound, which possesses photosensitive characteristics with bactericidal efficacy, to promote the accelerated recovery of infectious wounds. The Cs/small molecular compound (Cs-cpd.2) dressing was prepared using the freeze-drying method. Characterization of the synthesized Cs-cpd.2 indicated that it has high porosity and moisture absorption effect, hence enhancing the absorption of wound exudate. Experimental results showed that Cs-cpd.2 dressing has good bactericidal and bacteriostatic effects on Staphylococcus aureus under visible-light irradiation and has antibacterial effect in the dark. It was also found that the small molecular compound does not have cytotoxicity at a dose of 0-5 µM. Furthermore, Cs-cpd.2 that contained small molecular compound with a concentration of 0.3-1 µM has positive effect on both the cell viability rate and cell proliferation rate of human fibroblast CG1639. Cs-cpd.2 can significantly promote cell proliferation when the small molecular compound and the basic fibroblast growth factor bFGF were added together. Therefore, the proposed Cs-cpd.2 dressing is feasible for photodynamic therapy (PDT) and clinical wound dressing applications.

Structural Basis for Targeting T:T Mismatch with Triaminotriazine-Acridine Conjugate Induces a U-Shaped Head-to-Head Four-Way Junction in CTG Repeat DNA.

The potent DNA-binding compound triaminotriazine-acridine conjugate (Z1) functions by targeting T:T mismatches in CTG trinucleotide repeats that are responsible for causing neurological diseases such as myotonic dystrophy type 1, but its binding mechanism remains unclear. We solved a crystal structure of Z1 in a complex with DNA containing three consecutive CTG repeats with three T:T mismatches. Crystallographic studies revealed that direct intercalation of two Z1 molecules at both ends of the CTG repeat induces thymine base flipping and DNA backbone deformation to form a four-way junction. The core of the complex unexpectedly adopts a U-shaped head-to-head topology to form a crossover of each chain at the junction site. The crossover junction is held together by two stacked G:C pairs at the central core that rotate with respect to each other in an X-shape to form two nonplanar minor-groove-aligned G·C·G·C tetrads. Two stacked G:C pairs on both sides of the center core are involved in the formation of pseudo-continuous duplex DNA. Four metal-mediated base pairs are observed between the N7 atoms of G and CoII, an interaction that strongly preserves the central junction site. Beyond revealing a new type of ligand-induced, four-way junction, these observations enhance our understanding of the specific supramolecular chemistry of Z1 that is essential for the formation of a noncanonical DNA superstructure. The structural features described here serve as a foundation for the design of new sequence-specific ligands targeting mismatches in the repeat-associated structures.

Fecal microbiota transplantation confers beneficial metabolic effects of diet and exercise on diet-induced obese mice.

Diet and exercise are conventional methods for controlling body weight and are linked to alterations in gut microbiota. However, the associations of diet, exercise, and gut microbiota in the control of obesity remain largely unknown. In the present study, using 16S rRNA amplicon sequencing and fecal microbiota transplantation (FMT), normal fat diet (NFD), exercise and their combination resulted in improved metabolic profiles in comparison to sedentary lifestyle with high fat diet (HFD). Moreover, diet exerted more influence than exercise in shaping the gut microbiota. HFD-fed mice receiving FMT from NFD-exercised donors not only showed remarkably reduced food efficacy, but also mitigated metabolic profiles (p < 0.05). The transmissible beneficial effects of FMT were associated with bacterial genera Helicobacter, Odoribacter and AF12 and overrepresentation of oxidative phosphorylation and glycolysis genes. Our findings demonstrate that the beneficial effects of diet and exercise are transmissible via FMT, suggesting a potential therapeutic treatment for obesity.

Intestinal microbiota profiling and predicted metabolic dysregulation in psoriasis patients.

OBJECTIVES: The intestinal microbiota has been known to involve in obesity and host immune response. We aimed to investigate the intestinal microbiota and potential genetic function in relation to clinical presentation in psoriasis patients. METHODS: Faecal microbiota and predicted genetic function inferred from high-throughput 16S ribosomal RNA sequencing were analysed between psoriasis (n = 32) and age-, gender- and body mass index (BMI)-matched non-psoriasis subjects (n = 64), from a referral medical centre. The correlation between altered microbiota and disease activity, arthritis and systemic anti-psoriatic drugs was also investigated. RESULTS: We observed a distinct faecal microbial community structure in psoriasis patients, with an increased abundance of phylum Firmicutes and decreased abundance of phylum Bacteroidetes, across different subgroup of subjects. Ruminococcus and Megasphaera, of the phylum Firmicutes, were the top-two genera of discriminant abundance in psoriasis. A number of functional genes and metabolic pathways involving bacterial chemotaxis and carbohydrate transport were predicted over-represented, whereas genes related to cobalamin and iron transport were predicted under-represented in faecal microbiota of psoriasis patients. CONCLUSIONS: The distinct faecal microbial composition in psoriasis might be associated with altered transport of carbohydrate, cobalamin and iron, as well as chemotaxis.

Construction of emission-tunable nanoparticles based on a TICT-AIEgen: impact of aggregation-induced emission versus twisted intramolecular charge transfer.

Traditional fluorogens with aggregation-induced emission (AIEgens) generally exhibit strong luminescence with monotonous wavelengths in the aggregated state, whereas apparent solvatochromic emission intensities and wavelengths (shift) are observed in molecules with twisted intramolecular charge transfer (TICT) characteristic molecules. Herein, we develop a platform to construct strong luminescent nanoparticles with tunable emission colors based on a TICT-AIEgen, 3,6-divinylaryl-substituted carbazole (C12P). Also based on the same molecule, through different nanoparticle fabrication approaches, fluorescent nanoparticles with different emission colors were obtained. A detailed analysis reveals that AIE and TICT characteristics play different roles in nanoparticle emission, with AIE primarily controlling the emission intensity while TICT is more involved in manipulating the emission wavelengths. Applications of the as-prepared nanoparticles in cell imaging were preliminarily demonstrated.

Gastric microbiota and predicted gene functions are altered after subtotal gastrectomy in patients with gastric cancer.

Subtotal gastrectomy (i.e., partial removal of the stomach), a surgical treatment for early-stage distal gastric cancer, is usually accompanied by highly selective vagotomy and Billroth II reconstruction, leading to dramatic changes in the gastric environment. Based on accumulating evidence of a strong link between human gut microbiota and host health, a 2-year follow-up study was conducted to characterize the effects of subtotal gastrectomy. Gastric microbiota and predicted gene functions inferred from 16S rRNA gene sequencing were analyzed before and after surgery. The results demonstrated that gastric microbiota is significantly more diverse after surgery. Ralstonia and Helicobacter were the top two genera of discriminant abundance in the cancerous stomach before surgery, while Streptococcus and Prevotella were the two most abundant genera after tumor excision. Furthermore, N-nitrosation genes were prevalent before surgery, whereas bile salt hydrolase, NO and N2O reductase were prevalent afterward. To our knowledge, this is the first report to document changes in gastric microbiota before and after surgical treatment of stomach cancer.

Polymerase chain reaction-free detection of hepatitis B virus DNA using a nanostructured impedance biosensor.

A polymerase chain reaction (PCR)-free technique for the effective detection of genomic length hepatitis B virus (HBV) DNA is described in this study. The honeycomb-like barrier layer of an anodic aluminum oxide (AAO) film having a uniform nanohemisphere array was used as the substrate of the sensing electrode. A 30-nm gold film was sputtered onto the AAO barrier layer surface as the electrode, followed by electrochemical deposition of gold nanoparticles (GNPs) on the hemisphere surface. A specially designed single-strand 96-mer gene fragment of the target genomic DNA of HBV based on the genome sequences of HBV was immobilized on the nanostructured electrode as the capture probe. Target HBV DNA obtained from clinical samples was hybridized to the sensing probes. Detection results illustrate two dynamic linear ranges, 10(2)-10(3) and 10(3)-10(5.1) copies/mL, having R(2) values of 0.801 and 0.996 could be obtained, respectively. The detection limit of the proposed sending scheme was measured to be 111 copies/mL. The total of 45 target samples, including 20 samples with HBV concentration being lower than 10(2) copies/mL and 25 samples with HBV concentration being in the range of 10(3)-10(5.1) copies/mL, were used for real test. The concentration of these 45 HBV DNA samples was measured by the COBAS Ampliprep system. Comparing the measured results of the COBAS Ampliprep and our system, it was illustrated that the HBV DNA concentrations measured by the proposed method in this study had a high linear correlation with the COBAS Ampliprep, having R(2) values of 0.983. The proposed sensing scheme is highly feasible for future clinical applications.

Methylation-associated gene silencing of RARB in areca carcinogens induced mouse oral squamous cell carcinoma.

Regarding oral squamous cell carcinoma (OSCC) development, chewing areca is known to be a strong risk factor in many Asian cultures. Therefore, we established an OSCC induced mouse model by 4-nitroquinoline-1-oxide (4-NQO), or arecoline, or both treatments, respectively. These are the main two components of the areca nut that could increase the occurrence of OSCC. We examined the effects with the noncommercial MCGI (mouse CpG islands) microarray for genome-wide screening the DNA methylation aberrant in induced OSCC mice. The microarray results showed 34 hypermethylated genes in 4-NQO plus arecoline induced OSCC mice tongue tissues. The examinations also used methylation-specific polymerase chain reaction (MS-PCR) and bisulfite sequencing to realize the methylation pattern in collected mouse tongue tissues and human OSCC cell lines of different grades, respectively. These results showed that retinoic acid receptor ß (RARB) was indicated in hypermethylation at the promoter region and the loss of expression during cancer development. According to the results of real-time PCR, it was shown that de novo DNA methyltransferases were involved in gene epigenetic alternations of OSCC. Collectively, our results showed that RARB hypermethylation was involved in the areca-associated oral carcinogenesis.

Aerosolized bovine lactoferrin reduces lung injury and fibrosis in mice exposed to hyperoxia.

This study investigated the ability of aerosolized bovine lactoferrin (bLF) to protect the lungs from injury induced by chronic hyperoxia. Female CD-1 mice were exposed to hyperoxia (FiO2 = 80 %) for 7 days to induce lung injury and fibrosis. The therapeutic effects of bLF, administered via an aerosol delivery system, on the chronic lung injury induced by this period of hyperoxia were measured by bronchoalveolar lavage, lung histology, cell apoptosis, and inflammatory cytokines in the lung tissues. After exposure to hyperoxia for 7 days, the survival of the mice was significantly decreased to 20 %. The protective effects of bLF against hyperoxia were further confirmed by significant reductions in lung edema, total cell numbers in bronchoalveolar lavage fluid, inflammatory cytokines (IL-1ß and IL-6), pulmonary fibrosis, and apoptotic DNA fragmentation. The aerosolized bLF protected the mice from oxygen toxicity and increased the survival fraction to 66.7 % in the hyperoxic model. The results support the use of an aerosol therapy with bLF in intensive care units to reduce oxidative injury in patients with severe hypoxemic respiratory failure or chronic obstructive pulmonary disease.