Elsevier最新文献

The papain-like protease (PLpro) is a highly conserved domain encoded by the coronavirus (CoV) genome and it plays an essential role in the replication and maturation of the virus in addition to weakening host immune response. Due to the virus's reliance on PLpro for survival and propagation, small-molecule inhibitors of PLpro serve as an attractive model for direct-acting antiviral therapeutic agents against SARS-CoV-2. Building upon existing work aimed at designing covalent inhibitors against PLpro, we report the synthesis and structure-activity relationship of analogs based on the known covalent inhibitor 1 (Sanders, et al.2023). To evaluate the efficacy of synthesized derivatives, we conducted enzymatic inhibition assays, SARS-CoV-2/HeLa-ACE2 cellular potency and toxicity assays, and profiled the most promising analogs via in vitro ADME and in vivo pharmacokinetic studies. Additionally, we describe computational docking of profiled compounds bound to PLpro to elucidate the structure-activity relationship of compounds based on 1 and offer suggestions for optimizing the potency and selectivity of the electrophilic warhead and improving ADME and PK properties for this chemotype. Relative to the parent compound, new designs demonstrate comparable potency and target selectivity for PLpro. The accomplished SAR campaign provides novel insight for future development of antivirals against SARS-CoV-2.

Seeking new drug candidates among compounds of natural origin is an effective and widely used method of fighting various diseases, especially cancer. Lasalocid acid is one of the naturally occurring polyether ionophore antibiotics, which also exhibits interesting anticancer activity. Therefore, to expand the knowledge about the anticancer properties of lasalocid derivatives, a series of its new amides were synthesized and their antiproliferative activity against cancer cell lines was studied. Amides 7-9 with an aromatic substituent, displayed potent antiproliferative activity (IC₅₀: 0.84-5.18 μM) and demonstrated a good selectivity index (SI: 1.4-15.3). Furthermore, almost all of lasalocid amides overcame the drug resistance of the doxorubicin-resistant cancer cell line (LoVo/DX). Because the biological activity of ionophores is strictly connected with their ability to transport the Na⁺ cation through lipid bilayers, the crystal structure of the complex of compound 8 with the Na⁺ cation was resolved. Lasalocid amides exhibit a pseudocyclic structure and are able to coordinate the Na⁺ cation.

Effective detection technologies in food safety with the merits of portable and on-site detection potential are always in pressing demand. Herein, we developed a nanopore-assisted Enzyme-linked immunosorbent assay (NELISA) platform, which innovatively introduced hairpin DNA (HP DNA) probes as reaction substrates. This innovation of substrates effectively avoided the inherent limitations of colorimetric signals (i.e., low sensitivity and inaccurate results) and greatly improved the sensitivity and accuracy of NELISA platform. The alkaline phosphatase (ALP)-modified detection antibody (ALP-Ab2) can specifically bind to ricin and hydrolyze the phosphate groups modified on the HP DNA probes. Nanopore recordings demonstrated that two states of probes produced highly distinguishable nanopore events, enabling the qualitative and quantitative detection of ricin. This NELISA platform fully combined the specificity of ELISA with the ultra-sensitivity, and unique single-molecule fingerprint recognition of nanopore, showing a great on-site detection potential. This method achieved the ultrasensitive and reliable detection of ricin down to 2.46 fg/mL, which enhanced the detection sensitivity by at least 10⁶-fold compared to traditional ELISA. Furthermore, the proposed method was capable of accurately detecting ricin in real food samples with satisfactory recoveries.

Epidermal Growth Factor Receptor (EGFR) is an important target for the early evaluation, treatment, and postoperative follow-up in non-small cell lung cancer (NSCLC). Current detection technologies suffer from extended detection time and high rate of false positive amplification. Therefore, the development of rapid, highly sensitive and specific detection methods is of great significance for improving the diagnosis and treatment of lung cancer. In this study, we proposed a fast and sensitive detection method termed Thermus thermophilus Argonaute (Ttago)-Coupled-Multiplex-digital-recombinase polymerase amplification (RPA)-Clustered regularly interspaced short palindromic repeats (CRISPR)/Cas12a (TCMDC) detection method, integrating EGFR mutation template enrichment. Based on the cleavage principle of TtAgo, the wild type (WT) template was enriched under the action of double-guide DNA. Two CRISPR RNAs, not restricted by protospacer adjacent motif (PAM) sites, were introduced to target EGFR genes. By combining RPA with CRISPR-Cas12a, we established a single-pot, ultra-sensitive (1 copy, 0.1 %), and visually detectable method for EGFR detection. We further verified the feasibility of this approach using clinical serum samples from lung cancer patients, achieving rapid (within 1 h) and visual detection of EGFR, thereby presenting a promising clinical tool for the detection of lung cancer.

Introduction: Global outbreaks of mosquito-transmitted arbovirus infections, such as dengue (DENV) and chikungunya (CHIKV), are increasing. Differentiating these infections is challenging due to non-specific symptoms and serology limitations. PCR-based approaches offer higher sensitivity and specificity. This study evaluated the performance of TaqMan™ Arbovirus Triplex Kit (ZIKV/DENV/CHIKV) (TaqMan™ Kit) to detect DENV and CHIKV in clinical samples from patients in south India.

Methods: In total, 280 serum samples with 90 DENV-positive, 90 CHIKV-positive, and 100 negative samples were tested with TaqMan™ Kit and CDC Trioplex Real-Time RT-PCR assay. No Zika virus was detected. The sensitivity and specificity of viral RNA detection were determined, and discordant results were resolved using comparator PCRs, dengue NS1 antigen detection, virus-specific antibody results, or previously de-identified in-house PCR results.

Results: TaqMan™ Kit showed 100 % agreement with the comparator for DENV detection in 92 positive samples. Among 188 samples negative for DENV by the comparator, 30 showed positive results with the TaqMan™ kit, and 23 of those were confirmed as true positives. The resulting sensitivity and specificity for DENV detection were 100 % and 95.1 %, respectively. For CHIKV, 77 positive and 195 negative results were concordant. Eight samples showed discordant results, but upon resolution testing, sensitivity and specificity for CHIKV were 93.9 % and 100.0 %, respectively.

Conclusion: TaqMan™ Arbovirus Triplex Kit demonstrated high sensitivity and specificity (>93 %) for detecting circulating DENV and CHIKV strains. Multiplex PCR testing can improve case detection, surveillance, and public health responses while optimizing laboratory resources for outbreak control.

Monkeypox (mpox) is a rare viral disease that can cause severe illness in humans, with outbreaks occurring primarily in central and western Africa. Well-coordinated and synchronized efforts are necessary to understand the factors involved in disease transmission and develop effective health interventions. The aim of this study is to assess the relationship between climate factors and daily mpox cases, as well as to identify the most suitable predictive model for transmission. We analyzed confirmed mpox cases from May 5, 2022, to February 14, 2023, in the 33 most affected countries. We employed and compared the efficiency of four models: Poisson, negative binomial, zero-inflated Poisson, and zero-inflated negative binomial. We found a significant correlation between climate factors and daily mpox cases across most of the studied countries. Specifically, for each 1°C increase in the heat index (HI), daily cases increased by 7.7 % (IRR = 1.077, p < 0.05). Conversely, higher relative humidity (RH) decreased daily cases by 2.4 %, and increased wind speed (WS) reduced them by 7.3 %. The HI positively influences mpox spread, while RH and WS act as protective factors. Public health officials should consider these climate influences when developing targeted interventions.

The application of solid-state electrolytes (SSEs) is anticipated to enhance the safety performance of lithium metal batteries (LMBs). However, the progress of SSEs has been hindered by the unstable electrode-electrolyte interfaces (EEIs). In this study, in-situ polymerization of 1,3-dioxolane (DOL) is employed for the preparation of SSEs, with the addition of tributyl borate (TBB) to establish stable EEIs, particularly under high-voltage conditions. On one hand, the addition of TBB promotes the dissociation of lithium salts and increases the concentration of free Li⁺, resulting in an increase in room temperature ionic conductivity to 1.13 × 10^-4 S cm^-1 and an improvement in the Li⁺ transference number to 0.69 for the prepared poly-DOL electrolytes (PDE-TBB). Benefiting from the enhanced Li⁺ transport, the Li/PDE-TBB/Li symmetric cell exhibits a cycle life exceeding 1,000 h with a low polarization voltage as low as 12 mV, and the Li/PDE-TBB/LiFePO₄ cell demonstrates exceptional cyclic stability over 800 cycles at 1C, with a coulombic efficiency exceeding 99.8 % and a capacity retention of 89.6 %. On the other hand, PDE-TBB exhibits improved stability under high-voltage conditions and the capacity to establish robust boron-rich cathode electrolyte interphase (CEI) on the LiNi_0.8Co_0.1Mn_0.1O₂ (NCM811) surface, thereby enhancing the structural stability of cathode materials and ensuring exceptional cycling performance of Li/PDE-TBB/NCM811cell. This work presents a promising strategy for developing novel ether-based SSEs suitable for high-voltage lithium metal batteries.

The electrochemical performance of lithium metal batteries (LMBs) was hampered by the uncontrolled growth of lithium (Li) dendrites. To address this issue, the extensive application of artificial solid electrolyte interphase (SEI) coatings on anode surfaces emerged as an effective solution. Electrospinning, as an innovative technique for fabricating artificial SEI layers on the surface of copper (Cu) foil, effectively mitigated Li volume strain during cycling. In this study, an electrospun organic-inorganic composite nanofiber membrane was in-situ fabricated on Cu foil, serving as an artificial SEI layer (CuWs) for anode-free LMBs (AF-LMBs) to enhance battery performance. Lithiophilic polyvinylpyrrolidone was used as the polymer matrix, and Cu nitrate served as the inorganic functional particles capable of in-situ redox reactions. The CuWs with their three-dimensional (3D) network structure accommodated electrode volume changes and suppressed Li dendrite growth during Li deposition and stripping. Additionally, CuWs facilitated the in-situ generation of Li nitrate (LiNO₃), which helped stabilize SEI layer and enhance Li utilization. The release sites of LiNO₃ on the nanofibers enabled the in-situ reduction of metallic Cu, providing nucleation sites for Li deposition and forming the 3D ion-electron hybrid conductive networks. This CuWs layer reduced interfacial resistance and nucleation barriers, promoting uniform Li⁺ distribution on the anode surface. Li-Cu cells incorporating CuWs exhibited remarkable cycling stability, enduring over 460 cycles at 1.0 mA cm^-2 and 1.0 mAh cm^-2 with an average Coulombic efficiency of over 98.6 %. In Li-poor cells, the LFP|PE|CuWs achieved stable cycling for more than 30 cycles at 1.0 C, with a capacity retention rate of 92.0 %. These findings demonstrated that the CuWs membrane significantly enhanced the electrochemical performance of Li-poor cells and provided a novel artificial SEI protective strategy for advanced AF-LMBs with high energy density.