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A transferable SARS-CoV-2 IRES module enables dual translation initiation for enhanced antigen expression in COVID-19 mRNA vaccines

2026-06-01T00:00:00Z

Title: A transferable SARS-CoV-2 IRES module enables dual translation initiation for enhanced antigen expression in COVID-19 mRNA vaccines Authors: Seo, Han Young; Jung, Haewon; Lee, Se-Young; Jung, Hae-Gwang; Son, Yu-Min; Bak, Yeonju; Hwang, Seo-Yeon; Kim, Jung-Hee; Park, In Ho; Shin, Jeon-Soo; Oh, Jong-Won Abstract: mRNA vaccines are a versatile platform for infectious disease prevention and therapeutic applications, yet their performance is limited by exclusive reliance on cap-dependent translation, which is markedly suppressed under hypoxia and cellular stress. Here, we report a hybrid 5 ' untranslated region (5 ' UTR) that enables dual translation initiation via both cap-dependent and internal ribosome entry site (IRES) mechanisms. This element integrates a minimal stem-loop 4.5-5 module (SL4.5-5) from the SARS-CoV-2 genomic 5 ' UTR, in which a conserved 5 '-UUUCGU-3 ' motif within the SL5 loops is essential for function. Incorporating the SL4.5-5 module downstream of conventional 5 ' UTRs confers cap-independent translation capacity and enhances overall translation efficiency under translation-restrictive conditions such as hypoxia. When applied to the 5 ' UTRs of clinically validated COVID-19 vaccines, this module improves antigen expression in both modified and unmodified mRNAs. Notably, unmodified Omicron BA.5 and XBB.1.5 mRNA vaccines containing this element elicited potent humoral and cellular immune responses at sub-microgram doses, comparable to those induced by the approved N1-methylpseu-douridine-incorporated mRNA vaccine, raxtozinameran. These findings identify SL4.5-5 as a modular IRES element that enables dual translation initiation, promoting efficient protein synthesis under cap-dependent translation-restrictive conditions and expanding the functional landscape of mRNA vaccines and therapeutics beyond cap-dependent limitations.

Distinct serum metabolic profiles with supportive diagnostic value in differentiating tuberculosis and Mycobacterium avium complex pulmonary disease

2026-04-01T00:00:00Z

Title: Distinct serum metabolic profiles with supportive diagnostic value in differentiating tuberculosis and Mycobacterium avium complex pulmonary disease Authors: Kim, Keu Eun San; Lee, Ye Jin; Park, Ji Hae; Kwak, Nakwon; Kim, Su-Young; Jhun, Byung Woo; Yim, Jae-Joon; Shin, Sung Jae; 박지해 Abstract: Background: Pulmonary infectious diseases caused by Mycobacterium species, including Mycobacterium tuberculosis and Mycobacterium avium complex (MAC), remain significant public health threats. However, current gold-standard diagnostics are time-consuming and have limited ability to differentiate these clinically similar presentations. This study investigated serum metabolic distinctions between tuberculosis (TB) and MAC pulmonary disease (MAC-PD) to identify biomarkers with supportive diagnostic value for differential diagnosis. Methods: We performed LC/MS-based metabolic profiling of 181 serum samples from TB and MAC-PD patients. The study cohort was subsequently divided into a training set (TB, n = 30; MAC-PD, n = 30) and a validation set (TB, n = 51; MAC-PD, n = 70). Results: Five key metabolites were identified, including four sphingoid base lipids that were decreased in TB compared with MAC-PD, and 2-hydroxyglutaric acid (2-HG), which was increased. Logistic regression using this five-metabolite panel achieved strong discriminatory performance, with an area under the curve of 0.988 (95 % CI: 0.970-1.00 0) in the training set and 0.997 (95 % CI: 0.991-1.00 0) in the validation set. Consistent performance across multiple machine learning models reinforces the stability and supportive diagnostic value of the five-metabolite panel. Conclusions: This study provides a novel approach for the differential diagnosis of two major mycobacterial pulmonary diseases. The identified metabolites, particularly alterations in sphingoid base lipids and 2-HG, demonstrated robust discriminative potential. These findings support their potential role as biomarkers in clinical practice, enabling earlier and more accurate differentiation of TB and MAC-PD. (c) 2026 The Author(s). Published by Elsevier Ltd on behalf of King Saud Bin Abdulaziz University for Health Sciences. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Proteomic Profiling of Human Extracellular Vesicles Reveals Diagnostic Biomarkers for Colon Adenocarcinoma

2026-04-01T00:00:00Z

Title: Proteomic Profiling of Human Extracellular Vesicles Reveals Diagnostic Biomarkers for Colon Adenocarcinoma Authors: Seo, Yura; Han, Yoon Dae; Bojmar, Linda; Kim, Kyung‐A; Seo, Yurin; Kim, Taeyul K.; Lee, Suho; Kim, Yeleem; Choi, Hye Bin; Lim, Yujin H.; Kim, Chae Hyun; Sandberg, Alexander; Fan, Chuanwen; Lauritzen, Pernille; Molina, Henrik; Peralta, Christopher; Geri, Jacob B.; Burdette, Colin; Han, Dai Hoon; Gee, Heon Yung; Lee, Insuk; Shin, Jeon Soo; Kim, Hyunwook; Li, Leon; Tobias, Gabriel C.; Wortzel, Inbal; Shin, Sang Joon; Jung, Hyo‐Il; Lee, Min Goo; Paik, Soonmyung; Schwartz, Robert E.; Ahn, Joong Bae; Lyden, David; Kim, Han Sang; 김현욱 Abstract: Early detection of colon adenocarcinoma (COAD) remains suboptimal. Fecal tests fail to diagnose 30% of stage I cancer, and serum CEA lacks sensitivity (< 40%). Extracellular vesicles (EVs) circulate systemically and package tumor-related cargo, making them attractive non-invasive biomarkers for cancer diagnosis. We profiled the EV proteome from 233 human patients using LC-MS/MS, including stage I-IV tumors with matched non-tumor colon tissues (n = 50 each; n = 100), paired pre-/post-operative plasma (n = 90) and healthy plasma (n = 43). Circulating EVs contained both tumor-specific and stromal/immune cell-derived proteins, reflecting the systemic nature of EV biology in the cancer setting. Proteomic analysis identified 745 proteins enriched in tumor-derived EVs (e.g., SRPK1, THBS2) and 127 proteins enriched in adjacent tissues. Plasma EVs revealed 166 proteins enriched in COAD (e.g., UBA1, FCN1) and 233 enriched in healthy controls. Pathway analysis linked tumor EV cargo to angiogenesis, mRNA splicing, TGF-beta signalling and RNA translation. Notably, a cross-cancer comparison (pancreatic = 10, lung = 14 cases) revealed that 76% of tumor EV proteins were COAD-specific, highlighting tissue of origin specificity. We further developed a 10-protein EV panel comprising seven tumor-associated and three healthy-enriched EV proteins, which effectively distinguished COAD patients from healthy controls in the two validation cohorts (n = 104 and n = 215), achieving > 90% sensitivity for differentiating COAD from healthy and non-COAD colorectal conditions. Six weeks after curative resection, tumor-associated EV proteins decreased by > 70%, whereas healthy-associated proteins rebounded to baseline, indicating surgical responsiveness. Collectively, EV protein signatures provide a sensitive and tissue-specific window into tumor-host communication, further supporting blood-based early detection of COAD.

Cis-Acting Chaperoning by Macromolecular Tethering: A Built-In Layer of Cellular Chaperoning

2026-04-01T00:00:00Z

Title: Cis-Acting Chaperoning by Macromolecular Tethering: A Built-In Layer of Cellular Chaperoning Authors: Choi, Seong Il; Jin, Yoontae; Choi, Yura; Seong, Baik L. Abstract: The molecular chaperone paradigm has shaped modern views of assisted protein folding, yet it does not fully capture the physical context in which de novo folding occurs in cells. A defining feature of the cellular milieu is macromolecular tethering in cis, whereby nascent polypeptides remain physically linked-through covalent or persistent associations-to ribosomes, lipid bilayers, or pre-folded domains of multidomain proteins. Because molecular chaperones have traditionally been defined as reversible binders acting in trans, this cis-acting mode has remained conceptually underappreciated. Cellular macromolecules, by virtue of their steric bulk and surface charges, can suppress aggregation of tethered polypeptides, thereby increasing productive folding yield. By analogy to colloidal stability, this repulsion-mediated control of aggregation suggests that cellular macromolecules can exhibit intrinsic chaperone-like activity largely independent of whether the linkage occurs in cis or in trans. This property provides a conceptual basis for linking cis- and trans-acting chaperoning. Thus, macromolecular tethering in cis may constitute a built-in layer of cellular chaperoning, distinct in physical linkage yet mechanistically related to conventional molecular chaperones.