The different roles of V-ATPase a subunits in phagocytosis/endocytosis and autophagy.

Microglia are specialized macrophages responsible for the clearance of dead neurons and pathogens by phagocytosis and degradation. The degradation requires phagosome maturation and acidification provided by the vesicular- or vacuolar-type H+-translocating adenosine triphosphatase (V-ATPase), which is composed of the cytoplasmic V1 domain and the membrane-embedded Vo domain. The V-ATPase a subunit, an integral part of the Vo domain, has four isoforms in mammals. The functions of different isoforms on phagosome maturation in different cells/species remain controversial. Here we show that mutations of both the V-ATPase Atp6v0a1 and Tcirg1b/Atp6v0a3 subunits lead to the accumulation of phagosomes in zebrafish microglia. However, their mechanisms are different. The V-ATPase Atp6v0a1 subunit is mainly distributed in early and late phagosomes. Defects of this subunit lead to a defective transition from early phagosomes to late phagosomes. In contrast, The V-ATPase Tcirg1b/Atp6v0a3 subunit is primarily located on lysosomes and regulates late phagosome-lysosomal fusion. Defective Tcirg1b/Atp6v0a3, but not Atp6v0a1 subunit leads to reduced acidification and impaired macroautophagy/autophagy in microglia. We further showed that ATP6V0A1/a1 and TCIRG1/a3 subunits in mouse macrophages preferentially located in endosomes and lysosomes, respectively. Blocking these subunits disrupted early-to-late endosome transition and endosome-to-lysosome fusion, respectively. Taken together, our results highlight the essential and conserved roles played by different V-ATPase subunits in multiple steps of phagocytosis and endocytosis across various species.Abbrevations: Apoe: apolipoprotein E; ANXA5/annexin V: annexin A5; ATP6V0A1/a1: ATPase H+-transporting V0 subunit a1; ATP6V0A2/a2: ATPase H+-transporting V0 subunit a2; ATP6V0A4/a4: ATPase H+-transporting V0 subunit a4; dpf: days post-fertilization; EEA1: early endosome antigen 1; HOPS: homotypic fusion and protein sorting; LAMP1: lysosomal associated membrane protein 1; Lcp1: lymphocyte cytosolic protein 1 (L-plastin); Map1lc3/Lc3: microtubule-associated protein 1 light chain 3; NR: neutral red; PBS: phosphate-buffered saline; PtdIns: phosphatidylinositol; PtdIns3P: phosphatidylinositol-3-phosphate; PtdIns(3,5)P2: phosphatidylinositol (3,5)-bisphosphate; RAB4: RAB4, member RAS oncogene family; RAB5: RAB5, member RAS oncogene family; RAB7: RAB7, member RAS oncogene family; TCIRG1/Atp6v0a3/a3: T cell immune regulator 1, ATPase H+-transporting V0 subunit a3; V-ATPase: vacuolar-type H+-translocating adenosine triphosphatase; Xla.Tubb2b/NBT: tubulin beta 2B class IIb.

Correction: Incorporating mesopelagic fish into the evaluation of marine protected areas under climate change scenarios.

[This corrects the article DOI: 10.1007/s42995-023-00188-9.].

[Installed strategy and clinical observation of self-made extracorporeal membrane oxygenation system in the treatment of critically ill patients].

OBJECTIVE: To summarize the strategy and method for the treatment of critically ill patients with self-made extracorporeal membrane oxygenation (ECMO) system. METHODS: A observative study was conducted. Fifty-six patients with ECMO assisted support in Fuwai Central China Cardiovascular Disease Hospital from December 2020 to December 2021 were enrolled. According to the clinical situation of the patients and the wishes of the family, conventional ECMO package (conventional group) or self-made ECMO package (self-made group) was chosen. In the conventional group, the disposable ECMO package was used to install the machine, pre charge and exhaust the air. In the self-made group, the disposable consumables commonly used in extracorporeal circulation during cardiac surgery (including centrifugal pump heads, membrane oxygenation, tubes, connectors, etc.) were used to create a self-made ECMO system. Based on the patient's situation, personalized tube model selection and length control were carried out. The preparation time, auxiliary time, auxiliary method, total pre charge volume, free hemoglobin (FHb) levels after 2 hours of ECMO operation and operating costs, as well as changes in hemodynamics, arterial blood gas analysis, and blood indicators within 48 hours after ECMO placement in the two groups were recorded. The occurrence of adverse events related to the ECMO system during ECMO adjuvant therapy in two groups was simultaneously observed. RESULTS: Fifty-six patients were enrolled finally, with 28 cases in the conventional group and 28 cases in the self-made group, and all successfully completed the operation of ECMO. There was no statistically significant difference in ECMO system preparation time, auxiliary time, auxiliary method, and FHb levels after 2 hours of ECMO operation between the conventional group and the self-made group [preparation time (minutes): 13±4 vs. 15±5, auxiliary time (hours): 287±34 vs. 276±42, veno-arterial ECMO (cases): 22 vs. 24, veno-venous ECMO (cases): 6 vs. 4, FHb after 2 hours of ECMO operation (mg/L): 226±67 vs. 253±78, all P > 0.05]. However, the total pre charge volume and operating costs in the self-made group were significantly lower than those in the conventional group [total pre charge volume (mL): 420±25 vs. 650±10, operating costs (ten thousand yuan): 3.8±0.4 vs. 6.7±0.3, both P < 0.01]. The hemodynamics, arterial blood gas analysis, and blood indicators of patients in the two groups were relatively stable within 48 hours after ECMO operation, and most of the indicators between the two groups showed no statistically significant differences. The hemoglobin (Hb) levels at 12, 24, and 48 hours after the machine transfer in the self-made group were significantly higher than those in the conventional group (g/L: 128.5±23.7 vs. 117.5±24.3 at 12 hours, 121.3±31.3 vs. 109.6±33.2 at 24 hours, 118.5±20.1 vs. 105.2±25.7 at 48 hours, all P < 0.05). Both groups of patients did not experience any adverse event related to the ECMO system, such as membrane pulmonary infiltration, joint detachment, and massive hemolysis, during the ECMO assisted treatment process. CONCLUSIONS: When implementing ECMO for critically ill patients in clinical practice, a self-made ECMO system with disposable consumables commonly used in extracorporeal circulation during cardiac surgery can be used for cardiopulmonary function assistance support, thereby saving patients medical costs and alleviating their dependence on disposable ECMO package in clinical practice.

Shouhui Tongbian Capsule in treatment of constipation: Treatment and mechanism development.

Constipation is common in the diseases of the digestive system in clinics. With the change in diet structure and the increase in life pressure, the prevalence rate increases year by year. In traditional Chinese medicine (TCM), the location of the disease of constipation is in the large intestine, which is related to the dysfunction of lung, spleen, liver, kidney and other viscera. Its pathogenesis is conductive dysfunction of large intestine. Based on the theory, Shouhui Tongbian Capsule (SHTB) is composed of eight traditional Chinese medicines, including Polygoni multiflori Radix (Heshouwu in Chinese), Aloe (Luhui in Chinese), Cassiae Semen (Juemingzi in Chinese), Ginseng Radix et Rhizoma (Renshen in Chinese), Lycii Fructus (Gouqizi in Chinese), Asini Corii Colla (Ejiao in Chinese), Aurantii Fructus Immaturus (Zhishi in Chinese), and Atractylodis Macrocephalae Rhizoma (Baizhu in Chinese), which could help to release excessive turbid, and nourishing yin and supplementing qi in the treatment. This study has been carried out to review the latest advances of SHTB in the treatment of constipation. The results showed that significant effect of SHTB was found in the treatment of constipation, such as functional constipation, and constipation associated with tumor chemotherapy, colitis, type 2 diabetes and chronic cardiac failure. Besides, obvious adverse reactions were not observed. SHTB could effectively treat five types of constipation, provide direction for the future exploration of SHTB in the treatment of other types of constipation.

A comprehensive review of bupleuri radix and its bioactive components： with a major focus on treating chronic liver diseases.

ETHNOPHARMACOLOGICAL RELEVANCE: Bupleuri Radix (BR) has been recognized as an essential herbal medicine for relieving liver depression for thousands of years. Contemporary research has provided compelling evidence of its pharmacological effects, including anti-inflammatory, immunomodulatory, metabolic regulation, and anticancer properties, positioning it as a promising treatment option for various liver diseases. Hepatitis, steatohepatitis, cirrhosis, and liver cancer are among the prevalent and impactful liver diseases worldwide. However, there remains a lack of comprehensive systematic reviews that explore the prescription, bio-active components, and underlying mechanisms of BR in treating liver diseases. AIM OF THE REVIEW: To summarize the BR classical Chinese medical prescription and ingredients in treating liver diseases and their mechanisms to inform reference for further development and research. MATERIALS AND METHODS: Literature in the last three decades of BR and its classical Chinese medical prescription and ingredients were collated and summarized by searching PubMed, Wiley, Springer, Google Scholar, Web of Science, CNKI, etc. RESULTS: BR and its classical prescriptions, such as Xiao Chai Hu decoction, Da Chai Hu decoction, Si Ni San, and Chai Hu Shu Gan San, have been utilized for centuries as effective therapies for liver diseases, including hepatitis, steatohepatitis, cirrhosis, and liver cancer. BR is a rich source of active ingredients, such as saikosaponins, polysaccharides, flavonoids, sterols, organic acids, and so on. These bioactive compounds exhibit a wide range of beneficial effects, including anti-inflammatory, antioxidant, immunomodulatory, and lipid metabolism regulation. However, it is important to acknowledge that BR and its constituents can also possess hepatotoxicity, which is associated with cytochrome P450 (CYP450) enzymes and oxidative stress. Therefore, caution should be exercised when using BR in therapeutic applications to ensure the safe and appropriate utilization of its potential benefits while minimizing any potential risks. CONCLUSIONS: To sum up, BR, its compounds, and its based traditional Chinese medicine are effective in liver diseases through multiple targets, multiple pathways, and multiple effects. Advances in pharmacological and toxicological investigations of BR and its bio-active components in the future will provide further contributions to the discovery of novel therapeutics for liver diseases.

Network pharmacology and transcriptomic profiling elucidate the therapeutic effects of Ranunculus ternatus Thunb on liver fibrosis via MK3-NF-κB inhibition.

Activation of hepatic stellate cells (HSCs) is critical in the progression of liver fibrosis and is a promising target for anti-hepatic fibrosis drug development. Moreover, effective pharmacological interventions targeting this pathomechanism are scarce. Our study confirms the therapeutic value of ß-sitosterol, a major constituent of Ranunculus ternatus Thunb, in hepatic fibrosis and identifies its underlying mechanisms. After treatment with ß-sitosterol, CCL4-induced hepatic fibrosis was reversed in mice, while inflammatory and hepatic fibrosis indices were improved. Meanwhile, we explored the molecular mechanism of ß-sitosterol treatment for hepatic fibrosis and, based on RNA-seq results, found that the ameliorative effect of ß-sitosterol on hepatic fibrosis was associated with the MK3 and NF-κB signalling pathways. MK3, an important kinase in the MAPK pathway, plays a role in transmitting upstream and downstream signals, whereas the NF-κB signalling pathway has been shown to be associated with HSC activation. We verified the interaction between MK3 and IκB in HSC cells using endogenous Co-IP, whereas ß-sitosterol reduced the binding of MK3 to IκB and the activation of the NF-κB signalling pathway. Our findings reveal the mechanism of ß-sitosterol in the treatment of liver fibrosis, suggesting that ß-sitosterol may be a promising drug for the treatment of liver fibrosis and deserves further investigation.

Multi-interfacial bridging engineering of flexible MXene film for efficient electromagnetic shielding and energy conversion.

Accompanied by the progressive development of electronic equipment, excellent electromagnetic interference (EMI) shielding materials display a satisfying prospect in protecting electronic devices against electromagnetic pollution/radiation, while integrating energy conversion. Heretofore, it remains a conundrum to availably construct thin films with multi-interfacial bridging engineering as multifunctional shielding devices. To effectively achieve electromagnetic wave attenuation and integrate energy conversion, a co-mixed vacuum-assisted filtration strategy is designed to synthesize Au@MXene/cellulose nanocrystal/dodecylbenzenesulfonic acid-doped polyaniline (AMCP) films. Profited from the interfacial engineering, the total EMI shielding effectiveness (SE) can be increased by 27 % with the highest value of 67.9 dB. MXene with localized surface plasmon resonance characteristics gives the composite films good energy conversion performance, that is, the composite film can be rapidly heated up to 100 °C under the irradiation of an infrared lamp, and its surface temperature remains stable after continuous irradiation. Additionally, the infrared emissivity is as low as 0.173 within the 8-14 µm, which is necessary to adapt various application scenarios. Therefore, it is reliable that the AMCP films constructed by multicomponent offer a facile strategy for MXene-based EMI shielding devices with integration characteristics.

Incorporating mesopelagic fish into the evaluation of conservation areas for marine living resources under climate change scenarios.

Mesopelagic fish (meso-fish) are central species within the Southern Ocean (SO). However, their ecosystem role and adaptive capacity to climate change are rarely integrated into protected areas assessments. This is a pity given their importance as crucial prey and predators in food webs, coupled with the impacts of climate change. Here, we estimate the habitat distribution of nine meso-fish using an ensemble model approach (MAXENT, random forest, and boosted regression tree). Four climate model simulations were used to project their distribution under two representative concentration pathways (RCP4.5 and RCP8.5) for short-term (2006-2055) and long-term (2050-2099) periods. In addition, we assess the ecological representativeness of protected areas under climate change scenarios using meso-fish as indicator species. Our models show that all species shift poleward in the future. Lanternfishes (family Myctophidae) are predicted to migrate poleward more than other families (Paralepididae, Nototheniidae, Bathylagidae, and Gonostomatidae). In comparison, lanternfishes were projected to increase habitat area in the eastern SO but lose area in the western SO; the opposite was projected for species in other families. Important areas (IAs) of meso-fish are mainly distributed near the Antarctic Peninsula and East Antarctica. Negotiated protected area cover 23% of IAs at present and 38% of IAs in the future (RCP8.5, long-term future). Many IAs of meso-fish still need to be included in protected areas, such as the Prydz Bay and the seas around the Antarctic Peninsula. Our results provide a framework for evaluating protected areas incorporating climate change adaptation strategies for protected areas management. Supplementary Information: The online version contains supplementary material available at 10.1007/s42995-023-00188-9.

Delayed sternal Mycobacterium tuberculosis infection after left ventricular assist device implantation: A case report.

The incidence of Mycobacterium tuberculosis (Mtb) infection in patients with mechanical circulatory support devices is extremely rare. We present a case involving a 38-year-old male who experienced a delayed sternal Mtb infection following left ventricular assist device (LVAD) implantation. More than 5 months post-surgery, the patient was readmitted to the hospital presenting a subxiphoid abscess. The incision site displayed an unsatisfactory healing process after the incision and drainage of the abscess. Despite engaging in a rigorous treatment protocol, which included anti-infective therapy, vacuum-assisted closure, and surgical debridement, the patient's wound remained unhealed. Ultimately, after pus gene sequencing confirmed the diagnosis, the patient was administered a regimen combining anti-tuberculosis and anti-infective therapy, which culminated in the successful healing of the wound. This singular case study not only reveals the clinical progression of an unexpected Mtb infection post-implantation but also emphasizes the challenges encountered in diagnosis and management.

RAD54B promotes gastric cancer cell migration and angiogenesis via the Wnt/ß-catenin pathway.

BACKGROUND: Gastric cancer is an epidemic malignancy that is commonly diagnosed at the late stage. Evidence has elucidated that RAD54B exerts a crucial role in the progress of various tumors, but its specific role and mechanism in gastric cancer remain gloomy. MATERIALS AND METHODS: The level of RAD54B was detected by western blot. RAD54B expression was downregulated or upregulated in both MKN45 and AGS cells by the transfection of shRAD54B or overexpression plasmid, respectively. The role of RAD54B in the growth, migration, invasion and tube formation of gastric cancer was evaluated by Edu, colony formation, transwell and tube formation assays. In addition, the molecular mechanism of RAD54B in gastric cancer was also determined by western blot. Moreover, in vivo experiment was conducted in xenografted mice. RESULTS: The expression of RAD54B was discovered to be upregulated in gastric cancer based on the ATGC and GEPIA databases, which was also confirmed in gastric cancer cell lines. Moreover, overexpression of RAD54B enhanced the growth, migration, invasion, tube formation and Wnt/ß-catenin signaling axis in AGS and MKN45 cells. As expected, knockdown of RAD54B in AGS and MKN45 cells reversed these promotions. More importantly, in vivo assay also verified that RAD54B accelerated the growth of gastric cancer and Wnt/ß-catenin signaling pathway. CONCLUSIONS: Both loss-of-function and gain-of-function assays demonstrated that RAD54B facilitated gastric cancer cell progress and angiogenesis through the Wnt/ß-catenin axis.

Bile acids induce liver fibrosis through the NLRP3 inflammasome pathway and the mechanism of FXR inhibition of NLRP3 activation.

BACKGROUND: Altered patterns of bile acids (BAs) are frequently present in liver fibrosis, and BAs function as signaling molecules to initiate inflammatory responses. Therefore, this study was conducted to uncover the notably altered components of BAs and to explore the pathway of altered BA induced inflammation in the development of liver fibrosis. METHODS: Bile acids were quantified by ultraperformance liquid chromatography coupled to mass spectrometry (UPLC‒MS/MS). Cell Counting Kit-8 assays were used to determine the proliferative capacity of HSCs. Transwell assays and wound healing assays were used to determine the migratory capacity of LX2 cells. Protein expression was evaluated by western blotting. RESULTS: Plasma bile acid analysis showed higher levels of GCDCA, TCDCA, GCA and TCA in patients with liver fibrosis than in normal controls. The AUC of GCDCA was the highest. Western blotting showed that GCDCA treatment increased the expression of NLRP3-related proteins and collagen1 in vitro and significantly increased LX2 cells proliferation and migration. Furthermore, knockdown of NLRP3 or overexpression of FXR in LX2 cells decreased the expression of the above proteins, and FXR inhibited NLRP3 (ser 295) phosphorylation in vitro and vivo. In vivo, HE, Masson's trichrome, and Sirius Red staining showed that GCDCA increased collagen fibers in the mouse liver, and the expression of NLRP3-related proteins, collagen 1, and α-SMA in the liver increased significantly. However, the knockout of NLRP3 reversed these patterns. CONCLUSION: (1) Primary conjugated bile acids increased in patients with liver fibrosis; (2) GCDCA induce hepatic fibrosis via the NLRP3 inflammasome pathway; (3) FXR inhibits NLRP3 activity by restraining its phosphorylation; (4) knockdown or knockout of NLRP3 may relieve the onset of hepatic fibrosis.

Tanc1/2 TPR domain interacts with Myo18a C-terminus and undergoes liquid-liquid phase separation.

Tanc1 and its homologous protein Tanc2 are critical synaptic scaffold proteins which regulate synaptic spine densities and excitatory synapse strength. Recent studies indicated TANC1 and TANC2 are candidate genes of several neurodevelopmental disorders (NDDs). In this study, we identified and characterized a novel interaction between Tanc1/2 and Myo18a, mediated by the Tanc1/2 TPR domains and Myo18a coiled-coil domain and C-extension (CCex). Sequence analysis and size exclusion chromatography experiments reveal that high salt disrupts the interaction between Myo18a and Tanc1/2, indicating that the interaction is primarily driven by charge-charge interactions. More importantly, we found that the Tanc1-TPR/Myo18a CCex interaction could undergo liquid-liquid phase separation (LLPS) in both cultured cells and test tubes, which provides the biochemical basis and potential molecular mechanisms for the LLPS-mediated interactions between Myo18a and Tanc1/2.

Research on multi-target data association of the infrared fish-eye warning system.

The multi-target data association method is studied in order to realize multi-target tracking in infrared fish-eye warning system. The Neural Joint Probabilistic Data Association (NJPDA) algorithm is analyzed. It is found that the NJPDA algorithm only considers the distance information between the measurement and the target in the data association process, and its tracking accuracy needs to be further improved. Therefore, a new method fused with direction information is proposed based on the NJPDA algorithm. The proposed algorithm defines the concept of direction difference, introduces the direction information of target motion, and modifies the likelihood function by Gaussian weighting method, so as to fuse the direction information of target motion into the calculation of data interconnection probability. Experimental results demonstrate that the tracking success rate of the proposed algorithm is nearly 10 % higher than that of JPDA and NJPDA algorithms and its consuming time meets the real-time requirement of the infrared fish-eye warning system.

Sclerotome-derived PDGF signaling functions as a niche cue responsible for primitive erythropoiesis.

Primitive erythropoiesis serves a vital role in embryonic development, generating primitive red blood cells responsible for transportation of oxygen throughout the body. Although diverse niche factors are known to function in definitive hematopoiesis, the microenvironment contributing to primitive hematopoiesis remains largely elusive. Here, we report that platelet-derived growth factor (PDGF) signaling is required for erythroid progenitor differentiation in zebrafish. Ablating pdgfαa (also known as pdgfaa) and pdgfαb (also known as pdgfab) or blocking PDGF signaling with an inhibitor impairs erythroid progenitor differentiation, thus resulting in a significant decrease in the number of erythrocytes. We reveal that pdgfαb is expressed in sclerotomal cells, and that its receptor genes, pdgfra and pdgfrb, are expressed in the adjacent erythroid progenitor cells. Sclerotome-specific overexpression of pdgfαb effectively restores primitive erythropoiesis in pdgfαa-/-;pdgfαb-/- mutant embryos. In addition, we have defined ERK1/2 signaling as a downstream pathway of PDGF signaling during embryonic erythropoiesis. Taken together, our findings indicate that PDGF signaling derived from sclerotome functions as a niche cue for primitive erythropoiesis.

Dynamic interactions between E-cadherin and Ankyrin-G mediate epithelial cell polarity maintenance.

E-cadherin is an essential cell‒cell adhesion protein that mediates canonical cadherin-catenin complex formation in epithelial lateral membranes. Ankyrin-G (AnkG), a scaffold protein linking membrane proteins to the spectrin-based cytoskeleton, coordinates with E-cadherin to maintain epithelial cell polarity. However, the molecular mechanisms governing this complex formation and its relationships with the cadherin-catenin complex remain elusive. Here, we report that AnkG employs a promiscuous manner to encapsulate three discrete sites of E-cadherin by the same region, a dynamic mechanism that is distinct from the canonical 1:1 molar ratio previously described for other AnkG or E-cadherin-mediated complexes. Moreover, we demonstrate that AnkG-binding-deficient E-cadherin exhibited defective accumulation at the lateral membranes and show that disruption of interactions resulted in cell polarity malfunction. Finally, we demonstrate that E-cadherin is capable of simultaneously anchoring to AnkG and ß-catenin, providing mechanistic insights into the functional orchestration of the ankyrin-spectrin complex with the cadherin-catenin complex. Collectively, our results show that complex formation between E-cadherin and AnkG is dynamic, which enables the maintenance of epithelial cell polarity by ensuring faithful targeting of the adhesion molecule-scaffold protein complex, thus providing molecular mechanisms for essential E-cadherin-mediated complex assembly at cell‒cell junctions.

SASH1: A Novel Eph Receptor Partner and Insights into SAM-SAM Interactions.

The Eph (erythropoietin-producing human hepatocellular) receptor family, the largest subclass of receptor tyrosine kinases (RTKs), plays essential roles in embryonic development and neurogenesis. The intracellular Sterile Alpha Motif (SAM) domain presents a critical structural feature that distinguishes Eph receptors from other RTKs and participates in recruiting and binding downstream molecules. This study identified SASH1 (SAM and SH3 domain containing 1) as a novel Eph receptor-binding partner through SAM-SAM domain interactions. Our comprehensive biochemical analyses revealed that SASH1 selectively interacts with Eph receptors via its SAM1 domain, displaying the highest affinity for EphA8. The high-resolution crystal structure of the EphA8-SASH1 complex provided insights into the specific intermolecular interactions between these proteins. Cellular assays confirmed that EphA8 and SASH1 co-localize and co-precipitate in mammalian cells, with cancer mutations (EphA8 R942H or G978D) impairing this interaction. We demonstrated that SAM-SAM interaction is critical for SASH1-mediated regulation of EphA8 kinase activity, shedding new light on the Eph signaling pathway and expanding our understanding of the molecular basis of the tumor suppressor gene SASH1.

Recent Progress in Extracellular Vesicle-Based Carriers for Targeted Drug Delivery in Cancer Therapy.

Extracellular vesicles (EVs) are small, membrane-based vesicles released by cells that play a critical role in various physiological and pathological processes. They act as vehicles for transporting a variety of endogenous cargo molecules, enabling intercellular communication. Due to their natural properties, EVs have emerged as a promising "cell-free therapy" strategy for treating various diseases, including cancer. They serve as excellent carriers for different therapeutics, including nucleic acids, proteins, small molecules, and other nanomaterials. Modifying or engineering EVs can improve the efficacy, targeting, specificity, and biocompatibility of EV-based therapeutics for cancer therapy. In this review, we comprehensively outline the biogenesis, isolation, and methodologies of EVs, as well as their biological functions. We then focus on specific applications of EVs as drug carriers in cancer therapy by citing prominent recent studies. Additionally, we discuss the opportunities and challenges for using EVs as pharmaceutical drug delivery vehicles. Ultimately, we aim to provide theoretical and technical support for the development of EV-based carriers for cancer treatment.

Early life history affects fish size mainly by indirectly regulating the growth during each stage: a case study in a demersal fish.

The complex life histories of demersal fishes are artificially separated into multiple stages along with changes in morphology and habitat. It is worth exploring whether the phenotypes expressed earlier and later during the life cycle are related or decoupled. The life stages of first year Pacific cod (Gadus macrocephalus) were tracked over different hatch years and regions to test whether the early life history had a long-lasting effect on subsequent growth. We further explored the contribution of growth in the early and subsequent life history stages to body size at the end of each stage. In addition to the accessory growth centre and the first annual ring, the other two checks on the otolith possibly related to settlement and entering deeper waters were identified in 75 Pacific cod individuals. The direct and indirect relationships among the life history stages was interpreted based on path analysis. The results showed that growth prior to the formation of the accessory growth centre had a significant effect on the absolute growth of the fish before and after settlement and migration to deep water. However, there was no or moderate evidence that early growth affected the body size at each stage, which was mainly regulated by growth during the stage. This study supports the lasting effect of early growth and clarifies that it affects size mainly by indirectly regulating staged growth. Quantifying the phenotype relationships and identifying the internal mechanisms form the basis for assessing population dynamics and understanding the processes behind the changes. Supplementary Information: The online version contains supplementary material available at 10.1007/s42995-022-00145-y.

Bacterial outer membrane vesicles-cloaked modified zein nanoparticles for oral delivery of paclitaxel.

To improve the aqueous solubility and oral bioavailability of paclitaxel (PTX), a biomimetic system for oral administration of PTX was efficiently developed as an outer membrane vesicle (OMVs) of sodium caseinate (CAS) modified zein nanoparticles (OMVs-Zein-CAS-PTX-NPs) by Escherichia coli. To verify their structure and properties, the designed nanostructures were thoroughly characterized using various characterization techniques. The results indicated that hydrogen bonds and van der Waals forces mainly drove the interaction between PTX and Zein, but the complex is unstable. The physicochemical stability of PTX-loaded zein nanoparticles was improved by the addition of CAS. The biological characteristics of biofilms are reproduced by nanoparticles cloaked with outer membrane vesicles. OMVs-Zein-CAS-PTX-NPs delayed the release of PTX under simulated gastric and intestinal fluids due to OMVs protection. OMVs-Zein-CAS-PTX-NPs exhibited remarkable antitumor ability in vitro and improved the bioavailability of oral administration of PTX in vivo. Therefore, OMVs cloaked in nanoparticles may be a suitable delivery vehicle to provide an efficient application prospect for the oral administration of PTX.

Structure of the N-terminal coiled-coil domains of the ciliary protein Rpgrip1l.

Rpgrip1l is one of the key ciliary proteins located at the transition zone of the primary cilium, an important organelle for cells to sense the outer environment. Mutations in the RPGRIP1L gene are associated with various ciliopathies. Here, we focused on the N-terminal coiled-coil of Rpgrip1l. By comprehensive biochemical and structural characterizations, we demonstrated that the two predicted coiled-coil regions (CC12) located at Rpgrip1l N-terminus each can form a stable parallel dimer. We further showed that overexpression of Rpgrip1l CC12 in NIH/3T3 cells significantly shortened the length of primary cilia, and this effect depended on the dimer formation. In addition, we found that CC12 of the homolog protein Rpgrip1 in mouse and human were significantly different from Rpgrip1l. Finally, we confirmed that some disease-related mutations can alter the dimeric states of CC12 of Rpgrip1l or Rpgrip1, which might explain the pathogenic mechanisms.