TBK1-Zyxin signaling controls tumor-associated macrophage recruitment to mitigate antitumor immunity.

Mechanical control is fundamental for cellular localization within a tissue, including for tumor-associated macrophages (TAMs). While the innate immune sensing pathways cGAS-STING and RLR-MAVS impact the pathogenesis and therapeutics of malignant diseases, their effects on cell residency and motility remain incompletely understood. Here, we uncovered that TBK1 kinase, activated by cGAS-STING or RLR-MAVS signaling in macrophages, directly phosphorylates and mobilizes Zyxin, a key regulator of actin dynamics. Under pathological conditions and in STING or MAVS signalosomes, TBK1-mediated Zyxin phosphorylation at S143 facilitates rapid recruitment of phospho-Zyxin to focal adhesions, leading to subsequent F-actin reorganization and reduced macrophage migration. Intratumoral STING-TBK1-Zyxin signaling was evident in TAMs and critical in antitumor immunity. Furthermore, myeloid-specific or global disruption of this signaling decreased the population of CD11b+ F4/80+ TAMs and promoted PD-1-mediated antitumor immunotherapy. Thus, our findings identify a new biological function of innate immune sensing pathways by regulating macrophage tissue localization, thus providing insights into context-dependent mitigation of antitumor immunity.

Attention-guided variational graph autoencoders reveal heterogeneity in spatial transcriptomics.

The latest breakthroughs in spatially resolved transcriptomics technology offer comprehensive opportunities to delve into gene expression patterns within the tissue microenvironment. However, the precise identification of spatial domains within tissues remains challenging. In this study, we introduce AttentionVGAE (AVGN), which integrates slice images, spatial information and raw gene expression while calibrating low-quality gene expression. By combining the variational graph autoencoder with multi-head attention blocks (MHA blocks), AVGN captures spatial relationships in tissue gene expression, adaptively focusing on key features and alleviating the need for prior knowledge of cluster numbers, thereby achieving superior clustering performance. Particularly, AVGN attempts to balance the model's attention focus on local and global structures by utilizing MHA blocks, an aspect that current graph neural networks have not extensively addressed. Benchmark testing demonstrates its significant efficacy in elucidating tissue anatomy and interpreting tumor heterogeneity, indicating its potential in advancing spatial transcriptomics research and understanding complex biological phenomena.

The protein phosphatase PPM1A dephosphorylates and activates YAP to govern mammalian intestinal and liver regeneration.

The Hippo-YAP pathway responds to diverse environmental cues to manage tissue homeostasis, organ regeneration, tumorigenesis, and immunity. However, how phosphatase(s) directly target Yes-associated protein (YAP) and determine its physiological activity are still inconclusive. Here, we utilized an unbiased phosphatome screening and identified protein phosphatase magnesium-dependent 1A (PPM1A/PP2Cα) as the bona fide and physiological YAP phosphatase. We found that PPM1A was associated with YAP/TAZ in both the cytoplasm and the nucleus to directly eliminate phospho-S127 on YAP, which conferring YAP the nuclear distribution and transcription potency. Accordingly, genetic ablation or depletion of PPM1A in cells, organoids, and mice elicited an enhanced YAP/TAZ cytoplasmic retention and resulted in the diminished cell proliferation, severe gut regeneration defects in colitis, and impeded liver regeneration upon injury. These regeneration defects in murine model were largely rescued via a genetic large tumor suppressor kinase 1 (LATS1) deficiency or the pharmacological inhibition of Hippo-YAP signaling. Therefore, we identify a physiological phosphatase of YAP/TAZ, describe its critical effects in YAP/TAZ cellular distribution, and demonstrate its physiological roles in mammalian organ regeneration.

Aquaculture Molecular Breeding Platform (AMBP): a comprehensive web server for genotype imputation and genetic analysis in aquaculture.

It is of vital importance to understand the population structure, dissect the genetic bases of performance traits, and make proper strategies for selection in breeding programs. However, there is no single webserver covering the specific needs in aquaculture. We present Aquaculture Molecular Breeding Platform (AMBP), the first web server for genetic data analysis in aquatic species of farming interest. AMBP integrates the haplotype reference panels of 18 aquaculture species, which greatly improves the accuracy of genotype imputation. It also supports multiple tools to infer genetic structures, dissect the genetic architecture of performance traits, estimate breeding values, and predict optimum contribution. All the tools are coherently linked in a web-interface for users to generate interpretable results and evaluate statistical appropriateness. The webserver supports standard VCF and PLINK (PED, MAP) files, and implements automated pipelines for format transformation and visualization to simplify the process of analysis. As a demonstration, we applied the webserver to Pacific white shrimp and Atlantic salmon datasets. In summary, AMBP constitutes comprehensive resources and analytical tools for exploring genetic data and guiding practical breeding programs. AMBP is available at http://mgb.qnlm.ac.

Cell-to-cell communications of cGAS-STING pathway in tumor immune microenvironment. / è‚¿ç˜¤å ç–«å¾®çŽ¯å¢ƒä¸­cGAS-STINGä¿¡å·é€šè·¯çš„ç»†èƒžé—´ä¿¡å·ä¼ é€’.

Targeting cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) pathway is a promising strategy for tumor treatment. The pattern recognition receptor cGAS identifies dsDNA and catalyzes the formation of a second messenger 2'3'-cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), activating the downstream interferons and pro-inflammatory cytokines through the adaptor protein STING. Notably, in tumor immune microenvironment, key components of cGAS-STING pathway are transferred among neighboring cells. The intercellular transmission under these contexts serves to sustain and amplify innate immune responses while facilitating the emergence of adaptive immunity. The membrane-based system, including extracellular vesicles transport, phagocytosis and membrane fusion transmit dsDNA, cGAMP and activated STING, enhances the immune surveillance and inflammatory responses. The membrane proteins, including a specific protein channel and intercellular gap junctions, transfer cGAMP and dsDNA, which are crucial to regulate immune responses. The ligand-receptor interactions for interferon transmission amplifies the anti-tumor response. This review elaborates on the regulatory mechanisms of cell-to-cell communications of cGAS-STING pathway in tumor immune microenvironment, explores how these mechanisms modulate immunological processes and discusses potential interventions and immunotherapeutic strategies targeting these signaling cascades.

Battery-Free, Wireless, Cuff-Type, Multimodal Physical Sensor for Continuous Temperature and Strain Monitoring of Nerve.

Peripheral nerve injuries cause various disabilities related to loss of motor and sensory functions. The treatment of these injuries typically requires surgical operations for improving functional recovery of the nerve. However, capabilities for continuous nerve monitoring remain a challenge. Herein, a battery-free, wireless, cuff-type, implantable, multimodal physical sensing platform for continuous in vivo monitoring of temperature and strain from the injured nerve is introduced. The thin, soft temperature, and strain sensors wrapped around the nerve exhibit good sensitivity, excellent stability, high linearity, and minimum hysteresis in relevant ranges. In particular, the strain sensor integrated with circuits for temperature compensation provides reliable, accurate strain monitoring with negligible temperature dependence. The system enables power harvesting and data communication to wireless, multiple implanted devices wrapped around the nerve. Experimental evaluations, verified by numerical simulations, with animal tests, demonstrate the feasibility and stability of the sensor system, which has great potential for continuous in vivo nerve monitoring from an early stage to complete regeneration.

Lanthanide-Based Metal-Organic Frameworks Containing "V-Shaped" Tetracarboxylate Ligands: Synthesis, Crystal Structures, "Naked-Eye" Luminescent Detection, and Catalytic Properties.

Three lanthanide-based metal-organic frameworks, [Tb(HMDIA)(H2O)3]·H2O (Tb-MDIA), [Ho(HMDIA)(H2O)3]·(H2O)2 (Ho-MDIA), and [Nd(HMDIA)(H2O)3]·(H2O)2 (Nd-MDIA) from the same V-shaped ligand 5,5'-methylenediisophthalic acid (H4MDIA), were prepared by mixing Ln3+ and H4MDIA under solvothermal conditions. The crystal structures of the three complexes were determined by single-crystal X-ray diffraction. The different coordination modes of the organic ligands resulted in different framework structures among the three complexes. The luminescent properties of Ln-MDIA in the ultraviolet-visible region were also studied. Interestingly, the bright-green emitter Tb-MDIA showed high selectivity and sensitivity to allow the naked-eye visualization of Fe3+ ions and picric acid (PA) explosive, and both sensing mechanisms were revealed. Finally, Ho-MDIA and Nd-MDIA were shown to work as heterogeneous catalysts for the cyanosilylation reaction of aromatic aldehydes, and the catalysts could be recycled at least three times without any decrease in activity.

[Enzyme activity of neuraminidase 1 correlated with the biological behavior of prostate cancer PC3 and DU145 cell lines].

OBJECTIVE: To investigate the effects of the enzyme activity of neuraminidase 1 (Neu1) on the biological behavior of prostate cancer PC3 and DU145 cell lines. METHODS: We detected the expression of Neul in the prostate cancer PC3 and DU145 cell lines by Western blot. Using sialidase inhibitors and antibody blocking, we suppressed the enzyme activity of Neu1 and then measured the proliferation and invasiveness of the two cell lines by CCK-8 and Transwell assay, respectively. RESULTS: No statistically significant difference was found in the Neu1 expression between the PC3 and DU145 cell lines. The proliferation and invasiveness of the two types of cells were both increased after inhibition of the Neu1 enzyme activity. CONCLUSIONS: The enzyme activity of Neu1 is correlated with the biological behavior of prostate cancer PC3 and DU145 cells and capable of inhibiting the proliferation and invasiveness of the two types of cells.

Cyanobacterial blooms prediction in China's large hypereutrophic lakes based on MODIS observations and Bayesian theory.

Cyanobacterial harmful algal blooms (HABs) pose a significant threat to aquatic ecosystems, water quality, and public health, particularly in large hypereutrophic lakes. Developing accurate short-term prediction models is essential for early warning and effective management of HABs. This study introduces a Bayesian-based model aimed at predicting HABs in three of China's large hypereutrophic lakes: Lake Taihu, Lake Chaohu, and Lake Hulunhu. By integrating MODIS data from the Terra and Aqua satellites with meteorological data spanning from 2010 to 2018, the model forecasts HABs distributions 1, 4, and 7 days in advance. Validation with meteorological data from 2019 to 2020 showed high accuracy, with 0.83 at the pixel level, 0.74 for zonal predictions, and 0.64 for lake-wide HABs area forecasts. Further evaluation using 2023 weather forecast data yielded similar accuracies of 0.78, 0.57, and 0.62, respectively. In addition to predicting the spatial extent of HABs, the model provides binary HABs maps, outbreak areas, and HABs status within lake zones. This method for building prediction models significantly enhances early warning and management capabilities for HABs, providing a scalable framework that can be adapted to other regions facing similar threats from HABs.

Facilitating the Hydrogen Evolution Reaction on Basal-Plane S Sites on MoS2@Ni3S2 by Dual Ti and N Plasma Treatment.

Atomic engineering of the basal plane active sites in MoS2 holds great promise to boost the electrocatalytic activity for hydrogen evolution reactions (HER), yet the performance optimization and mechanism exploration are still not satisfactory. Herein, we proposed a dual-plasma engineering strategy to implant Ti and N heteroatoms into the basal plane of MoS2 supported by Ni3S2 nanorods on nickel foam (MSNF) for efficient electrocatalysis of HER. Owing to the low formation energy of Ti dopants in MoS2 and the extra charge carriers introduced by N dopants, the optimally codoped samples N1.0@Ti500-MSNF demonstrate significant morphology changes from nanorods to urchin-like nanospheres with the surface active areas increased by seven-fold, as well as enhanced electrical conductivity in comparison with the nondoped counterparts. The HER performance of N1.0@Ti500-MSNF is comparable with the Pt-based catalyst: overpotential of 26 mV at 20 mA cm-2, Tafel slope of 35.6 mV dec-1, and long-term stability over 50 h. First-principles calculation reveals that N doping accelerates the dissociation of water molecules while Ti doping activates the adjacent S sites for hydrogen adsorption by lowering the Gibbs free energy, resulting in excellent HER activity. This work thus provides an effective strategy for basal plane engineering of MoS2 heterostructures toward high-performance HER and sustainable energy supply at reasonable costs.

Plasma oxidative lipidomics reveals signatures for sepsis-associated acute kidney injury.

BACKGROUND: Oxidized lipids are essential bioactive lipid mediators generated during infection that regulate oxidative stress and the inflammatory response, but their signatures in patients with sepsis-associated acute kidney injury (SA-AKI) are poorly understood. This study analyzed the oxidative lipidomics of plasma from patients with SA-AKI to reveal the underlying biomarkers and pathophysiological mechanisms involved in sepsis. MATERIALS: A total of 67 patients with SA-AKI and 20 age- and sex-matched healthy controls (HCs) participated in this prospective cohort study. Among the patients with SA-AKI, 14 cases had stage I-II AKI and 53 cases had stage III AKI. Oxidative lipidomic analysis of plasma samples was conducted using ultra performance liquid chromatography coupled with tandem mass spectrometric (UPLC-MS /MS) detection. RESULTS: Among 21 kinds of differentially oxidized lipids, 5(S),12(S)-DiHETE, 5-isoPGF2VI, 5,6-DiHETrE, 11,12-EET and 9,10-DiHOME showed the best performance. The prediction model incorporating them has shown highly sensitive and specific in distinguishing different stages of SA-AKI from HCs. The annotation of Kyoto Encyclopedia of Genes and Genomes illustrated that the overall downregulation of vascular smooth muscle contraction was closely related to the pathophysiological mechanism of SA-AKI. CONCLUSION: This study revealed alterations in the characteristic oxidized lipids in the plasma of SA-AKI patients, and these lipids had high diagnostic efficiency and potential targeted intervention value for SA-AKI.

Bioaccumulation of organochlorine pesticides in Antarctic krill (Euphausia superba): Profile, influencing factors, and mechanisms.

Accumulation of organochlorine pesticides (OCPs) in Antarctic krill (Euphausia superba), a keystone species in the Southern Ocean, is potentially harmful to the Antarctic ecosystem and human health. In the current study, we collected E. superba specimens (including muscle and carapace tissues) from Bransfield Strait in northern Antarctic Peninsula and South Georgia to analyze the profile, influencing factors and mechanisms of OCPs bioaccumulation in them. Results indicated that the biological traits (δ13C, δ15N and lipid contents) of krill were significantly affected by habitat. There may exist growth dilution of OCPs in Antarctic krill and no fresh OCPs input in Antarctica, except for endosulfan I. Based on lipid-normalized concentrations, no significant differences were observed between the two regions at most sampling sites. However, OCP levels showed tissue and sex dependence. Boosted regression trees (BRTs) and partial least squares structural equation models (PLS-SEMs) were built to better investigate the main factors affecting the bioaccumulation of OCPs. Lipid content, negatively correlated with OCP levels, was the main factor. In vitro silicon modeling indicated that CYP3A4 metabolism capacity in krill contributed to the OCP residues except for endosulfan I. The results of this study expand current knowledge of OCPs in Antarctic marine biota, as well as their influencing factors and potential mechanisms.

Impact of COVID-19 Pandemic on Elevated Anxiety Symptoms of Maintenance Hemodialysis Patients in China: A One-Year Follow-Up Study.

Recent studies have shown that coronavirus disease 2019 (COVID-19) aggravates anxiety in patients with maintenance hemodialysis (MHD), but it is still unclear how long this adverse effect will last. This study aims to investigate the impact of COVID-19 on the elevated anxiety symptoms of MHD patients 1 year after the outbreak. Assessment of elevated anxiety symptoms was performed on patients with MHD during early COVID-19 (February 17-February 29, 2020) and 1-year follow-up (March 1-March 13, 2021), and a total of 100 patients had completed face-to-face questionnaires at the first and 1-year follow-up. At the beginning of the outbreak, 40% of the patients with MHD had anxiety symptoms [self-rating anxiety scale (SAS) score ≥ 50], and 11% (SAS score: 60-69) and 2% (SAS score ≥ 70) of the patients had moderate and severe anxiety symptoms, respectively. Multivariate analysis shows that possibility of unaccompanied transfer, possibility of family members or themselves being infected in a hospital, added body temperature monitoring during dialysis, and increased medical procedures are the risk factors in elevated anxiety symptoms during early COVID-19. At the 1-year follow-up, the incidence of anxiety symptoms in the same group of patients declined to 28%, and all the patients had mild anxiety symptoms (SAS score: 50-59), which is significantly lower than that of the early COVID-19 pandemic with statistically significant difference (p = 0.003). Increased protective measures taken by the medical staves were the only risk factor in elevated anxiety symptoms during the 1-year follow-up. This study shows that COVID-19 has a direct impact on the deterioration of anxiety symptoms in patients with MHD. With the changes of the requirements for COVID-19 prevention and control, as well as the enhancement of propaganda and education of the pandemic and psychological care, the severity and risk factors of anxiety symptoms in the patients with MHD are changing. Thus, targeted interventions are suggested to improve the psychological endurance of the patients with MHD.

Optimization of tetramycin production in Streptomyces ahygroscopicus S91.

BACKGROUND: Tetramycin is a 26-member tetraene antibiotic used in agriculture. It has two components, tetramycin A and tetramycin B. Tetramycin B is obtained by the hydroxylation of tetramycin A on C4. This reaction is catalyzed by the cytochrome P450 monooxygenase TtmD. The two components of tetramycin have different antifungal activities against different pathogenic fungi. Therefore, the respective construction of high-yield strains of tetramycin A and tetramycin B is conducive to more targeted action on pathomycete and has a certain practical value. RESULTS: Streptomyces ahygroscopicus S91 was used as the original strain to construct tetramycin A high-yield strains by blocking the precursor competitive biosynthetic gene cluster, disrupting tetramycin B biosynthesis, and overexpressing the tetramycin pathway regulator. Eventually, the yield of tetramycin A in the final strain was up to 1090.49 ± 136.65 mg·L- 1. Subsequently, TtmD, which catalyzes the conversion from tetramycin A to tetramycin B, was overexpressed. Strains with 2, 3, and 4 copies of ttmD were constructed. The three strains had different drops in tetramycin A yield, with increases in tetramycin B. The strain with three copies of ttmD showed the most significant change in the ratio of the two components. CONCLUSIONS: A tetramycin A single-component producing strain was obtained, and the production of tetramycin A increased 236.84% ± 38.96% compared with the original strain. In addition, the content of tetramycin B in a high-yield strain with three copies of ttmD increased from 26.64% ± 1.97 to 51.63% ± 2.06%.

The great Atlantic Sargassum belt.

Pelagic Sargassum is abundant in the Sargasso Sea, but a recurrent great Atlantic Sargassum belt (GASB) has been observed in satellite imagery since 2011, often extending from West Africa to the Gulf of Mexico. In June 2018, the 8850-kilometer GASB contained >20 million metric tons of Sargassum biomass. The spatial distribution of the GASB is mostly driven by ocean circulation. The bloom of 2011 might be a result of Amazon River discharge in previous years, but recent increases and interannual variability after 2011 appear to be driven by upwelling off West Africa during boreal winter and by Amazon River discharge during spring and summer, indicating a possible regime shift and raising the possibility that recurrent blooms in the tropical Atlantic and Caribbean Sea may become the new norm.