Farnesyltransferase inhibitor lonafarnib suppresses respiratory syncytial virus infection by blocking conformational change of fusion glycoprotein.

Respiratory syncytial virus (RSV) is the major cause of bronchiolitis and pneumonia in young children and the elderly. There are currently no approved RSV-specific therapeutic small molecules available. Using high-throughput antiviral screening, we identified an oral drug, the prenylation inhibitor lonafarnib, which showed potent inhibition of the RSV fusion process. Lonafarnib exhibited antiviral activity against both the RSV A and B genotypes and showed low cytotoxicity in HEp-2 and human primary bronchial epithelial cells (HBEC). Time-of-addition and pseudovirus assays demonstrated that lonafarnib inhibits RSV entry, but has farnesyltransferase-independent antiviral efficacy. Cryo-electron microscopy revealed that lonafarnib binds to a triple-symmetric pocket within the central cavity of the RSV F metastable pre-fusion conformation. Mutants at the RSV F sites interacting with lonafarnib showed resistance to lonafarnib but remained fully sensitive to the neutralizing monoclonal antibody palivizumab. Furthermore, lonafarnib dose-dependently reduced the replication of RSV in BALB/c mice. Collectively, lonafarnib could be a potential fusion inhibitor for RSV infection.

The Emerging Role of Ubiquitin-Specific Protease 36 (USP36) in Cancer and Beyond.

The balance between ubiquitination and deubiquitination is instrumental in the regulation of protein stability and maintenance of cellular homeostasis. The deubiquitinating enzyme, ubiquitin-specific protease 36 (USP36), a member of the USP family, plays a crucial role in this dynamic equilibrium by hydrolyzing and removing ubiquitin chains from target proteins and facilitating their proteasome-dependent degradation. The multifaceted functions of USP36 have been implicated in various disease processes, including cancer, infections, and inflammation, via the modulation of numerous cellular events, including gene transcription regulation, cell cycle regulation, immune responses, signal transduction, tumor growth, and inflammatory processes. The objective of this review is to provide a comprehensive summary of the current state of research on the roles of USP36 in different pathological conditions. By synthesizing the findings from previous studies, we have aimed to increase our understanding of the mechanisms underlying these diseases and identify potential therapeutic targets for their treatment.

The emerging role of deubiquitylating enzyme USP21 as a potential therapeutic target in cancer.

Although certain members of the Ubiquitin-specific peptidases (USPs) have been recognized as promising therapeutic targets for various diseases, research progress regarding USP21 has been relatively sluggish in its early stages. USP21 is a crucial member of the USPs subfamily, involved in diverse cellular processes such as apoptosis, DNA repair, and signal transduction. Research findings from the past decade demonstrate that USP21 mediates the deubiquitination of multiple well-known target proteins associated with critical cellular processes relevant to both disease and homeostasis, particularly in various cancers.This reviewcomprehensively summarizes the structure and biological functions of USP21 with an emphasis on its role in tumorigenesis, and elucidates the advances on the discovery of tens of small-molecule inhibitors targeting USP21, which suggests that targeting USP21 may represent a potential strategy for cancer therapy.

The infection kinetics and transmission potential of two Guaico Culex viruses in Culex quinquefasciatus mosquitoes.

Guaico Culex virus (GCXV) is a newly identified segmented Jingmenvirus from Culex spp. mosquitoes in Central and South America. The genome of GCXV is composed of four or five single-stranded positive RNA segments. However, the infection kinetics and transmission capability of GCXV in mosquitoes remain unknown. In this study, we used reverse genetics to rescue two GCXVs (4S and 5S) that contained four and five RNA segments, respectively, in C6/36 â€‹cells. Further in vitro characterization revealed that the two GCXVs exhibited comparable replication kinetics, protein expression and viral titers. Importantly, GCXV RNAs were detected in the bodies, salivary glands, midguts and ovaries of Culex quinquefasciatus at 4-10 days after oral infection. In addition, two GCXVs can colonize Cx. quinquefasciatus eggs, resulting in positive rates of 15%-35% for the second gonotrophic cycle. In conclusion, our results demonstrated that GCXVs with four or five RNA segments can be detected in Cx. quinquefasciatus eggs during the first and second gonotrophic cycles after oral infection.

Rapid development of double-hit mRNA antibody cocktail against orthopoxviruses.

The Orthopoxvirus genus, especially variola virus (VARV), monkeypox virus (MPXV), remains a significant public health threat worldwide. The development of therapeutic antibodies against orthopoxviruses is largely hampered by the high cost of antibody engineering and manufacturing processes. mRNA-encoded antibodies have emerged as a powerful and universal platform for rapid antibody production. Herein, by using the established lipid nanoparticle (LNP)-encapsulated mRNA platform, we constructed four mRNA combinations that encode monoclonal antibodies with broad neutralization activities against orthopoxviruses. In vivo characterization demonstrated that a single intravenous injection of each LNP-encapsulated mRNA antibody in mice resulted in the rapid production of neutralizing antibodies. More importantly, mRNA antibody treatments showed significant protection from weight loss and mortality in the vaccinia virus (VACV) lethal challenge mouse model, and a unique mRNA antibody cocktail, Mix2a, exhibited superior in vivo protection by targeting both intracellular mature virus (IMV)-form and extracellular enveloped virus (EEV)-form viruses. In summary, our results demonstrate the proof-of-concept production of orthopoxvirus antibodies via the LNP-mRNA platform, highlighting the great potential of tailored mRNA antibody combinations as a universal strategy to combat orthopoxvirus as well as other emerging viruses.

Curriculum vitae of CUG binding protein 1 (CELF1) in homeostasis and diseases: a systematic review.

RNA-binding proteins (RBPs) are kinds of proteins with either singular or multiple RNA-binding domains (RBDs), and they can assembly into ribonucleic acid-protein complexes, which mediate transportation, editing, splicing, stabilization, translational efficiency, or epigenetic modifications of their binding RNA partners, and thereby modulate various physiological and pathological processes. CUG-BP, Elav-like family 1 (CELF1) is a member of the CELF family of RBPs with high affinity to the GU-rich elements in mRNA, and thus exerting control over critical processes including mRNA splicing, translation, and decay. Mounting studies support that CELF1 is correlated with occurrence, genesis and development and represents a potential therapeutical target for these malignant diseases. Herein, we present the structure and function of CELF1, outline its role and regulatory mechanisms in varieties of homeostasis and diseases, summarize the identified CELF1 regulators and their structure-activity relationships, and prospect the current challenges and their solutions during studies on CELF1 functions and corresponding drug discovery, which will facilitate the establishment of a targeted regulatory network for CELF1 in diseases and advance CELF1 as a potential drug target for disease therapy.

Sleep duration and mortality in patients with chronic noncommunicable disease: a population-based cohort study.

BACKGROUND: Inadequate sleep behaviors may confer a higher risk of premature death, however, evidence in patients with chronic noncommunicable disease (NCD) is scarce. To investigate the relationship between sleep duration and mortality from all-cause and heart diseases in NCD patients from a prospective cohort. METHODS: Totally, 14,171 participants with at least one NCD, including 8275 with hypertension, 7547 with high cholesterol, 4065 with diabetes, and 5815 with chronic renal failure were enrolled from the National Health and Nutrition Examination Survey during 2005-2014. Cox proportional hazard models were performed to estimate the hazard ratio (HR) for sleep duration and mortality after adjusting for potential confounding factors. RESULTS: After a median follow-up of 9 years, 2514 all-cause deaths were identified. Compared with sleeping 7-8 h/day, sleeping over 8 h/day was significantly associated with a higher risk of all-cause mortality, where the multivariable-HRs were 1.29 (1.11, 1.50) for hypertension, 1.23 (1.01, 1.51) for high cholesterol, 1.44 (1.13, 1.82) for diabetes, and 1.36 (1.10, 1.68) for chronic renal failure. Similar patterns were observed for heart disease mortality. A nonlinear association was detected between sleep duration and mortality in patients with NCD. Age modified the association in patients with hypertension (P-interaction: 0.036). Trouble sleeping modified the association in patients with diabetes (P-interaction: 0.042). CONCLUSIONS: Long sleep duration was associated with higher risks of all-cause and heart disease mortality in patients with chronic NCD. Our findings highlight that improving sleep behaviors may decrease the risk of premature deaths and help to NCD tertiary prevention.

Characterization of Two Gonadal Genes, zar1 and wt1b, in Hermaphroditic Fish Asian Seabass (Lates calcarifer).

Zygote arrest-1 (Zar1) and Wilms' tumor 1 (Wt1) play an important role in oogenesis, with the latter also involved in testicular development and gender differentiation. Here, Lczar1 and Lcwt1b were identified in Asian seabass (Lates calcarifer), a hermaphrodite fish, as the valuable model for studying sex differentiation. The cloned cDNA fragments of Lczar1 were 1192 bp, encoding 336 amino acids, and contained a zinc-binding domain, while those of Lcwt1b cDNA were 1521 bp, encoding a peptide of 423 amino acids with a Zn finger domain belonging to Wt1b family. RT-qPCR analysis showed that Lczar1 mRNA was exclusively expressed in the ovary, while Lcwt1b mRNA was majorly expressed in the gonads in a higher amount in the testis than in the ovary. In situ hybridization results showed that Lczar1 mRNA was mainly concentrated in oogonia and oocytes at early stages in the ovary, but were undetectable in the testis. Lcwt1b mRNA was localized not only in gonadal somatic cells (the testis and ovary), but also in female and male germ cells in the early developmental stages, such as those of previtellogenic oocytes, spermatogonia, spermatocytes and spermatids. These results indicated that Lczar1 and Lcwt1b possibly play roles in gonadal development. Therefore, the findings of this study will provide a basis for clarifying the mechanism of Lczar1 and Lcwt1b in regulating germ cell development and the sex reversal of Asian seabass and even other hermaphroditic species.

The subgenomic flaviviral RNA suppresses RNA interference through competing with siRNAs for binding RISC components.

During the life cycle of mosquito-borne flaviviruses, substantial subgenomic flaviviral RNA (sfRNA) is produced via incomplete degradation of viral genomic RNA by host XRN1. Zika virus (ZIKV) sfRNA has been detected in mosquito and mammalian somatic cells. Human neural progenitor cells (hNPCs) in the developing brain are the major target cells of ZIKV, and antiviral RNA interference (RNAi) plays a critical role in hNPCs. However, whether ZIKV sfRNA was produced in ZIKV-infected hNPCs as well as its function remains not known. In this study, we demonstrate that abundant sfRNA was produced in ZIKV-infected hNPCs. RNA pulldown and mass spectrum assays showed ZIKV sfRNA interacted with host proteins RHA and PACT, both of which are RNA-induced silencing complex (RISC) components. Functionally, ZIKV sfRNA can antagonize RNAi by outcompeting small interfering RNAs (siRNAs) in binding to RHA and PACT. Furthermore, the 3' stem loop (3'SL) of sfRNA was responsible for RISC components binding and RNAi inhibition, and 3'SL can enhance the replication of a viral suppressor of RNAi (VSR)-deficient virus in a RHA- and PACT-dependent manner. More importantly, the ability of binding to RISC components is conversed among multiple flaviviral 3'SLs. Together, our results identified flavivirus 3'SL as a potent VSR in RNA format, highlighting the complexity in virus-host interaction during flavivirus infection.IMPORTANCEZika virus (ZIKV) infection mainly targets human neural progenitor cells (hNPCs) and induces cell death and dysregulated cell-cycle progression, leading to microcephaly and other central nervous system abnormalities. RNA interference (RNAi) plays critical roles during ZIKV infections in hNPCs, and ZIKV has evolved to encode specific viral proteins to antagonize RNAi. Herein, we first show that abundant sfRNA was produced in ZIKV-infected hNPCs in a similar pattern to that in other cells. Importantly, ZIKV sfRNA acts as a potent viral suppressor of RNAi (VSR) by competing with siRNAs for binding RISC components, RHA and PACT. The 3'SL of sfRNA is responsible for binding RISC components, which is a conserved feature among mosquito-borne flaviviruses. As most known VSRs are viral proteins, our findings highlight the importance of viral non-coding RNAs during the antagonism of host RNAi-based antiviral innate immunity.

Spin-torque-driven antiferromagnetic resonance.

The intrinsic fast dynamics make antiferromagnetic spintronics a promising avenue for faster data processing. Ultrafast antiferromagnetic resonance-generated spin current provides valuable access to antiferromagnetic spin dynamics. However, the inverse effect, spin-torque-driven antiferromagnetic resonance (ST-AFMR), which is attractive for practical utilization of fast devices but seriously impeded by difficulties in controlling and detecting Néel vectors, remains elusive. We observe ST-AFMR in Y3Fe5O12/α-Fe2O3/Pt at room temperature. The Néel vector oscillates and contributes to voltage signal owing to antiferromagnetic negative spin Hall magnetoresistance-induced spin rectification effect, which has the opposite sign to ferromagnets. The Néel vector in antiferromagnetic α-Fe2O3 is strongly coupled to the magnetization in Y3Fe5O12 buffer, resulting in the convenient control of Néel vectors. ST-AFMR experiment is bolstered by micromagnetic simulations, where both the Néel vector and the canted moment of α-Fe2O3 are in elliptic resonance. These findings shed light on the spin current-induced dynamics in antiferromagnets and represent a step toward electrically controlled antiferromagnetic terahertz emitters.

Adenosine Triphosphate-Activated Cascade Reactor for On-Demand Antibacterial Treatment Through Controlled Hydroxyl Radical Generation.

Nanozymes have shown promise for antibacterial applications, but their effectiveness is often hindered by low catalytic performances in physiological conditions and uncontrolled production of hydroxyl radicals (·OH). To address these limitations, a comprehensive approach is presented through the development of an adenosine triphosphate (ATP)-activated cascade reactor (GGPcs). The GGPcs reactor synergistically combines the distinct properties of zeolitic imidazolate framework-8 (ZIF-8) and chitosan-integrated hydrogel microsphere. The ZIF-8 allows for the encapsulation of G-quadruplex/hemin DNAzyme to achieve ATP-responsive ·OH generation at neutral pH, while the hydrogel microsphere creates a confinement environment that facilitates glucose oxidation and provides a sufficient supply of H2O2. Importantly, the integrated chitosan in the hydrogel microsphere shields ZIF-8 from undesired disruption caused by gluconic acid, ensuring the responsive specificity of ZIF-8 toward ATP. By activating GGPcs with ATP secreted by bacteria, its effectiveness as an antibacterial agent is demonstrated for the on-demand treatment of bacterial infection with minimal side effects. This comprehensive approach has the potential to facilitate the design of advanced nanozyme systems and broaden their biological applications.

Chimeric antigen receptor natural killer cells: a promising antitumor immunotherapy.

Chimeric antigen receptor (CAR) T cells have been successfully used in adoptive cell therapy for malignancies. However, some obstacles, including side effects such as graft-versus-host disease and cytokine release syndrome, therapy resistance, limited sources, as well as high cost, limited the application of CAR T cells. Recently, CAR natural killer (NK) cells have been pursued as the effector cells for adoptive immunotherapy for their attractive merits of strong intrinsic antitumor activity and relatively mild side effects. Additionally, CAR NK cells can be available from various sources and do not require strict human leukocyte antigen matching, which suggests them as promising "off-the-shelf" products for clinical application. Although the use of CAR NK cells is restrained by the limited proliferation and impaired efficiency within the immunosuppressive tumor microenvironment, further investigation in optimizing CAR structure and combination therapies will overcome these challenges. This review will summarize the advancement of CAR NK cells, CAR NK cell manufacture, the clinical outcomes of CAR NK therapy, the challenges in the field, and prospective solutions. Besides, we will discuss the emerging application of other immune cells for CAR engineering. Collectively, this comprehensive review will provide a valuable and informative summary of current progress and evaluate challenges and future opportunities of CAR NK cells in tumor treatment.

Analysis of the protective efficacy of approved COVID-19 vaccines against Omicron variants and the prospects for universal vaccines.

By the end of 2022, different variants of Omicron had rapidly spread worldwide, causing a significant impact on the Coronavirus disease 2019 (COVID-19) pandemic situation. Compared with previous variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), these new variants of Omicron exhibited a noticeable degree of mutation. The currently developed platforms to design COVID-19 vaccines include inactivated vaccines, mRNA vaccines, DNA vaccines, recombinant protein vaccines, virus-like particle vaccines, and viral vector vaccines. Many of these platforms have obtained approval from the US Food and Drug Administration (FDA) or the WHO. However, the Omicron variants have spread in countries where vaccination has taken place; therefore, the number of cases has rapidly increased, causing concerns about the effectiveness of these vaccines. This article first discusses the epidemiological trends of the Omicron variant and reviews the latest research progress on available vaccines. Additionally, we discuss progress in the development progress and practical significance of universal vaccines. Next, we analyze the neutralizing antibody effectiveness of approved vaccines against different variants of Omicron, heterologous vaccination, and the effectiveness of multivalent vaccines in preclinical trials. We hope that this review will provide a theoretical basis for the design, development, production, and vaccination strategies of novel coronavirus vaccines, thus helping to end the SARS-CoV-2 pandemic.

An updated review of epidemiological characteristics, immune escape, and therapeutic advances of SARS-CoV-2 Omicron XBB.1.5 and other mutants.

The rapid evolution of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has led to the emergence of new variants with different genetic profiles, with important implications for public health. The continued emergence of new variants with unique genetic features and potential changes in biological properties poses significant challenges to public health strategies, vaccine development, and therapeutic interventions. Omicron variants have attracted particular attention due to their rapid spread and numerous mutations in key viral proteins. This review aims to provide an updated and comprehensive assessment of the epidemiological characteristics, immune escape potential, and therapeutic advances of the SARS-CoV-2 Omicron XBB.1.5 variant, as well as other variants.

Ruderman-Kittel-Kasuya-Yosida-Type Interlayer Dzyaloshinskii-Moriya Interaction in Synthetic Magnets.

Conduction electron spins interacting with magnetic impurity spins can mediate an interlayer exchange interaction, namely, the Ruderman-Kittel-Kasuya-Yosida (RKKY) interaction. This discovery opened the way to significant technological developments in the field of magnetic storage and spintronics. So far, the RKKY-type interlayer interaction has been found to construct symmetric coupling of magnetism; however, the asymmetric counterpart remains unexplored. Here we report unprecedented RKKY-type interlayer Dzyaloshinskii-Moriya interaction (DMI) in synthetic magnets, exhibiting a damped oscillatory feature. This asymmetric interlayer interaction is found to be dramatically dependent on the intermediate coupling layer. By introducing the Fert-Lévy model to the trilayer system, we reveal that the in-plane inversion symmetry breaking plays a pivotal role for generating interlayer DMI and the RKKY oscillation is an intrinsic behavior in metallic multilayers. Our finding fills up the empty block for RKKY-type asymmetric interlayer exchange coupling in comparison to the well-known (symmetric) RKKY-type interlayer exchange coupling.

Lysine-specific demethylase 7A (KDM7A): A potential target for disease therapy.

Histone demethylation is a kind of epigenetic modification mediated by a variety of enzymes and participates in regulating multiple physiological and pathological events. Lysine-specific demethylase 7A is a kind of α-ketoglutarate- and Fe(II)-dependent demethylase belonging to the PHF2/8 subfamily of the JmjC demethylases. KDM7A is mainly localized in the nucleus and contributes to transcriptional activation via removing mono- and di-methyl groups from the lysine residues 9 and 27 of Histone H3. Mounting studies support that KDM7A is not only necessary for normal embryonic, neural, and skeletal development, but also associated with cancer, inflammation, osteoporosis, and other diseases. Herein, the structure of KDM7A is described by comparing the similarities and differences of its amino acid sequences of KDM7A and other Histone demethylases; the functions of KDM7A in homeostasis and dyshomeostasis are summarized via documenting its content and related signaling; the currently known KDM7A-specific inhibitors and their structural relationship are listed based on their structure optimization and pharmacological activities; and the challenges and opportunities in exploring functions and developing targeted agents of KDM7A are also prospected via presenting encountered problems and potential solutions, which will provide an insight in functional exploration and drug discovery for KDM7A-related diseases.

Ordered creation and motion of skyrmions with surface acoustic wave.

Magnetic skyrmions with a well-defined spin texture have shown unprecedented potential for various spintronic applications owning to their topologically non-trivial and quasiparticle properties. To put skyrmions into practical technology, efficient manipulation, especially the inhibition of skyrmion Hall effect (SkHE) has been intensively pursued. In spite of the recent progress made on reducing SkHE in several substituted systems, such as ferrimagnets and synthetic antiferromagnets, the organized creation and current driven motion of skyrmions with negligible SkHE in ferromagnets remain challenging. Here, by embedding the [Co/Pd] multilayer into a surface acoustic wave (SAW) delay line where the longitudinal leaky SAW is excited to provide both the strain and thermal effect, we experimentally realized the ordered generation of magnetic skyrmions. The resultant current-induced skyrmions movement with negligible SkHE was observed, which can be attributed to the energy redistribution of the system during the excitation of SAW. Our findings open up an unprecedentedly new perspective for manipulating topological solitons, which could possibly trigger the future discoveries in skyrmionics and spin acousto-electronics.

Total Synthesis of (-)-Retigeranic Acid A: A Reductive Skeletal Rearrangement Strategy.

The asymmetric total synthesis of (-)-retigeranic acid A was described, which relies on a crucial reductive skeletal rearrangement cascade for the controllable assembly of diverse angular triquinane subunits. Taken together with an intramolecular Michael/aldol cyclization, an ODI-[5 + 2] cycloaddition/pinacol rearrangement cascade, a Wolff ring contraction and a stereoselective HAT reduction, our synthetic approach has enabled the access to (-)-retigeranic acid A in a concise and practical manner.

ATTIC is an integrated approach for predicting A-to-I RNA editing sites in three species.

A-to-I editing is the most prevalent RNA editing event, which refers to the change of adenosine (A) bases to inosine (I) bases in double-stranded RNAs. Several studies have revealed that A-to-I editing can regulate cellular processes and is associated with various human diseases. Therefore, accurate identification of A-to-I editing sites is crucial for understanding RNA-level (i.e. transcriptional) modifications and their potential roles in molecular functions. To date, various computational approaches for A-to-I editing site identification have been developed; however, their performance is still unsatisfactory and needs further improvement. In this study, we developed a novel stacked-ensemble learning model, ATTIC (A-To-I ediTing predICtor), to accurately identify A-to-I editing sites across three species, including Homo sapiens, Mus musculus and Drosophila melanogaster. We first comprehensively evaluated 37 RNA sequence-derived features combined with 14 popular machine learning algorithms. Then, we selected the optimal base models to build a series of stacked ensemble models. The final ATTIC framework was developed based on the optimal models improved by the feature selection strategy for specific species. Extensive cross-validation and independent tests illustrate that ATTIC outperforms state-of-the-art tools for predicting A-to-I editing sites. We also developed a web server for ATTIC, which is publicly available at http://web.unimelb-bioinfortools.cloud.edu.au/ATTIC/. We anticipate that ATTIC can be utilized as a useful tool to accelerate the identification of A-to-I RNA editing events and help characterize their roles in post-transcriptional regulation.