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Development of potent and broad‐spectrum drugs against severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) remains one of the top priorities, especially in the cases of the emergence of mutant viruses and inability of current vaccines to prevent viral transmission. In this study, we have generated a novel membrane fusion‐inhibitory lipopeptide IPB29, which is currently under clinical trials; herein, we report its design strategy and preclinical data. First, we surprisingly found that IPB29 with a rigid linker between the peptide sequence and lipid molecule had greatly improved α‐helical structure and antiviral activity. Second, IPB29 potently inhibited a large panel of SARS‐CoV‐2 variants including the previously and currently circulating viruses, such as Omicron XBB.5.1 and EG.5.1. Third, IPB29 could also cross‐neutralize the bat‐ and pangolin‐isolated SARS‐CoV‐2‐related CoVs (RatG13, PCoV‐GD, and PCoV‐GX) and other human CoVs (SARS‐CoV, MERS‐CoV, HCoV‐NL63, and HCoV‐229E). Fourth, IPB29 administrated as an inhalation solution (IPB29‐IS) in Syrian hamsters exhibited high therapeutic and preventive efficacies against SARS‐CoV‐2 Delta or Omicron variant. Fifth, the pharmacokinetic profiles and safety pharmacology of IPB29‐IS were extensively characterized, providing data to support its evaluation in humans. In conclusion, our studies have demonstrated a novel design strategy for viral fusion inhibitors and offered an ideal drug candidate against SARS‐CoV‐2 and other coronaviruses. [ABSTRACT FROM AUTHOR]

LCB1 is a computationally designed three-helix miniprotein that precisely targets the spike (S) receptor-binding motif (RBM) of SARS-CoV-2, exhibiting remarkable antiviral efficacy; however, emerging SARS-CoV-2 variants could substantially compromise its neutralization effectiveness. In this study, we constructed two multivalent LCB1 fusion proteins termed LCB1T and LCB1T-Fc, and characterized their potency in inhibiting SARS-CoV-2 pseudovirus and authentic virus in vitro. In the inhibition of various SARS-CoV-2 variants, the two LCB1 fusion proteins exhibited markedly improved inhibitory activities compared to LCB1 as anticipated; however, it was observed that relative to the D614G mutation hosting variant, the variants Delta, Lambda, and Omicron BQ.1.1, XBB, XBB.1.5, and EG.5.1 caused various degrees of resistance to the two fusion proteins' inhibition, with XBB, XBB.1.5, and EG.5.1 variants showing high-level resistance. Moreover, we demonstrated that bat coronavirus RaTG13 and pangolin coronavirus PCoV-GD/PCoV-GX were highly sensitive to two LCB1 fusion proteins, but not LCB1, inhibition. Importantly, our findings revealed a notable decrease in the blocking capacity of the multivalent LCB1 inhibitor on the interaction between the virus's RBD/S and the cell receptor ACE2 when confronted with the XBB variant compared to WT and the Omicron BA.1 variant. In conclusion, our studies provide valuable insights into the antiviral profiling of multivalent LCB1 inhibitors and offer a promising avenue for the development of novel broad-spectrum antiviral therapeutics. [ABSTRACT FROM AUTHOR]

Background: To retrospectively analyze the short-term outcomes of catheter-based versus direct foam sclerotherapy when combined with high ligation (HL) for the treatment of great saphenous vein (GSV) incompetence. Methods: From July 2018 to October 2019, a total of 82 lower limbs of 70 patients with GSV incompetence received HL combined with catheter-based foam sclerotherapy (CFS group) or direct foam sclerotherapy (DFS group) for GSV proximal trunk. Among them, 40 limbs of 36 patients were treated with CFS, and 42 limbs of 34 patients were treated with DFS. The occlusion of GSV proximal trunk was evaluated with venous duplex ultrasound examinations; Venous Clinical Severity Scores (VCSS) was used to assess clinical improvement; Aberdeen Varicose Veins Questionnaire (AVVQ) was used to assess quality-of-life scores; and Complications was used for the safety evaluation. Results: At day 7 post-operatively, complete occlusion of proximal trunk of the GSV was achieved in 92.5% legs of the CFS group and 71.4% of the DFS group (p = 0.014). Additionally, anterograde flow was found in 7.5% legs of the CFS group and 26.2% of the DFS group (p = 0.025). No significant differences in the occurrence of complications were observed between the two groups. The median follow-up was 285.5 days in the DFS group and 318 days in the CFS group (p = 0.140). VCSS and AVVQ reduction were significant in both CFS group and DFS group (5.3 ± 2.5, 5.5 ± 2.4, p < 0.001 for VCSS; 15.9 ± 8.0, 16.3 ± 8.6, p < 0.001 for AVVQ), but no significant difference were observed between two groups (p = 0.655 for VCSS, p = 0.934 for AVVQ). Conclusions: Although the occlusion of great saphenous vein proximal trunk were different, two modalities result in similar clinical and quality-of-life improvements. DFS is a feasible alternative to CFS when combined with HL. [ABSTRACT FROM AUTHOR]

The role of the thymus in HIV-1 pathogenesis remains unclear. We developed an assay to quantify the number of recent thymic emigrants in blood based on the detection of a major excisional DNA byproduct (termed alpha1 circle) of T cell receptor rearrangement. By studying 532 normal individuals, we found that alpha1 circle numbers in blood remain high for the first 10-15 yr of life, a sharp drop is seen in the late teen years, and a gradual decline occurs thereafter. Compared with age-matched uninfected control individuals, alpha1 circle numbers in HIV-1-infected adults were significantly reduced; however, there were many individuals with normal alpha1 circle numbers. In 74 individuals receiving highly active antiretroviral therapy, we found no appreciable effect on alpha1 circle numbers in those whose baseline values were already within the normal range, but significant increases were observed in those with a preexisting impairment. The increases in alpha1 circle numbers were, however, numerically insufficient to account for the rise in levels of naive T lymphocytes. Overall, it is difficult to invoke thymic regenerative failure as a generalized mechanism for CD4 lymphocyte depletion in HIV-1 infection, as alpha1 circle numbers are normal in a substantial subset of HIV-1-infected individuals.

In response to the localized corrosion generated by underground casing, which seriously affects the safe operation of salt cavern compressed air storage, we used commercial finite element software, ANSYS, to propose a partial model applicable to casings with pitting and strip corrosion. The results show that the pitting depth of the casing is closely related to fracture and collapse pressure. As pitting corrosion depth increases, its effect on fracture and collapse pressure becomes more significant. The greater the number of corrosion pits, the lower the compressive strength of the casing, and the casing tends to be more prone to fracture. The area with large stress is mainly distributed along the long axis of the strip corrosion. In the short axis of the strip corrosion, there is no stress concentration and appears as a low stress region. The effect of strip corrosion depth on failure pressure is greater than the effect of strip corrosion length. In this work, we developed a method to predict residual strength, which is useful to assess not only well integrity but, additionally, safety of the casing used during petroleum and natural gas exploration and production. [ABSTRACT FROM AUTHOR]

The casing leakage phenomenon seriously affects the safety and economic problems of oil and gas production and transportation. In this paper, the numerical simulation study of the casing's micro-leakage flow field and acoustic field is carried out by taking the oil and gas well casing as the research object. The CFD numerical model of the casing micro-leakage is established, and the influence of the size of the leakage hole, the shape of the leakage hole, and the pressure difference between the inside and outside the casing on the microleakage flow field is analyzed. An acoustic-vibroacoustic coupling calculation model based on Fluent and LMS Virtual LAB is established, and the sound pressure value and distribution at different frequencies are calculated. The results show that the flow rate of the leakage hole increases with the pressure difference between the inside and the outside leakage hole and the area of the leakage hole. Moreover, the flow rate of the circular leakage hole is higher for the same leakage hole area. The simulation model based on the equivalent sound source can be used to calculate and analyze the sound field in the tubing. By sound field computation based on the near-field equivalent sound source, when the frequency is 32,000 Hz, the amplitude of sound pressure is maximum. In addition, the sound pressure is greatly reduced once the sound wave passes through the tubing pipeline. Lastly, the sound pressure is higher at the position facing the leakage hole in the tubing, making detecting the leakage sound field signal easier. The results can provide a reference for further research on oil casing microleakage detection technology. [ABSTRACT FROM AUTHOR]