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Signal transducer and activator of transcription (STAT) proteins communicate from cell-surface receptors to drive transcription of immune response genes. The parasite Toxoplasma gondii blocks STAT1-mediated gene expression by secreting the intrinsically disordered protein TgIST that traffics to the host nucleus, binds phosphorylated STAT1 dimers, and occupies nascent transcription sites that unexpectedly remain silenced. Here we define a core region within internal repeats of TgIST that is necessary and sufficient to block STAT1-mediated gene expression. Cellular, biochemical, mutational, and structural data demonstrate that the repeat region of TgIST adopts a helical conformation upon binding to STAT1 dimers. The binding interface is defined by a groove formed from two loops in the STAT1 SH2 domains that reorient during dimerization. TgIST binding to this newly exposed site at the STAT1 dimer interface alters its conformation and prevents the recruitment of co-transcriptional activators, thus defining the mechanism of blocked transcription. Intrinsically disordered proteins (IDP) are pleotropic proteins with diverse functions. Here the authors show that an IDP, TgIST, from T. gondii blocks interferon-induced gene expression by binding to the STAT1 dimer interface and preventing the recruitment of co-transcriptional activators, CBP/p300, to STAT1 to inhibit expression of immunity genes.

People are evolutionarily predisposed to associate threat relevant stimuli with fear or aversiveness and show an attentional bias toward threat. Attentional bias modification (ABM) has been shown to reduce threat biases, while quantitative reviews assessing the effectiveness of bias modification yielded inconsistent results. The current study examined the relationship between the training effect of attentional bias to threat and the type of threatening stimuli. Twenty-two participants performed a modified dot-probe task while undergoing functional near-infrared spectroscopy (fNIRS) imaging. Results indicated that there was a strong pattern of attentional avoidance among individuals in an animal but not human threat condition. Furthermore, findings from fNIRS confirmed that the influence from type of threatening stimulus would be modulated by cortical activation patterns, especially in the ventrolateral prefrontal cortices (vlPFC) and angular gyrus. Overall, these results suggest that stimulus-specific may play a major role in personalization of specific psychological interventions.

The emergence of current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) and potential future spillovers of SARS-like coronaviruses into humans pose a major threat to human health and the global economy. Development of broadly effective coronavirus vaccines that can mitigate these threats is needed. Here, we utilized a targeted donor selection strategy to isolate a large panel of human broadly neutralizing antibodies (bnAbs) to sarbecoviruses. Many of these bnAbs are remarkably effective in neutralizing a diversity of sarbecoviruses and against most SARS-CoV-2 VOCs, including the Omicron variant. Neutralization breadth is achieved by bnAb binding to epitopes on a relatively conserved face of the receptor-binding domain (RBD). Consistent with targeting of conserved sites, select RBD bnAbs exhibited protective efficacy against diverse SARS-like coronaviruses in a prophylaxis challenge model in vivo. These bnAbs provide new opportunities and choices for next-generation antibody prophylactic and therapeutic applications and provide a molecular basis for effective design of pan-sarbecovirus vaccines.A broadly neutralizing antibody (bnAb) response is required to combat SARS-CoV-2 variants of concern (VOCs). The authors isolated and characterized a large panel of sarbecovirus bnAbs from vaccinated individuals who had recovered from COVID-19, finding that many of these antibodies were able to neutralize all VOCs, including Omicron, and demonstrate prophylaxis in mice infected with diverse sarbecoviruses.

Mutual influences between anxiety and working memory (WM) have been extensively studied, and their curvilinear relationship resembles the classic Yerkes-Dodson law of arousal and performance. Given the genetic bases of both anxiety and WM, it is likely that the individual differences in the Yerkes-Dodson law of anxiety and WM may have genetic correlates. The current genome wide association study (GWAS) enrolled 1115 healthy subjects to search for genes that are potential moderators of the association between anxiety and WM. Results showed that CPNE3 rs10102229 had the strongest effect, p  = 3.38E−6 at SNP level and p  = 2.68E−06 at gene level. Anxiety and WM had a significant negative correlation (i.e., more anxious individuals performed worse on the WM tasks) for the TT genotype of rs10102229 (resulting in lower expression of CPNE3), whereas the correlation was positive (i.e., more anxious individuals performed better on the WM tasks) for the CC carriers. The same pattern of results was found at the gene level using gene score analysis. These effects were replicated in an independent sample (N = 330). The current study is the first to report a gene that moderates the relation between anxiety and WM and potentially provides a genetic explanation for the classic Yerkes-Dodson law.

As for the contact mechanics between the catheter and trachea tissue during bronchoscopy, the anterior and curved part of the catheter were selected for analysis. The material parameters of each sample were obtained by uniaxial tensile experiments. And this paper verified the stress changes during the contact process using ABAQUS software from three aspects: different material property parameters, contact angle, and catheter bending angle. The results show that: when the characteristic parameter is 90°, the force on the trachea is minimal. And the force changes in a small range when the contact angle is kept at 45°–75°. When the catheter enters the next level of the trachea, the bending part is in contact with the trachea wall. At this time, keeping the bending angle at 15°–30° helps to reduce the contact force. This study could provide a theoretical basis for surgical instruments’ interventional therapy.

Studying the antibody response to SARS-CoV-2 informs on how the human immune system can respond to antigenic variants as well as other SARS-related viruses. Here, we structurally identified a YYDRxG motif encoded by IGHD3-22 in CDR H3 that facilitates antibody targeting to a functionally conserved epitope on the SARS-CoV-2 receptor binding domain. A computational search for a YYDRxG pattern in publicly available sequences uncovered 100 such antibodies, many of which can neutralize SARS-CoV-2 variants and SARS-CoV. Thus, the YYDRxG motif represents a common convergent solution for the human humoral immune system to target sarbecoviruses including the Omicron variant. These findings suggest an epitope-targeting strategy to identify potent and broadly neutralizing antibodies for design of pan-sarbecovirus vaccines and antibody therapeutics. Structural and computational analyses reveal a recurring YYDRxG motif in a class of human antibodies that target a conserved epitope on sarbecoviruses including the Omicron variant.

Background. RNA helicases have various essential functions in basically all aspects of RNA metabolism, not only unwinding RNA but also disturbing the interaction of RNA with proteins. Recently, RNA helicases have been considered potential targets in cancers. So far, there has been no detailed investigation of the biological functions of RNA helicase DHX37 in cancers. Objective. We aim to identify the prognostic value of DHX37 associated with tumor microenvironments in cancers. Methods. DHX37 expression was examined via the Oncomine database and Tumor Immune Estimation Resource (TIMER). We explored the prognostic role of DHX37 in cancers across various databases. Coexpression genes, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG), and fundamental regulators were performed via LinkedOmics. Confirming the prognostic value of DHX37 in liver hepatocellular carcinoma (LIHC) and lung adenocarcinoma (LUAD), we explored the role of DHX37 in infiltrated lymphocytes in cancers using the Gene Expression Profiling Interactive Analysis (GEPIA) and TIMER databases. Results. Through GO and KEGG analyses, expression of DHX37 was also correlated with complex function-specific networks involving the ribosome and RNA metabolic signaling pathways. In LIHC and LUAD, DHX37 expression showed significant positive correlations with markers of Tregs, myeloid-derived suppressor cells (MDSCs), and T cell exhaustion, contributing to immune tolerance. Conclusion. These results indicate that DHX37 can serve as a prognostic biomarker in LIHC and LUAD while having an important role in immune tolerance by activating the function of Tregs, MDSC, and T cell exhaustion.

High levels of nitrogenous compounds such as proteins and alkaloids in cigar tobacco leaves can negatively impact combustion, smoke smoothness, and overall sensory quality. At the same time, the formation of aroma-active compounds during fermentation is essential for desirable flavor development. This study aimed to isolate a functional bacterial strain capable of accelerating nitrogen compound degradation and enhancing aroma quality through bioaugmented fermentation. A total of 65 bacterial strains were isolated from naturally fermented cigar tobacco using a tobacco extract-based medium. Sixteen showed significant protease activity, and (CCTCC M20211370) was selected for further study. Laboratory- and industrial-scale fermentation trials were conducted with this strain. Volatile compounds were analyzed using gas chromatography-mass spectrometry (GC-MS), microbial community dynamics were assessed via high-throughput sequencing, and sensory evaluations were performed to assess quality improvements. Inoculation with significantly increased desirable aroma compounds such as neophytadiene and β-ionone, while reducing harmful compounds including nicotine and myosmine. The microbial structure was reshaped, with enrichment of beneficial genera like and . Sensory analysis confirmed improved aroma complexity, featuring enhanced floral, honey-sweet, and resinous notes. effectively improved cigar tobacco quality by promoting nitrogen compound degradation and modulating microbial metabolism to enhance aroma development. These findings support its potential as a bioaugmentation agent in industrial cigar fermentation. Further genomic and enzymatic studies are warranted to elucidate its functional mechanisms and facilitate large-scale application.

Though radiofrequency ablation (RFA) is considered to be an effective treatment for hepatocellular carcinoma (HCC), but more than 30% of patients may suffer insufficient RFA (IRFA), which can promote more aggressive of the residual tumor. One possible method to counter this is to accurately identify the margin of the HCC. Colony-stimulating factor 1 receptor (CSF-1R) has been found to be restrictively expressed by tumor associated macrophages (TAMs) and monocytes which more prefer to locate at the boundary of HCC. Using biotinylation method, we developed a CSF-1R-conjugated nanobubble CSF-1R (NBCSF–1R) using a thin-film hydration method for margin detection of HCC. CSF-1R expression was higher in macrophages than in HCC cell lines. Furthermore, immunofluorescence showed that CSF-1R were largely located in the margin of xenograft tumor and IFRA models. In vitro , NBCSF–1R was stable and provided a clear ultrasound image even after being stored for 6 months. In co-culture, NBCSF–1R adhered to macrophages significantly better than HCC cells ( p = 0.05). In in vivo contrast-enhanced ultrasound imaging, the washout half-time of the NBCSF–1R was significantly greater than that of NBCTRL and Sonovue® ( p = 0.05). The signal intensity of the tumor periphery was higher than the tumor center or non-tumor region after NBCSF–1R injection. Taken together, NBCSF–1R may potentially be used as a non-invasive diagnostic modality in the margin detection of HCC, thereby improving the efficiency of RFA. This platform may also serve as a complement method to detect residual HCC after RFA; and may also be used for targeted delivery of therapeutic drugs or genes.

Antigenic imprinting, which describes the bias of the antibody response due to previous immune history, can influence vaccine effectiveness. While this phenomenon has been reported for viruses such as influenza, there is little understanding of how prior immune history affects the antibody response to SARS-CoV-2. This study provides evidence for antigenic imprinting through immunization with two Sarbecoviruses, the subgenus that includes SARS-CoV-2. Mice were immunized subsequently with two antigenically distinct Sarbecovirus strains, namely SARS-CoV-1 and SARS-CoV-2. We found that sequential heterologous immunization induced cross-reactive binding antibodies for both viruses and delayed the emergence of neutralizing antibody responses against the booster strain. Our results provide fundamental knowledge about the immune response to Sarbecovirus and important insights into the development of pan-sarbecovirus vaccines and guiding therapeutic interventions.