Tumor necrosis factor receptor superfamily member 4 (TNFRSF4), also known as OX40, plays a crucial role in the regulation of T-cell immune responses under normal physiological conditions. Abnormal expression of OX40 and its cognate ligand OX40L (TNFSF4) have been associated with various autoimmune diseases, indicating that blocking the OX40/OX40L pathway could be a promising strategy for the treatment of a broad range of T cell-mediated autoimmune diseases. Here, we screened and characterized a fully human anti-OX40 antibody (JY007) from a naïve human scFv phage library. JY007 has an affinity constant of 7.71 nmol/L and effectively inhibited the OX40-OX40L interaction at both molecular and cellular levels, with IC₅₀ values of 1.088 and 10.12 nmol/L, respectively. Furthermore, JY007 demonstrated the ability to deplete activated T lymphocytes through antibody-dependent cellular cytotoxicity (ADCC) activity, with an EC₅₀ of 5.592 pmol/L. The combination of ADCC and its antagonist activity against OX40 suggests potential efficacy in suppressing inflammatory responses mediated by the OX40/OX40L pathway. Additionally, we employed molecular docking, site-directed mutagenesis, and competitive ELISA to pinpoint the epitopes on OX40. The results revealed that JY007 binds to Pro³⁷, Ser³⁸, and Asp⁴⁰ of OX40. Interestingly, we also found that the most potent anti-OX40 antibody drug in the clinical stage, KHK4083, binds to different OX40 amino-acid residues, including Asp⁷⁴, Lys⁸², Asp¹¹⁷, Ser¹¹⁸, Tyr¹¹⁹, and Lys¹²⁰. This divergence suggests that the novel monoclonal antibody JY007 holds promise as a potential therapeutic option for patients with atopic dermatitis and may find broad applications in the treatment of autoimmune diseases.

Sacoglossan sea slugs have attracted considerable scientific attention due to their capacity to retain functional macroalgal chloroplasts inside their cells. This endosymbiotic association is nutritionally relevant for these organisms and represents an interesting research issue for biotechnological applications. The Caribbean species Elysia crispata can integrate chloroplasts from different macroalgal species. The lipidome of chloroplasts includes lipid classes unique to these photosynthetic organelles. Specialized lipids, such as the glycolipids MGDG, DGDG, and SQDG, are essential for maintaining the integrity of both the thylakoid membranes and the overall chloroplast membrane structure. Additionally, lipids are a diverse group of biomolecules playing essential roles at nutritional and physiological levels. A combined approach using LC–HR-MS and MS/MS was employed to determine the polar lipid profile of the photosynthetic sea slug E. crispata from two habitats in the north-western tropical Atlantic (Sistema Arrecifal Veracruzano and Mahahual) and two different feeding conditions (fed and after 1 week of starvation). Significant differences were identified in the abundance of structural and signalling phospholipids (PC, PI, PG, PS, CL) suggesting different nutritional states between populations. The composition of glycolipids demonstrated a clear separation by habitat, but not by feeding conditions. The lower abundance of glycolipids in the Mahahual samples suggests a lower density of chloroplasts in their tissues compared to Veracruz individuals. These results corroborate that 1 week of starvation is insufficient to initiate the degradation of plastid membranes. This study confirms the advantages of using lipidomics as a tool to enhance our knowledge of the ecology of marine invertebrates.

MS/MS-based molecular networking is an effective strategy to rapidly dereplicate known compounds and to guide the discovery process for new and novel natural products. In the present study, the chemical diversity of indole diterpenoids from the marine-derived fungus Penicillium sp. N4-3 was investigated using molecular networking techniques. Guided by this information, targeted isolation resulted in two new indole diterpenoids shearinines R and S (1, 2) and an oxidative artifact shearinine T (3), together with the verification of two known analogs (4, 5). Furthermore, five indole diterpenoids (6−10), including three putatively new ones, shearinines U−W (6, 9, 10), were predicted from the molecular ion cluster by the combination of GNPS molecular networking and manual analysis of MS/MS fragmentation clusters. Shearinines T (3) and W (10) are characterized by an oxidative cleavage of the C-2–C-18 double bond. Feature fragment ions of these shearinines revealed two type of dominant ions related to the indole moiety and the breaking of C-9 side chain or Ring I. Compound 1 showed antibacterial activities against a panel of pathogenic bacteria with IC₅₀ values ranging from 6.34 to 47.96 μg/mL and inhibited the growth of the human hepatic (HepG2) and gastric (SGC-7901) cancer cells lines with IC₅₀ values of 6.27 and 19.16 μg/mL, respectively.

Kelps are pivotal to temperate coastal ecosystems, providing essential habitat and nutrients for diverse marine life, and significantly enhancing local biodiversity. The impacts of elevated CO₂ levels on kelps may induce far-reaching effects throughout the marine food web, with potential consequences for biodiversity and ecosystem functions. This study considers the kelp Macrocystis pyrifera and its symbiotic microorganisms as a holistic functional unit (holobiont) to examine their collective response to heightened CO₂ levels. Over a 4 month cultivation from the fertilization of M. pyrifera gametes to the development of juvenile sporophytes, our findings reveal that elevated CO₂ levels influence the structure of the M. pyrifera symbiotic microbiome, alter metabolic profiles, and reshape microbe-metabolite interactions using 16S rRNA amplicon sequencing and liquid chromatography coupled to mass spectrometry analysis. Notably, Dinoroseobacter, Sulfitobacter, Methylotenera, Hyphomonas, Milano-WF1B-44 and Methylophaga were selected as microbiome biomarkers, which showed significant increases in comparative abundance with elevated CO₂ levels. Stress-response molecules including fatty-acid metabolites, oxylipins, and hormone-like compounds such as methyl jasmonate and prostaglandin F2a emerged as critical metabolomic indicators. We propose that elevated CO₂ puts certain stress on the M. pyrifera holobiont, prompting the release of these stress-response molecules. Moreover, these molecules may aid the kelp’s adaptation by modulating the microbial community structure, particularly influencing potential pathogenic bacteria, to cope with environmental change. These results will enrich the baseline data related to the chemical interactions between the microbiota and M. pyrifera and provide clues for predicting the resilience of kelps to future climate change.

Climate change, particularly extreme climate events, is likely to alter the population connectivity in diverse taxa. While the population connectivity for highly migratory species is expected to be vulnerable to climate change, the complex migration patterns has made the measurement difficult and studies rare. However, otolith biogeochemistry provides the possibility to evaluate these climate-induced impacts. Japanese Spanish mackerel Scomberomorus niphonius is a highly migratory fish that is widely distributed in the northwest Pacific. Otoliths biogeochemistry of age-1 spawning or spent individuals from three consecutive years (2016–2018), during which a very strong El Niño was experienced (2015–2016), were analyzed to evaluate the temporal variation of connectivity for S. niphonius population along the coast of China. The elemental concentrations of the whole otolith showed that Ba:Ca and Mg:Ca values were found to significantly increase in the El Niño year. The random forest classification and clustering analysis indicated a large-scale connectivity between East China Sea and the Yellow Sea in the El Niño year whereas the local S. niphonius assemblages in different spawning areas were more self-sustaining after the El Niño year. These findings lead to the hypothesis that environmental conditions associated with the El Niño Southern Oscillation (ENSO) events in the Northern Pacific Ocean would likely influence the population connectivity of S. niphonius. If so, extreme climate events can result in profound changes in the extent, pattern and connectivity of migratory fish populations. Our study demonstrates that otolith biogeochemistry could provide insight towards revealing how fish population response to extreme climate events.

Temperature is well known as the major environmental factor that influences survival and growth of fish, which are poikilothermic animals. However, it is still unclear about the mechanism that underscores thermal-controlled fish physiology, especially nutritional utilization and metabolism, which are vitally important in aquaculture. In the present study, juvenile turbot was force-fed with amino acid mixture and its postprandial absorption, nutrient sensing and metabolism under low (12, 15 ℃), optimal (18 ℃) to high (21, 24 ℃) temperatures were explored. Intestinal trypsin and lipase activity were highly sensitive to water temperature, and highest under optimal temperatures for turbot, whereas amylase remained constant. Selective groups of intestinal amino acid transporters were upregulated in cold temperatures, but the amino acid absorption capability was increased with rising temperature. The mechanistic target of rapamycin (mTOR) signaling pathway was most active at optimal temperature. Postprandial muscle protein deposition achieved maximum level under optimal temperature. Amino acid catabolic enzymes branched-chain aminotransferase and branched-chain α-keto acid dehydrogenase activities were increased with rising temperatures. High temperature increased significantly energy metabolism and stimulated cellular stress in liver. These findings highlight the critical role of temperature in modulating amino acid dynamics, metabolic processes and stress responses in juvenile turbot, providing valuable insights for optimizing aquaculture practices.

Heterotrophic bacterial production and respiration, two important contributors to carbon cycling, play an important role in global biogeochemical cycles. However, recent research suggests that these two processes may be decoupled, and the underlying changes in community structure and their interactions remain unclear. In this study, two research expeditions to the North Pacific Subtropical Gyre (NPSG) during the summer and winter of 2020–2021 revealed seasonal shifts in bacterial metabolism and community structure in response to environmental factors. The findings indicated notable seasonal fluctuations in bacterial abundance and production in the surface waters. Both peaked in winter compared to summer. Alterations in bacterial abundance that were further evident at the community level demonstrated significant seasonal differences in bacterial community structure and diversity and revealed, in particular, the intricacy of the networks and interactions among bacterial communities in winter. Bacterial respiration displayed no significant seasonal variations and was decoupled from bacterial abundance and production. The implication was that bacterial production did not directly dictate bacterial respiration. Specific taxa exerted a more substantial influence on bacterial respiration, potentially including groups with high respiration rates but relatively low abundance, thus challenging the notion that highly abundant taxa are invariably the most metabolically active. Moreover, the interplay between different bacterial taxa and their interactions may also impact the overall strength of bacterial community respiration. These findings significantly enhance our understanding of the decoupling between bacterial production and respiration, which is crucial for unraveling the complex mechanisms underlying carbon cycling and energy flow in marine ecosystems.

Analysis of the secondary metabolite biosynthesis gene cluster (BGC) from marine Streptomyces sp. SNJ102 revealed the presence of a noncanonical nonribosomal peptide synthetase (NRPS), predicted to produce a depsipeptide compound. The NRPS gene cluster was captured by transformation-associated recombination and heterologously expressed in Streptomyces albus. The production of the new compound was confirmed using high-resolution liquid chromatography-mass spectrometry, and its structure was elucidated using nuclear magnetic resonance spectroscopy. The structure of the new depsipeptide was more similar to the monomeric structure of cyclic depsipeptides derived from fungi than to other Streptomyces-derived depsipeptides. In addition, the bacterial depsipeptide, which we named jejumide, showed promising anti-inflammatory activity. These results demonstrate that genome mining and successful heterologous expression of cryptic nonlinear NRPS BGCs from marine bacteria will facilitate the discovery of novel nonribosomal peptides and understanding of the complicated biosynthetic mechanism of nonlinear NRPS.

Marinisomatota (formerly recognized as Marinimicrobia, Marine Group A, and SAR406) are ubiquitous and abundant in marine environments, traditionally characterized as heterotrophic microorganisms. However, certain members of Marinisomatota have demonstrated the capacity to harness light for carbon dioxide fixation and the synthesis of organic compounds, thriving in the translucent zone or transitioning between the translucent and aphotic layers. The metabolic strategies driving the shift in trophic behaviors, and the factors influencing these transitions, remain largely unexplored. In this study, we investigate the metabolic strategies, ecological distribution, and dietary patterns of Marinisomatota through the analysis of metagenomic and metatranscriptomic data sourced from the global open oceans. A total of 1,588 Marinisomatota genomes were retrieved, representing one class, two orders, 14 families, 31 genera, and 67 species. These organisms are predominantly found in low-latitude marine regions, with relative abundances ranging from 0.18 to 36.21%. Among the 14 families, S15-B10, TCS55, UBA1611, UBA2128, and UBA8226 exhibit potential for light-dependent processes associated with Crassulacean acid metabolism (M00169). Three distinct metabolic strategies were identified within Marinisomatota: MS0 (photoautotrophic potential), MS1 (heterotrophic with a pronounced glycolytic pathway), and MS2 (heterotrophic without glycolysis). The emergence of these metabolic strategies may be a response to nutrient limitations within the ocean. This study reveals the potential for mixotrophic strategies in Marinisomatota, underscoring the critical interplay between life history traits and metabolic strategies in the evolution of novel nutritional groups.