The HIV-1 Protein Vpr Targets the Endoribonuclease Dicer for Proteasomal Degradation to Boost Macrophage Infection

The HIV-1 protein Vpr enhances macrophage infection, triggers G2 cell cycle arrest, and targets cells for NK-cell killing. Vpr acts through the CRL4DCAF1 ubiquitin ligase complex to cause G2 arrest and trigger expression of NK ligands. Corresponding ubiquitination targets have not been identified. UNG2 and SMUG1 are the only known substrates for Vpr-directed depletion through CRL4DCAF1. Here we identify the endoribonuclease Dicer as a target of HIV-1 Vpr-directed proteasomal degradation through CRL4DCAF1. We show that HIV-1 Vpr inhibits short hairpin RNA function as expected upon reduction of Dicer levels. Dicer inhibits HIV-1 replication in T cells. We demonstrate that Dicer also restricts HIV-1 replication in human monocyte-derived macrophages (MDM) and that reducing Dicer expression in MDMs enhances HIV-1 infection in a Vpr-dependent manner. Our results support a model in which Vpr complexes with human Dicer to boost its interaction with the CRL4DCAF1 ubiquitin ligase complex and its subsequent degradation

Multi-task Learning-based CSI Feedback Design in Multiple Scenarios

For frequency division duplex systems, the essential downlink channel state information (CSI) feedback includes the links of compression, feedback, decompression and reconstruction to reduce the feedback overhead. One efficient CSI feedback method is the Auto-Encoder (AE) structure based on deep learning, yet facing problems in actual deployments, such as selecting the deployment mode when deploying in a cell with multiple complex scenarios. Rather than designing an AE network with huge complexity to deal with CSI of all scenarios, a more realistic mode is to divide the CSI dataset by region/scenario and use multiple relatively simple AE networks to handle subregions' CSI. However, both require high memory capacity for user equipment (UE) and are not suitable for low-level devices. In this paper, we propose a new user-friendly-designed framework based on the latter multi-tasking mode. Via Multi-Task Learning, our framework, Single-encoder-to-Multiple-decoders (S-to-M), designs the multiple independent AEs into a joint architecture: a shared encoder corresponds to multiple task-specific decoders. We also complete our framework with GateNet as a classifier to enable the base station autonomously select the right task-specific decoder corresponding to the subregion. Experiments on the simulating multi-scenario CSI dataset demonstrate our proposed S-to-M's advantages over the other benchmark modes, i.e., significantly reducing the model complexity and the UE's memory consumptionComment: 31 pages, 13 figures, 10 Table

The HIV1 Protein Vpr Acts to Enhance Constitutive DCAF1-Dependent UNG2 Turnover

The HIV1 protein Vpr assembles with and acts through an ubiquitin ligase complex that includes DDB1 and cullin 4 (CRL4) to cause G2 cell cycle arrest and to promote degradation of both uracil DNA glycosylase 2 (UNG2) and single-strand selective mono-functional uracil DNA glycosylase 1 (SMUG1). DCAF1, an adaptor protein, is required for Vpr-mediated G2 arrest through the ubiquitin ligase complex. In work described here, we used UNG2 as a model substrate to study how Vpr acts through the ubiquitin ligase complex. We examined whether DCAF1 is essential for Vpr-mediated degradation of UNG2 and SMUG1. We further investigated whether Vpr is required for recruiting substrates to the ubiquitin ligase or acts to enhance its function and whether this parallels Vpr-mediated G2 arrest.We found that DCAF1 plays an important role in Vpr-independent UNG2 and SMUG1 depletion. UNG2 assembled with the ubiquitin ligase complex in the absence of Vpr, but Vpr enhanced this interaction. Further, Vpr-mediated enhancement of UNG2 degradation correlated with low Vpr expression levels. Vpr concentrations exceeding a threshold blocked UNG2 depletion and enhanced its accumulation in the cell nucleus. A similar dose-dependent trend was seen for Vpr-mediated cell cycle arrest.This work identifies UNG2 and SMUG1 as novel targets for CRL4(DCAF1)-mediated degradation. It further shows that Vpr enhances rather than enables the interaction between UNG2 and the ubiquitin ligase. Vpr augments CRL4(DCAF1)-mediated UNG2 degradation at low concentrations but antagonizes it at high concentrations, allowing nuclear accumulation of UNG2. Further, the protein that is targeted to cause G2 arrest behaves much like UNG2. Our findings provide the basis for determining whether the CRL4(DCAF1) complex is alone responsible for cell cycle-dependent UNG2 turnover and will also aid in establishing conditions necessary for the identification of additional targets of Vpr-enhanced degradation

Polyphenolic natural products as photosensitizers for antimicrobial photodynamic therapy: recent advances and future prospects

Antimicrobial photodynamic therapy (aPDT) has become a potent contender in the fight against microbial infections, especially in the context of the rising antibiotic resistance crisis. Recently, there has been significant interest in polyphenolic natural products as potential photosensitizers (PSs) in aPDT, given their unique chemical structures and inherent antimicrobial properties. Polyphenolic natural products, abundant and readily obtainable from natural sources, are generally regarded as safe and highly compatible with the human body. This comprehensive review focuses on the latest developments and future implications of using natural polyphenols as PSs in aPDT. Paramount polyphenolic compounds, including curcumin, hypericin, quercetin, hypocrellin, celastrol, riboflavin, resveratrol, gallic acid, and aloe emodin, are elaborated upon with respect to their structural characteristics, absorption properties, and antimicrobial effects. Furthermore, the aPDT mechanism, specifically its targeted action on microbial cells and biofilms, is also discussed. Polyphenolic natural products demonstrate immense potential as PSs in aPDT, representing a promising alternate approach to counteract antibiotic-resistant bacteria and biofilm-related infections

Activation-Induced T Helper Cell Death Contributes to Th1/Th2 Polarization following Murine Schistosoma japonicum Infection

In chronic infectious diseases, such as schistosomiasis, pathogen growth and immunopathology are affected by the induction of a proper balanced Th1/Th2 response to the pathogen and by antigen-triggered activation-induced T cell death. Here, by using S. japonicum infection or schistosome antigens-immunized mouse model, or antigens in vitro stimulation, we report that during the early stage of S. japonicum infection, nonegg antigens trigger Th2 cell apoptosis via the granzyme B signal pathway, contributing to Th1 polarization, which is thought to be associated with worm clearance and severe schistosomiasis. Meanwhile, after the adult worms lay their eggs, the egg antigens trigger Th1 cell apoptosis via the caspase pathway, contributing to Th2 polarization, which is associated with mild pathology and enhanced survival of both worms and their hosts. Thus, our study suggests that S. japonicum antigen-induced Th1 and Th2 cell apoptosis involves the Th1/Th2 shift and favorites both hosts and parasites

Interleukin-18 and IL-18BP in inflammatory dermatological diseases

Interleukin (IL)-18, an interferon-γ inducer, belongs to the IL-1 family of pleiotropic pro-inflammatory factors, and IL-18 binding protein (IL-18BP) is a native antagonist of IL-18 in vivo, regulating its activity. Moreover, IL-18 exerts an influential function in host innate and adaptive immunity, and IL-18BP has elevated levels of interferon-γ in diverse cells, suggesting that IL-18BP is a negative feedback inhibitor of IL-18-mediated immunity. Similar to IL-1β, the IL-18 cytokine is produced as an indolent precursor that requires further processing into an active cytokine by caspase-1 and mediating downstream signaling pathways through MyD88. IL-18 has been implicated to play a role in psoriasis, atopic dermatitis, rosacea, and bullous pemphigoid in human inflammatory skin diseases. Currently, IL-18BP is less explored in treating inflammatory skin diseases, while IL-18BP is being tested in clinical trials for other diseases. Thereby, IL-18BP is a prospective therapeutic target

The nature and combination of subunits used in epitope-based Schistosoma japonicum vaccine formulations affect their efficacy

<p>Abstract</p> <p>Background</p> <p>Schistosomiasis remains a major public health problem in endemic countries and is caused by infections with any one of three primary schistosome species. Although there are no vaccines available to date, this strategy appears feasible since natural immunity develops in individuals suffering from repeated infection during a lifetime. Since vaccinations resulting in both Th1- and Th2-type responses have been shown to contribute to protective immunity, a vaccine formulation with the capacity for stimulating multiple arms of the immune response will likely be the most effective. Previously we developed partially protective, single Th- and B cell-epitope-based peptide-DNA dual vaccines (PDDV) (T3-PDDV and B3-PDDV, respectively) capable of eliciting immune responses against the <it>Schistosoma japonicum </it>22.6 kDa tegument antigen (Sj22.6) and a 62 kDa fragment of myosin (Sj62), respectively.</p> <p>Results</p> <p>In this study, we developed PDDV cocktails containing multiple epitopes of <it>S. japonicum </it>from Sj22.6, Sj62 and Sj97 antigens by predicting cytotoxic, helper, and B-cell epitopes, and evaluated vaccine potential <it>in vivo</it>. Results showed that mice immunized with a single-epitope PDDV elicited either Tc, Th, or B cell responses, respectively, and mice immunized with either the T3- or B3- single-epitope PDDV formulation were partially protected against infection. However, mice immunized with a multicomponent (3 PDDV components) formulation elicited variable immune responses that were less immunoprotective than single-epitope PDDV formulations.</p> <p>Conclusions</p> <p>Our data show that combining these different antigens did not result in a more effective vaccine formulation when compared to each component administered individually, and further suggest that immune interference resulting from immunizations with antigenically distinct vaccine targets may be an important consideration in the development of multicomponent vaccine preparations.</p

Ter94 ATPase Complex Targets K11-Linked Ubiquitinated Ci to Proteasomes for Partial Degradation

SummaryThe Cubitus interruptus (Ci)/Gli family of transcription factors can be degraded either completely or partially from a full-length form (Ci155/GliFL) to a truncated repressor (Ci75/GliR) by proteasomes to mediate Hedgehog (Hh) signaling. The mechanism by which proteasomes distinguish ubiquitinated Ci/Gli to carry out complete versus partial degradation is not known. Here, we show that Ter94 ATPase and its mammalian counterpart, p97, are involved in processing Ci and Gli3 into Ci75 and Gli3R, respectively. Ter94 regulates the partial degradation of ubiquitinated Ci by Cul1-Slimb-based E3 ligase through its adaptors Ufd1-like and dNpl4. We demonstrate that Cul1-Slimb-based E3 ligase, but not Cul3-Rdx-based E3 ligase, modifies Ci by efficient addition of K11-linked ubiquitin chains. Ter94Ufd1-like/dNpl4 complex interacts directly with Cul1-Slimb, and, intriguingly, it prefers K11-linked ubiquitinated Ci. Thus, Ter94 ATPase and K11-linked ubiquitination in Ci contribute to the selectivity by proteasomes for partial degradation

Dynamics of Th17 Cells and Their Role in Schistosoma japonicum Infection in C57BL/6 Mice

Th17 immune cells secrete the IL-17 cytokine and contribute to host defenses against certain infections. Recent studies linked IL-17 with the severity of liver inflammation and suggested that Th17 cells contribute to the pathology in schistosomiasis, a serious disease caused by parasitic worms such as Schistosoma japonicum widespread in vertebrates including humans. However, the role of Th17 cells in protection against S. japonicum infection is still unclear. For the first time, we describe here the changes in Th17 cell levels during S. japonicum infection and suggest that the schistosome egg antigens are primarily responsible for stimulating the generation of host Th17 cells after S. japonicum infection. We further show that the level of Th17 cells in the host is determined by a combination of factors, namely exposure to complex parasitic antigens that either induce or suppress their generation. We also suggest that lowering IL-17 levels may favor the host's protective responses against S. japonicum infection. Our findings help to better understand the relationship between the host and parasite in terms of immune protection and pathology in schistosomiasis and may contribute to the future development of vaccination and therapeutic strategies

Advancements and trends in exosome research in lung cancer from a bibliometric analysis (2004-2023)

BackgroundLung cancer, characterized by its high morbidity and lethality, necessitates thorough research to enhance our understanding of its pathogenesis and discover novel therapeutic approaches. Recent studies increasingly demonstrate that lung cancer cells can modulate the tumor microenvironment, promoting tumor growth, and metastasis through the release of exosomes. Exosomes are small vesicles secreted by cells and contain a variety of bioactive molecules such as proteins, nucleic acids, and metabolites. This paper presents a comprehensive review of exosome research in lung cancer and its progress through bibliometric analysis.MethodsPublications related to exosomes in lung cancer patients were systematically searched on the Web of Science Core Collection (WoSCC) database. Bibliometric analysis was performed using VOSviwers, CiteSpace, and the R package “Bibliometrics”. Publications were quantitatively analyzed using Microsoft Office Excel 2019. The language of publication was restricted to “English” and the search strategy employed TS=(exosomes or exosomes or exosomes) and TS=(lung cancer). The search period commenced on January 1, 2004, and concluded on November 12, 2023, at noon. The selected literature types included Articles and Reviews.ResultsThe study encompassed 1699 papers from 521 journals across 71 countries and 2105 institutions. Analysis revealed a consistent upward trend in lung cancer exosome research over the years, with a notable surge in recent times. This surge indicates a growing interest and depth of inquiry into lung cancer exosomes. Major research institutions in China and the United States, including Nanjing Medical University, Shanghai Jiao Tong University, Chinese Academy Of Sciences, and Utmd Anderson Cancer Center, emerged as crucial research hubs. The annual publication count in this field witnessed a continuous rise, particularly in recent years. Key terms such as lung cancer, non-small cell lung cancer (NSCLC), microvesicles, intercellular communication, exosomal miRNAs, and oncology dominated the research landscape. Fields like cell biology, biochemistry, biotechnology, and oncology exhibited close relation with this research. Clotilde Théry emerged as the most cited author in the field, underlining her significant contributions. These results demonstrate the broad impact of exosome research in lung cancer, with key terms covering not only disease-specific aspects such as lung cancer and NSCLC but also basic biological concepts like microvesicles and intercellular communication. Explorations into exosomal microRNAs and oncology have opened new avenues for lung cancer exosome research. In summary, lung cancer exosome research is poised to continue receiving attention, potentially leading to breakthroughs in treatment and prevention.ConclusionPublications on lung cancer exosomes show a rising trend year by year, with China and the United States ranking first and second in terms of the number of publications. However, there is insufficient academic learning cooperation and exchanges between the two sides, and Chinese universities account for a large proportion of research institutions in this field. Jing Li is the most productive author, Clotilde Théry is the most co-cited author, and Cancers is the journal with the highest number of publications. The current focus in the field of lung cancer exosomes is on biomarkers, liquid biopsies, immunotherapy, and tumor microenvironment