BCMA-BBZ-OX40 CAR-T Therapy Using an Instant Manufacturing Platform in Multiple Myeloma.

BACKGROUND: Chimeric antigen receptor (CAR)-T cell has revolutionary efficacy against relapsed/refractory multiple myeloma (R/R MM). However, current CAR-T cell therapy has several limitations including long vein-to-vein time and limited viability. METHODS: A 4-1BB-costimulated B-cell maturation antigen (BCMA) CAR-T integrating an independently-expressed OX40 (BCMA-BBZ-OX40) was designed and generated by a traditional manufacturing process (TraditionCART) or instant manufacturing platform (named InstanCART). The tumor-killing efficiency, differentiation, exhaustion, and expansion level were investigated in vitro and in tumor-bearing mice. An investigator-initiated clinical trial was performed in patients with R/R MM to evaluate the outcomes of both TraditionCART and InstanCART. The primary objective was safety within 1 month after CAR-T cell infusion. The secondary objective was the best overall response rate. RESULTS: Preclinical studies revealed that integrated OX40 conferred BCMA CAR-T cells with superior cytotoxicity and reduced exhaustion levels. InstanCART process further enhanced the proliferation and T-cell stemness of BCMA-BBZ-OX40 CAR-T cells. BCMA-BBZ-OX40 CAR-T cells were successfully administered in 22 patients with R/R MM, including 15 patients with TraditionCART and 7 patients with InstanCART. Up to 50% (11/22) patients had a high-risk cytogenetic profile and 36% (8/22) had extramedullary disease. CAR-T therapy caused grade 1-2 cytokine release syndrome in 19/22 (80%) patients, grade 1 neurotoxicity in 2/22 (9%) patients and led to ≥grade 3 adverse events including neutropenia (20/22, 91%), thrombocytopenia (15/22, 68%), anemia (12/22, 55%), creatinine increased (1/22, 5%), hepatic enzymes increased (5/22, 23%), and sepsis (1/22, 5%). The best overall response rate was 100%, and 64% (14/22) of the patients had a complete response or better. The median manufacturing time was shorter for InstanCART therapy (3 days) than for TraditionCART therapy (10 days). Expansion and duration were dramatically higher for InstanCART cells than for TraditionCART cells. CONCLUSIONS: BCMA-BBZ-OX40 CAR-T cells were well tolerated and exhibited potent responses in patients with R/R MM. InstanCART shortened the manufacturing period compared to TraditionCART, and improved the cellular kinetics. Our results demonstrated the potency and feasibility of OX40-modified BCMA CAR-T cells using InstanCART technology for R/R MM therapy. TRIAL REGISTRATION NUMBER: This trial was registered at www. CLINICALTRIALS: gov as #NCT04537442.

Construction and drug screening of Co-culture system using extrahepatic cholangiocarcinoma organoids and tumor-associated macrophages.

Patient-derived organoids (PDOs) have been proposed as a novel in vitro tumor model that can be applied to tumor research and drug screening. However, current tumor organoid models lack components of the tumor microenvironment, particularly tumor-associated macrophages(TAMs).We collected peripheral blood and tumor samples from 6 patients with extrahepatic cholangiocarcinoma(eCCA). Monocytes were induced into TAMs by cytokine and conditioned medium, and then co-cultured with tumor organoids. Our comprehensive analysis and comparison of histopathology and genomics results confirmed that this co-culture model can better capture intra- and inter-tumor heterogeneity retain the specific mutations of the original tumor. Drug sensitivity data in vitro revealed that gemcitabine and cisplatin are effective drugs for cholangiocarcinoma, but TAMs in the tumor microenvironment promote organoids growth and chemotherapy resistance. In conclusion, our organoid model of cholangiocarcinoma co-cultured with TAMs can not only shorten the model construction cycle, but also preserve the heterogeneity of original tumors to improve the accuracy of drug screening, and can also be applied to the researches of TAMs and tumors.

Challenges and improvements in HER2 scoring and histologic evaluation: insights from a national proficiency testing scheme for breast cancer diagnosis in China.

BACKGROUND: In 2022, our team launched the pioneering national proficiency testing (PT) scheme for the pathological diagnosis of breast cancer, rapidly establishing its credibility throughout China. Aiming to continuously monitor and improve the proficiency of Chinese pathologists in breast pathology, the second round of the PT scheme was initiated in 2023, which will expand the number of participating institutions, and will conduct a nationwide investigation into the interpretation of HER2 0, 1+, and 2+/FISH- categories in China. METHODS: The methodology employed in the current round of PT scheme closely mirrors that of the preceding cycle in 2022, which is designed and implemented according to the "Conformity assessment-General requirements for proficiency testing"(GB/T27043-2012/ISO/IEC 17043:2010). More importantly, we utilized a statistics-based method to generate assigned values to enhance their robustness and credibility. RESULTS: The final PT results, published on the website of the National Quality Control Center for Cancer ( http://117.133.40.88:3927 ), showed that all participants passed the testing. However, a few institutions demonstrated systemic biases in scoring HER2 0, 1+, and 2+/FISH- with accuracy levels below 59%, considered unsatisfactory. Especially, the concordance rate for HER2 0 cases was only 78.1%, indicating challenges in distinguishing HER2 0 from low HER2 expression. Meanwhile, areas for histologic type and grade interpretation improvement were also noted. CONCLUSIONS: Our PT scheme demonstrated high proficiency in diagnosing breast cancer in China. But it also identified systemic biases in scoring HER2 0, 1+, and 2+/FISH- at some institutions. More importantly, our study highlighted challenges in the evaluation at the extreme lower end of the HER2 staining spectrum, a crucial area for further research. Meanwhile, it also revealed the need for improvements in interpreting histologic types and grades. These findings strengthened the importance of robust quality assurance mechanisms, like the nationwide PT scheme conducted in this study, to maintain high diagnostic standards and identify areas requiring further training and enhancement.

Rapid and inexpensive synthesis of liter-scale SiC aerogels.

Ceramic aerogels are promising materials for thermal insulation and protection under harsh environments. Yet current synthesis methods fail to provide an energy-, time-, and cost-effective route for high-throughput production and large-scale applications, especially for non-oxide ceramic aerogels. Here we reported a way to synthesize SiC aerogels within seconds and over liter scale, with a demonstrated throughput of ~16 L min-1 in a typical lab experiment. The key lies in renovated combustion synthesis and a fast expansion from powder reactants to aerogel products over 1000% in volume. The synthesis process is self-sustainable and requires minimal energy input. The product is very cheap, with an estimated price of ~$0.7 L-1 (~$7 kg-1). The obtained SiC aerogels have excellent thermo-mechanical properties, including low thermal conductivity, high elasticity, and damage tolerance. Our invention not only offers a practical pathway for large-scale applications of ceramic aerogels, but also calls for rethinking of combustion synthesis in one-step conversion from raw chemicals to bulk products ready for practical applications.

Achieving Super-Metallophobicity on Silicon-based Ceramics at High Temperature.

As a critical concept in physical chemistry, superwettability is widely concerned in both fundamental science and practical engineering in past few decades. Despite this, investigation on high temperature superwettability is still a void, which is significant both in scientific and industrial fields. Herein, a ceramic with specific high temperature non-wetting property, Si2N2O is proposed. Compared with other materials, Si2N2O is elucidated with better practical non-wetting property against various non-ferrous metals. Combining with micro-nanostructures, the metallophobicity is further improved (contact angle >150° and contact angle hysteresis ≈0°). The extraordinary metal repellency is defined as "super-metallophobicity", which is proved to be induced by distinctive thermodynamic and dynamic wetting behavior on the rough surface. The research of super-metallophobicity not only sheds light on superwettability at high temperature, but also offers worthy insights for future potential material design in a wide range of applications, such as metallurgy, 3D printing and semiconductor industry.

Study on Spontaneous Combustion Characteristics and Microstructure of Bituminous Coal under Water Immersion.

The stagnant water above the coal seam flows into the goaf, causing the goaf coal to be soaked by water for a long time. Compared with dry raw coal, water-soaked coal has a stronger tendency for spontaneous combustion, which poses a serious threat to mining operators. To unravel the impact of water immersion on coal's self-heating properties, an investigation was conducted employing techniques such as simultaneous thermogravimetric analysis/differential scanning calorimetry (TG/DSC), scanning electron microscopy (SEM), low-temperature nitrogen adsorption based on the BET theory, and Fourier transform infrared spectroscopy (FTIR). The variations in the characteristic temperature, microphysical structure, and active functional groups of bituminous coal with water immersion degrees of 10, 30, 50, and 100% were studied, and the experimental results showed that (1) during the initial stage of coal self-ignition oxidation, moisture can cause a delay in the characteristic temperature points of bituminous coal. When the degree of water saturation in bituminous coal reaches 100%, both the critical temperature (T 1) and the cracking temperature (T 2) peak at 48.14 and 205.06 °C, respectively. However, after the water evaporation phase is complete, water soaking promotes the spontaneous combustion of bituminous coal. (2) The number of pores and fractures in bituminous coal is positively correlated with the amount of water soaked, with the average pore diameter increasing from 10.124 nm in raw coal to 15.547 nm in the A4 coal sample. Moreover, when the degree of water immersion reaches 100%, the proportion of mesopores and macropores increases to 38.89 and 19.95%, respectively. (3) Compared to untreated coal, the number of functional groups in water-soaked coal samples increases. With the increase in water immersion, the hydroxyl (-OH) content of raw coal and four kinds of bituminous coal with different degrees of immersion was 40.8, 41.3, 42, 43.9, and 42.9%, respectively, showing a trend of increasing first and then decreasing. When the degree of water immersion of bituminous coal is 50%, the natural tendency is the strongest. These findings contribute to elucidating the underlying mechanism of water immersion's impact on coal self-ignition, thereby holding significant implications for enhancing fire safety measures in mine working areas.

Enhancing mechanical performance of hydroxyapatite-based bone implants via citric acid post-processing in binder jetting additive manufacturing.

Binder jetting is a promising technology in the additive manufacturing of bone implants, particularly for printing brittle bioceramics that are susceptible to thermal residual stresses. However, challenges in this field include low strength and undesirable size changes due to post-sintering treatments, as well as the absence of necessary organic matter like Glycosaminoglycans, citric acid, etc. To address these issues, a novel approach was introduced using citric acid (CA) as a post-processing agent to enhance the mechanical performance of green samples and add organic matter, with boric acid (BA) as a control. A hydroxyapatite (HA) based powder mixed with 25 wt.% high-viscosity polyvinyl alcohol (PVA) was prepared and printed using a self-made printer with deionized water as the binder. The post-processing effects were analyzed in terms of mechanical properties and microstructure. The application of 5 wt.% CA solution increased the thickness of the PVA film between HA particles by 320.0%, leading to an increase in compressive strength (7.37 ± 0.28 MPa) and modulus (102.81 ± 6.74 MPa) by 840.7% and 1571.3%, respectively, achieving the mechanical standards for human trabecular bone. This work presents a simple and rapid room-temperature post-processing strategy for enhancing the mechanical properties of bone implants produced by binder jetting additive manufacturing.

Removal of proteins and lipids affects structure, in vitro digestion and physicochemical properties of rice flour modified by heat-moisture treatment.

BACKGROUND: The objective of this experiment was to investigate the role of endogenous proteins and lipids in the structural and physicochemical properties of starch in heat-moisture treatment (HMT) rice flour and to reveal their effect on starch digestibility under heat. RESULTS: The findings indicate that, in the absence of endogenous proteins and lipids acting as a physical barrier, especially proteins, the interaction between rice flour and endogenous proteins and lipids diminished. This reduction led to fewer starch-protein inclusion complexes and starch-lipid complexes, altering the granule aggregation structure of rice flour. It resulted in a decrease in particle size, an increase in agglomeration between starch granules, and more surface cracking on rice granules. Under HMT conditions with a moisture content of 30%, slight gelatinization of the starch granules occurred, contributing to an increased starch hydrolysis rate. In addition, the elevated thermal energy effect of HMT enhanced interactions between starch molecular chains. These resulted in a decrease in crystallinity, short-range ordering, and the content of double-helix structure within starch granules. These structural transformations led to higher pasting temperatures, improved hot and cold paste stability, and a decrease in peak viscosity, breakdown, setback, and enthalpy of pasting of the starch granules. CONCLUSION: The combined analysis of microstructure, physicochemical properties, and in vitro digestion characteristics has enabled us to further enhance our understanding of the interaction mechanisms between endogenous proteins, lipids, and starches during HMT. © 2024 Society of Chemical Industry.

Globally distributed marine Gemmatimonadota have unique genomic potentials.

BACKGROUND: Gemmatimonadota bacteria are widely distributed in nature, but their metabolic potential and ecological roles in marine environments are poorly understood. RESULTS: Here, we obtained 495 metagenome-assembled genomes (MAGs), and associated viruses, from coastal to deep-sea sediments around the world. We used this expanded genomic catalog to compare the protein composition and update the phylogeny of these bacteria. The marine Gemmatimonadota are phylogenetically different from those previously reported from terrestrial environments. Functional analyses of these genomes revealed these marine genotypes are capable of degradation of complex organic carbon, denitrification, sulfate reduction, and oxidizing sulfide and sulfite. Interestingly, there is widespread genetic potential for secondary metabolite biosynthesis across Gemmatimonadota, which may represent an unexplored source of novel natural products. Furthermore, viruses associated with Gemmatimonadota have the potential to "hijack" and manipulate host metabolism, including the assembly of the lipopolysaccharide in their hosts. CONCLUSIONS: This expanded genomic diversity advances our understanding of these globally distributed bacteria across a variety of ecosystems and reveals genetic distinctions between those in terrestrial and marine communities. Video Abstract.

Tunneling nanotubes mediate KRas transport: Inducing tumor heterogeneity and altering cellular membrane mechanical properties.

Mutation in oncogene KRas plays a crucial role in the occurrence and progression of numerous malignant tumors. Malignancy involves changes in cell mechanics for extensive cellular deformation during metastatic dissemination. We hypothesize that oncogene KRas mutations are intrinsic to alterations in cellular mechanics that promote malignant tumor generation and progression. Here, we demonstrate the use of optical tweezers coupled with a confocal fluorescence imaging system and gene interference technique to reveal that the mutant KRas protein can be transported between homogeneous and heterogeneous tumor cells by tunneling nanotubes (TNTs), resulting in a significant reduction of membrane tension and acceleration of membrane phospholipid flow in the recipient cells. Simultaneously, the changes in membrane mechanical properties of the tumor cells also enhance the metastatic and invasive ability of the tumors, which further contribute to the deterioration of the tumors. This finding helps to clarify the association between oncogene mutations and changes in the mechanical properties of tumor cells, which provides a theoretical basis for the development of cancer treatment strategies. STATEMENT OF SIGNIFICANCE: Here, we present a laser confocal fluorescence system integrated with optical tweezers to observe the transfer of mutant KRasG12D protein from mutant cells to wild-type cells through TNTs. Malignancy involves changes in cell mechanics for extensive cellular deformation during metastatic dissemination. Our results demonstrate a significant decrease in membrane tension and an increase in membrane phospholipid flow in recipient cells. These alterations in mechanical properties augment the migration and invasive capabilities of tumor cells, contributing to tumor malignancy. Our findings propose that cellular mechanical properties could serve as new markers for tumor development, and targeting membrane tension may hold potential as a therapeutic strategy.

[Clinical analysis of breast reconstruction with endoscopic-assisted harvesting of latissimus dorsi muscle flap for breast cancer].

Objective: To investigate the benefits and drawbacks of breast reconstruction with endoscopic-assisted harvesting of the latissimus dorsi muscle flap for breast cancer and treatment experience of postoperative operation-related complications. Methods: A retrospective analysis was performed on clinical data of 26 female patients with breast cancer who met the selection criteria between September 2021 and March 2023 aging 48.7 years (range, 26-69 years). All tumors were unilateral, with 17 on the left side and 9 on the right side. The tumor size ranged from 1.0 to 7.0 cm, with an average of 2.7 cm. The pathological staging included T 1 in 11 cases, T 2 in 14 cases, and T 3 in 1 case; N 0 in 10 cases, N 1 in 11 cases, N 2 in 2 cases, and N 3 in 3 cases; no distant metastasis (M 0) occurred when first diagnosed. Among them, 10 cases underwent breast conserving surgery, and 16 cases underwent nipple-sparing mastectomy. All patients underwent breast reconstruction with endoscopic-assisted harvesting of the latissimus dorsi muscle flap. The operation time, incision length, and postoperative drainage volume in 3 days were recorded. Breast-Q "Satisfaction with back" scale was conducted to evaluate patients' satisfaction with back at 6 months after operation. Results: The operation time was 280-480 minutes (mean, 376.7 minutes), the incision length was 10-15 cm (mean, 12.2 cm), the postoperative drainage volume in 3 days was 500-1 600 mL (mean, 930.2 mL). There were 4 cases of postoperative seroma, 1 case of incision rupture, 1 case of paresthesia of the thoracic wall, and 1 case of edema of the ipsilateral upper limb. All patients were followed up 12-30 months (mean, 20.1 months). No latissimus dorsi muscle flap necrosis, latissimus dorsi muscle atrophy, or shoulder joint dysfunction occurred during follow-up; 2 patients had recurrence of lymph nodes in the ipsilateral axilla after operation, but no distant metastasis occurred. Breast-Q score at 6 months after operation was 64-100 (mean, 79.5). The average score was 78.6 (range, 64-100) in patients underwent nipple-sparing mastectomy and 81.0 (range, 78-100) in patients underwent breast conserving surgery. Conclusion: Breast reconstruction with endoscopic-assisted harvesting of the latissimus dorsi muscle flap for breast cancer is proven to be a surgical approach with safety and cosmetic effects with mild postoperative operation-related complications and considerable patient satisfaction.

SGLT2 inhibition, blood lipids, and cardiovascular disease: A Mendelian randomization study.

AIMS: We aim to investigate the causal effect of blood lipids mediating sodium-glucose cotransporter 2 (SGLT2) inhibition in cardiovascular disease (CVD) using Mendelian randomization (MR). METHODS AND RESULTS: A two-sample two-step MR study was conducted to evaluate the association of SGLT2 inhibition with CVDs and the mediation effects of blood lipids linking SGLT2 inhibition with CVDs. Genetic instruments for SGLT2 inhibition were identified as genetic variants, which were associated with the expression of the SLC5A2 gene and glycated haemoglobin level (HbA1c). SGLT2 inhibition was associated with reduced risk of heart failure (HF) (OR 0.44 [95% CI 0.32-0.61]; P = 6.0 × 10-7), atrial fibrillation (AF) (0.47 [0.37-0.61]; P = 1.81 × 10-8), coronary artery disease (CAD) (0.47 [0.30-0.73]; P = 7.46 × 10-4), myocardial infarction (MI) (0.30 [0.15-0.61]; P = 7.44 × 10-4), any stroke (AS) (0.28 [0.18-0.42]; P = 1.14 × 10-9), and ischaemic stroke (IS) (0.27 [0.17-0.44]; P = 1.97 × 10-7). Our results indicated that the proportion mediated of the mediating effect of total cholesterol was 1.7% (OR 0.99 [95% CI 0.98, 0.99], P = 0.004), 4.7% (0.96 [0.95, 0.98], P = 0.002), and 2.7% (0.97 [0.95, 0.98], P = 0.002) in the association between SGLT2 inhibition and the risk of HF, CAD, and MI, respectively. For low-density lipoprotein cholesterol, the proportion mediated of the mediating effect was 2.2% for HF (OR 0.98 [95% CI 0.98, 0.99], P = 0.003), 8.6% for CAD (0.93 [0.91, 0.95], P = 5.74 × 10-4), and 5.0% for MI (0.95 [0.94, 0.96], P = 6.97 × 10-4). For non-high-density lipoprotein cholesterol, the proportion mediated of the mediating effect was 3.4% for HF (OR 0.98 [95% CI 0.97, 0.98], P = 4.42 × 10-6), 11.8% for CAD (0.92 [0.90, 0.93], P = 7.23 × 10-8), 5.7% for MI (0.94 [0.92, 0.95], P = 8.17 × 10-7), 1.5% for AS (0.98 [0.98, 0.99], P = 0.001), and 1.4% for IS (0.98 [0.98, 0.99], P = 0.004). CONCLUSIONS: Our study showed the association of SGLT2 inhibition with the reduced risk of CVDs and blood lipids might mediate this association.

Molecular insights into degron recognition by CRL5ASB7 ubiquitin ligase.

The ankyrin (ANK) SOCS box (ASB) family, encompassing ASB1-18, is the largest group of substrate receptors of cullin 5 Ring E3 ubiquitin ligase. Nonetheless, the mechanism of substrate recognition by ASB family proteins has remained largely elusive. Here we present the crystal structure of ASB7-Elongin B-Elongin C ternary complex bound to a conserved helical degron. ASB7 employs its ANK3-6 to form an extended groove, effectively interacting with the internal α-helix-degron through a network of side-chain-mediated electrostatic and hydrophobic interactions. Our structural findings, combined with biochemical and cellular analyses, identify the key residues of the degron motif and ASB7 required for their recognition. This will facilitate the identification of additional physiological substrates of ASB7 by providing a defined degron motif for screening. Furthermore, the structural insights provide a basis for the rational design of compounds that can specifically target ASB7 by disrupting its interaction with its cognate degron.

Biodegradable Microembolics with Nanografted Polyanions Enable High-Efficiency Drug Loading and Sustained Deep-Tumor Drug Penetration for Locoregional Chemoembolization Treatment.

Transarterial chemoembolization (TACE), the mainstay treatment of unresectable primary liver cancer that primarily employs nondegradable drug-loaded embolic agents to achieve synergistic vascular embolization and locoregional chemotherapy effects, suffers from an inferior drug burst behavior lacking long-term drug release controllability that severely limits the TACE efficacy. Here we developed gelatin-based drug-eluting microembolics grafted with nanosized poly(acrylic acid) serving as a biodegradable ion-exchange platform that leverages a counterion condensation effect to achieve high-efficiency electrostatic drug loading with electropositive drugs such as doxorubicin (i.e., drug loading capacity >34 mg/mL, encapsulation efficiency >98%, and loading time <10 min) and an enzymatic surface-erosion degradation pattern (∼2 months) to offer sustained locoregional pharmacokinetics with long-lasting deep-tumor retention capability for TACE treatment. The microembolics demonstrated facile microcatheter deliverability in a healthy porcine liver embolization model, superior tumor-killing capacity in a rabbit VX2 liver cancer embolization model, and stabilized extravascular drug penetration depth (>3 mm for 3 months) in a rabbit ear embolization model. Importantly, the microembolics finally exhibited vessel remodeling-induced permanent embolization with minimal inflammation responses after complete degradation. Such a biodegradable ion-exchange drug carrier provides an effective and versatile strategy for enhancing long-term therapeutic responses of various local chemotherapy treatments.

Tangeretin Enhances Muscle Endurance and Aerobic Metabolism in Mice via Targeting AdipoR1 to Increase Oxidative Myofibers.

Slow oxidative myofibers play an important role in improving muscle endurance performance and maintaining body energy homeostasis. However, the targets and means to regulate slow oxidative myofibers proportion remain unknown. Here, we show that tangeretin (TG), a natural polymethoxylated flavone, significantly activates slow oxidative myofibers-related gene expression and increases type I myofibers proportion, resulting in improved endurance performance and aerobic metabolism in mice. Proteomics, molecular dynamics, cellular thermal shift assay (CETSA) and drug affinity responsive target stability (DARTS) investigations revealed that TG can directly bind to adiponectin receptor 1 (AdipoR1). Using AdipoR1-knockdown C2C12 cells and muscle-specific AdipoR1-knockout mice, we found that the positive effect of TG on regulating slow oxidative myofiber related markers expression is mediated by AdipoR1 and its downstream AMPK/PGC-1α pathway. Together, our data uncover TG as a natural compound that regulates the identity of slow oxidative myofibers via targeting the AdipoR1 signaling pathway. These findings further unveil the new function of TG in increasing the proportion of slow oxidative myofibers and enhancing skeletal muscle performance.

Genomic characterization of the bacterial phylum Candidatus Effluviviacota, a cosmopolitan member of the global seep microbiome.

The microbial communities of marine seep sediments contain unexplored physiological and phylogenetic diversity. Here, we examined 30 bacterial metagenome-assembled genomes (MAGs) from cold seeps in the South China Sea, the Indian Ocean, the Scotian Basin, and the Gulf of Mexico, as well as from deep-sea hydrothermal sediments in the Guaymas Basin, Gulf of California. Phylogenetic analyses of these MAGs indicate that they form a distinct phylum-level bacterial lineage, which we propose as a new phylum, Candidatus Effluviviacota, in reference to its preferential occurrence at diverse seep areas. Based on tightly clustered high-quality MAGs, we propose two new genus-level candidatus taxa, Candidatus Effluvivivax and Candidatus Effluvibates. Genomic content analyses indicate that Candidatus Effluviviacota are chemoheterotrophs that harbor the Embden-Meyerhof-Parnas glycolysis pathway. They gain energy by fermenting organic substrates. Additionally, they display potential capabilities for the degradation of cellulose, hemicellulose, starch, xylan, and various peptides. Extracellular anaerobic respiration appears to rely on metals as electron acceptors, with electron transfer primarily mediated by multiheme cytochromes and by a flavin-based extracellular electron transfer (EET) mechanism that involves NADH-quinone oxidoreductase-demethylmenaquinone-synthesizing enzymes, uncharacterized membrane proteins, and flavin-binding proteins, also known as the NUO-DMK-EET-FMN complex. The heterogeneity within the Ca. Effluviviacota phylum suggests varying roles in energy metabolism among different genera. While NUO-DMK-EET-FMN electron transfer has been reported predominantly in Gram-positive bacteria, it is now identified in Ca. Effluviviacota as well. We detected the presence of genes associated with bacterial microcompartments in Ca. Effluviviacota, which can promote specific metabolic processes and protect the cytosol from toxic intermediates. IMPORTANCE: The newly discovered bacterial phylum Candidatus Effluviviacota is widespread across diverse seepage ecosystems, marine environments, and freshwater environments, with a notable preference for cold seeps. While maintaining an average abundance of approximately 1% in the global gene catalog of cold seep habitats, it has not hitherto been characterized. The metabolic versatility of Ca. Effluviviacota in anaerobic carbon, hydrogen, and metal cycling aligns with its prevalence in anoxic niches, with a preference for cold seep environments. Variations in metabolic potential between Ca. Effluvivivax and Ca. Effluvibates may contribute to shaping their respective habitat distributions.

Decoding the Epigenetic Landscape: Insights into 5mC and 5hmC Patterns in Mouse Cortical Cell Types.

The DNA modifications, 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC), represent powerful epigenetic regulators of temporal and spatial gene expression. Yet, how the cooperation of these genome-wide, epigenetic marks determine unique transcriptional signatures across different brain cell populations is unclear. Here we applied Nanopore sequencing of native DNA to obtain a complete, genome-wide, single-base resolution atlas of 5mC and 5hmC modifications in neurons, astrocytes and microglia in the mouse cortex (99% genome coverage, 40 million CpG sites). In tandem with RNA sequencing, analysis of 5mC and 5hmC patterns across cell types reveals astrocytes drive uniquely high brain 5hmC levels and support two decades of research regarding methylation patterns, gene expression and alternative splicing, benchmarking this resource. As such, we provide the most comprehensive DNA methylation data in mouse brain as an interactive, online tool (NAM-Me, https://olsenlab.shinyapps.io/NAMME/) to serve as a resource dataset for those interested in the methylome landscape.

Tea, coffee, and caffeine intake and risk of dementia and Alzheimer's disease: a systematic review and meta-analysis of cohort studies.

Background: Limited and conflicting evidence exists for the associations between tea, coffee, and caffeine intake and risk of dementia and Alzheimer's disease (AD). This meta-analysis aimed to elucidate these associations and quantify potential dose-response relationships. Methods: PubMed, EMBASE, and Web of Science were searched up to 11 June 2024 for cohort studies. Random effects models were used to calculate pooled relative risks (RRs) and 95% confidence intervals (CIs), with the dose-response relationship assessed using restricted cubic splines. The Grading of Recommendations Assessment Development and Evaluation (GRADE) tool was used to assess the risk of bias. Results: Our analysis encompassed 38 cohorts, totalling 751 824 participants and 13 017 dementia and 17 341 AD cases. For dementia, compared with the lowest category, the pooled RRs (95% CI) in the highest category of tea, coffee, and caffeine were 0.84 (0.74-0.96, n = 6), 0.95 (0.87-1.02, n = 9), and 0.94 (0.70-1.25, n = 5), with all rated as low certainty in GRADE. For AD, the pooled RRs (95% CI) in the highest category of tea, coffee, and caffeine compared to the lowest category were 0.93 (0.87-1.00, n = 6), 1.01 (0.90-1.12, n = 10), and 1.34 (1.04-1.74, n = 2), with certainty ratings of low, low, and very low, respectively. Dose-response analysis indicated a non-linear relationship between coffee intake (Poverall = 0.04 and Pnonlinear = 0.01) and dementia risk, showing the protective association of risk of dementia with 1 to 3 cups per day of coffee intake. There is a linear association between tea intake and risk of dementia, with a significantly decreased risk of dementia for each 1 cup per day increase in tea consumption (0.96, 95% CI 0.94-0.99, Poverall = 0.01 and Pnonlinear = 0.68). Conclusion: Increased tea consumption was associated with a decreased risk of dementia and AD, and a non-linear relationship was found between coffee and dementia, supporting public health recommendations for dementia prevention.

Multidimensional biological characteristics of ground glass nodules.

The detection rate of ground glass nodules (GGNs) has increased in recent years because of their malignant potential but relatively indolent biological behavior; thus, correct GGN recognition and management has become a research focus. Many scholars have explored the underlying mechanism of the indolent progression of GGNs from several perspectives, such as pathological type, genomic mutational characteristics, and immune microenvironment. GGNs have different major mutated genes at different stages of development; EGFR mutation is the most common mutation in GGNs, and p53 mutation is the most abundant mutation in the invasive stage of GGNs. Pure GGNs have fewer genomic alterations and a simpler genomic profile and exhibit a gradually evolving genomic mutation profile as the pathology progresses. Compared to advanced lung adenocarcinoma, GGN lung adenocarcinoma has a higher immune cell percentage, is under immune surveillance, and has less immune escape. However, as the pathological progression and solid component increase, negative immune regulation and immune escape increase gradually, and a suppressive immune environment is established gradually. Currently, regular computer tomography monitoring and surgery are the main treatment strategies for persistent GGNs. Stereotactic body radiotherapy and radiofrequency ablation are two local therapeutic alternatives, and systemic therapy has been progressively studied for lung cancer with GGNs. In the present review, we discuss the characterization of the multidimensional molecular evolution of GGNs that could facilitate more precise differentiation of such highly heterogeneous lesions, laying a foundation for the development of more effective individualized treatment plans.

Phase-Directed Assembly of Triboelectric Nanopaper for Self-Powered Noncontact Sensing.

Noncontact sensing technology serves as a pivotal medium for seamless data acquisition and intelligent perception in the era of the Internet of Things (IoT), bringing innovative interactive experiences to wearable human-machine interaction perception networks. However, the pervasive limitations of current noncontact sensing devices posed by harsh environmental conditions hinder the precision and stability of signals. In this study, the triboelectric nanopaper prepared by a phase-directed assembly strategy is presented, which possesses low charge transfer mobility (1618 cm2 V-1 s-1) and exceptional high-temperature stability. Wearable self-powered noncontact sensors constructed from triboelectric nanopaper operate stably under high temperatures (200 °C). Furthermore, a temperature warning system for workers in hazardous environments is demonstrated, capable of nonintrusively identifying harmful thermal stimuli and detecting motion status. This research not only establishes a technological foundation for accurate and stable noncontact sensing under high temperatures but also promotes the sustainable intelligent development of wearable IoT devices under extreme environments.