Immune checkpoint therapy-elicited sialylation of IgG antibodies impairs antitumorigenic type I interferon responses in hepatocellular carcinoma.

The reinvigoration of anti-tumor T cells in response to immune checkpoint blockade (ICB) therapy is well established. Whether and how ICB therapy manipulates antibody-mediated immune response in cancer environments, however, remains elusive. Using tandem mass spectrometric analysis of modification of immunoglobulin G (IgG) from hepatoma tissues, we identified a role of ICB therapy in catalyzing IgG sialylation in the Fc region. Effector T cells triggered sialylation of IgG via an interferon (IFN)-γ-ST6Gal-I-dependent pathway. DC-SIGN+ macrophages represented the main target cells of sialylated IgG. Upon interacting with sialylated IgG, DC-SIGN stimulated Raf-1-elicited elevation of ATF3, which inactivated cGAS-STING pathway and eliminated subsequent type-I-IFN-triggered antitumorigenic immunity. Although enhanced IgG sialylation in tumors predicted improved therapeutic outcomes for patients receiving ICB therapy, impeding IgG sialylation augmented antitumorigenic T cell immunity after ICB therapy. Thus, targeting antibody-based negative feedback action of ICB therapy has potential for improving efficacy of cancer immunotherapies.

Reverse-QTY code design of active human serum albumin self-assembled amphiphilic nanoparticles for effective anti-tumor drug doxorubicin release in mice.

Human serum albumin (HSA) is a highly water-soluble protein with 67% alpha-helix content and three distinct domains (I, II, and III). HSA offers a great promise in drug delivery with enhanced permeability and retention effect. But it is hindered by protein denaturation during drug entrapment or conjugation that result in distinct cellular transport pathways and reduction of biological activities. Here we report using a protein design approach named reverse-QTY (rQTY) code to convert specific hydrophilic alpha-helices to hydrophobic to alpha-helices. The designed HSA undergo self-assembly of well-ordered nanoparticles with highly biological actives. The hydrophilic amino acids, asparagine (N), glutamine (Q), threonine (T), and tyrosine (Y) in the helical B-subdomains of HSA were systematically replaced by hydrophobic leucine (L), valine (V), and phenylalanine (F). HSArQTY nanoparticles exhibited efficient cellular internalization through the cell membrane albumin binding protein GP60, or SPARC (secreted protein, acidic and rich in cysteine)-mediated pathways. The designed HSArQTY variants displayed superior biological activities including: i) encapsulation of drug doxorubicin, ii) receptor-mediated cellular transport, iii) tumor cell targeting, and iv) antitumor efficiency compare to denatured HSA nanoparticles. HSArQTY nanoparticles provided superior tumor targeting and antitumor therapeutic effects compared to the albumin nanoparticles fabricated by antisolvent precipitation method. We believe that the rQTY code is a robust platform for specific hydrophobic modification of functional hydrophilic proteins with clear-defined binding interfaces.

Association between alcohol consumption and sleep traits: observational and mendelian randomization studies in the UK biobank.

Previous studies have shown that excessive alcohol consumption is associated with poor sleep. However, the health risks of light-to-moderate alcohol consumption in relation to sleep traits (e.g., insomnia, snoring, sleep duration and chronotype) remain undefined, and their causality is still unclear in the general population. To identify the association between alcohol consumption and multiple sleep traits using an observational and Mendelian randomization (MR) design. Observational analyses and one-sample MR (linear and nonlinear) were performed using clinical and individual-level genetic data from the UK Biobank (UKB). Two-sample MR was assessed using summary data from genome-wide association studies from the UKB and other external consortia. Phenotype analyses were externally validated using data from the National Health and Nutrition Examination Survey (2017-2018). Data analysis was conducted from January 2022 to October 2022. The association between alcohol consumption and six self-reported sleep traits (short sleep duration, long sleep duration, chronotype, snoring, waking up in the morning, and insomnia) were analysed. This study included 383,357 UKB participants (mean [SD] age, 57.0 [8.0] years; 46% male) who consumed a mean (SD) of 9.0 (10.0) standard drinks (one standard drink equivalent to 14 g of alcohol) per week. In the observational analyses, alcohol consumption was significantly associated with all sleep traits. Light-moderate-heavy alcohol consumption was linearly linked to snoring and the evening chronotype but nonlinearly associated with insomnia, sleep duration, and napping. In linear MR analyses, a 1-SD (14 g) increase in genetically predicted alcohol consumption was associated with a 1.14-fold (95% CI, 1.07-1.22) higher risk of snoring (P < 0.001), a 1.28-fold (95% CI, 1.20-1.37) higher risk of evening chronotype (P < 0.001) and a 1.24-fold (95% CI, 1.13-1.36) higher risk of difficulty waking up in the morning (P < 0.001). Nonlinear MR analyses did not reveal significant results after Bonferroni adjustment. The results of the two-sample MR analyses were consistent with those of the one-sample MR analyses, but with a slightly attenuated overall estimate. Our findings suggest that even low levels of alcohol consumption may affect sleep health, particularly by increasing the risk of snoring and evening chronotypes. The negative effects of alcohol consumption on sleep should be made clear to the public in order to promote public health.

Smart Physical-Based Transdermal Drug Delivery System:Towards Intelligence and Controlled Release.

Transdermal drug delivery systems based on physical principles have provided a stable, efficient, and safe strategy for disease therapy. However, the intelligent device with real-time control and precise drug release is required to enhance treatment efficacy and improve patient compliance. This review summarizes the recent developments, application scenarios, and drug release characteristics of smart transdermal drug delivery systems fabricated with physical principle. Special attention is paid to the progress of intelligent design and concepts in of physical-based transdermal drug delivery technologies for real-time monitoring and precise drug release. In addition, facing with the needs of clinical treatment and personalized medicine, the recent progress and trend of physical enhancement are further highlighted for transdermal drug delivery systems in combination with pharmaceutical dosage forms to achieve better transdermal effects and facilitate the development of smart medical devices. Finally, the next generation and future application scenarios of smart physical-based transdermal drug delivery systems are discussed, a particular focus in vaccine delivery and tumor treatment.

The microtubule-associated protein WDL4 modulates auxin distribution to promote apical hook opening in Arabidopsis.

The unique apical hook in dicotyledonous plants protects the shoot apical meristem and cotyledons when seedlings emerge through the soil. Its formation involves differential cell growth under the coordinated control of plant hormones, especially ethylene and auxin. Microtubules are essential players in plant cell growth that are regulated by multiple microtubule-associated proteins (MAPs). However, the role and underlying mechanisms of MAP-microtubule modules in differential cell growth are poorly understood. In this study, we found that the previously uncharacterized Arabidopsis MAP WAVE-DAMPENED2-LIKE4 (WDL4) protein plays a positive role in apical hook opening. WDL4 exhibits a temporal expression pattern during hook development in dark-grown seedlings that is directly regulated by ethylene signaling. WDL4 mutants showed a delayed hook opening phenotype while overexpression of WDL4 resulted in enhanced hook opening. In particular, wdl4-1 mutants exhibited stronger auxin accumulation in the concave side of the apical hook. Furthermore, the regulation of the auxin maxima and trafficking of the auxin efflux carriers PIN-FORMED1 (PIN1) and PIN7 in the hook region is critical for WDL4-mediated hook opening. Together, our study demonstrates that WDL4 positively regulates apical hook opening by modulating auxin distribution, thus unraveling a mechanism for MAP-mediated differential plant cell growth.

Modeling denitrification nitrogen losses in China's rice fields based on multiscale field-experiment constraints.

Denitrification plays a critical role in soil nitrogen (N) cycling, affecting N availability in agroecosystems. However, the challenges in direct measurement of denitrification products (NO, N2 O, and N2 ) hinder our understanding of denitrification N losses patterns across the spatial scale. To address this gap, we constructed a data-model fusion method to map the county-scale denitrification N losses from China's rice fields over the past decade. The estimated denitrification N losses as a percentage of N application from 2009 to 2018 were 11.8 ± 4.0% for single rice, 12.4 ± 3.7% for early rice, and 11.6 ± 3.1% for late rice. The model results showed that the spatial heterogeneity of denitrification N losses is primarily driven by edaphic and climatic factors rather than by management practices. In particular, diffusion and production rates emerged as key contributors to the variation of denitrification N losses. These findings humanize a 38.9 ± 4.8 kg N ha-1 N loss by denitrification and challenge the common hypothesis that substrate availability drives the pattern of N losses by denitrification in rice fields.

Detection and Analysis of Commonly Used Infection Indicators in Patients with Acute Urticaria.

INTRODUCTION: In this study, we investigated the correlation and clinical significance of peripheral blood leukocytes, neutrophils, C-reactive protein (CRP), and procalcitonin (PCT) in patients with acute urticaria. METHODS: Complete blood count with differential, CRP, and PCT tests were conducted on patients with acute urticaria. A total of 614 patients with acute urticaria were divided into three groups: the first group consisted of patients with elevated leukocyte and neutrophil count, the second group consisted of patients with normal leukocyte and neutrophil count, and the third group consisted of patients with abnormal leukocyte and neutrophil count. A correlation analysis was conducted to investigate the levels of leukocytes, neutrophils, CRP, and PCT in the three groups. RESULTS: The results of Kruskal-Wallis' nonparametric test revealed statistically significant variations in leukocytes, neutrophils, CRP, and PCT among the three groups (p < 0.001). However, CRP and PCT showed no statistically significant differences between the second and third groups (p < 0.001, p = 0.0041, p = 0.0032). Additional multiple comparisons in Spearman correlation analysis indicated statistically significant differences (p = 0.55). Across all groups, there was a statistically significant difference in the correlation between CRP-PCT and leukocytes-neutrophils (p = 0.53). CONCLUSION: Leukocytes and neutrophils are sensitive to the impact of medications and stress on the body. Combining CRP and PCT, as well as routine blood test, may be a comprehensive assessment of infection presence and severity in patients, providing guidance for antibiotic treatment.

Spin coated ultrathin PEDOT:PSS/SWCNT film with high electronic conductivity.

Conductive Poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) has been extensively used as non-metallic electrodes. However, the relatively low electrical conductivity of pristine PEDOT:PSS film restricts its further application. Although doping high content conductive filler or increasing the film thickness are effective for enhancing the electrical property, the transparency is sacrificed, which limits the application of PEDOT:PSS films. In this study, preparing PEDOT:PSS composite film with highly conductive and transparent property was the primary purpose. To achieve this goal, single-walled carbon nanotubes (SWCNTs) and dimethyl sulfoxide (DMSO) was chosen to composite with PEDOT:PSS. The spin-coated SWCNT/PEDOT:PSS composite film exhibited excellent electrical conductivity and transparency. The electrical conductivity of composite film with desired transmittance property (78%) reached the highest value (1060.96 S cm-1) at the SWCNTs content was 6 wt%. Under the modification process applied in this work, the non-conductive PSS was partially removed by incorporated DMSO and SWCNTs. Then, the molecular chains of PEDOT stretched and adsorbed onto the surface of SWCNTs, forming a highly efficient three-dimensional conductive structure, which contributed to the enhancement of electrical conductivity and transparency. Additionally, the spin-coating process allowed for the reduction of film thickness, ensuring better transparency. This research contributed to expanding the further applications of PEDOT:PSS films in high-performance transparent film electrodes.

Ultrabright Acrylic Polymers with Tunable Fluorescence Enabled by Imprisoning Single TICT Probe.

Bright and colorful fluorescent polymers are ideal materials for a variety of applications. Although polymers could be made fluorescent by physical doping or chemical binding of fluorescent units, it is a great challenge to get colorful and highly emissive polymers with a single fluorophore. Here the development of a general and facile method to synthesize ultrabright and colorful polymers using a single twisted intramolecular charge transfer (TICT) probe is reported. By incorporating polymerizable, highly fluorescent, and environmental sensitive TICT probe, a series of colorful acrylic polymers (emission from 481 to 543 nm) with almost 100% fluorescence quantum yields are prepared. Like the solvatochromic effect, functional groups within side chains of acrylic polymers (including alkyl chain, tetrahydrofurfuryl group, and hydroxyl group) provide varied environmental polarity for the incorporated fluorophore, resulting in a series of colorful polymeric materials. Benefiting from the excellent photophysical properties, the polymers show great potential in encryption, cultural relics protection, white light-emitting diode bulb making, and fingerprint identification.

The effects of pks+ Escherichia coli and bile acid in colorectal tumorigenesis among people with cholelithiasis or cholecystectomy.

BACKGROUND AND AIM: Patients with cholelithiasis (CL) or cholecystectomy (CE) would have more chances of getting colorectal adenoma (CRA) or cancer (CRC). We aimed to figure out the effects of gut microbiota and bile acid on colorectal neoplasm in CL and CE patients. METHODS: This was a retrospective observational study that recruited 514 volunteers, including 199 people with normal gallbladders (normal), 152 CL, and 163 CE patients. Discovery cohort was established to explore the difference in gut microbiota through 16S rRNA and metagenomics sequencing. Validation cohort aimed to verify the results through quantitative polymerase chain reaction (qPCR). RESULTS: Significant enrichment of Escherichia coli was found in patients with cholelithiasis or cholecystectomy both in the discovery cohort (16S rRNA sequencing, PNormal-CL = 0.013, PNormal-CE = 0.042; metagenomics sequencing, PNormal-CE = 0.026) and validation cohort (PNormal-CL < 0.0001, PNormal-CE < 0.0001). Pks+ E. coli was found enriched in CL and CE patients through qPCR (in discovery cohort: PNormal-CE = 0.018; in validation cohort: PNormal-CL < 0.0001, PNormal-CE < 0.0001). The differences in bile acid metabolism were found both through Tax4Fun analysis of 16S rRNA sequencing (Ko00120, primary bile acid biosynthesis, PNormal-CE = 0.014; Ko00121, secondary bile acid biosynthesis, PNormal-CE = 0.010) and through metagenomics sequencing (map 00121, PNormal-CE = 0.026). The elevation of serum total bile acid of CE patients was also found in validation cohort (PNormal-CE < 0.0001). The level of serum total bile acid was associated with the relative abundance of pks+ E. coli (r = 0.1895, P = 0.0012). CONCLUSIONS: E. coli, especially pks+ species, was enriched in CL and CE patients. Pks+ E. coli and bile acid metabolism were found associated with CRA and CRC in people after cholecystectomy.

A protein encoded by circular ZNF609 RNA induces acute kidney injury by activating the AKT/mTOR-autophagy pathway.

Autophagy plays a crucial role in the development and progression of ischemic acute kidney injury (AKI). However, the function and mechanism of circular RNAs (circRNAs) in the regulation of autophagy in ischemic AKI remain unexplored. Herein, we find that circ-ZNF609, originating from the ZNF609 locus, is highly expressed in the kidney after ischemia/reperfusion injury, and urinary circ-ZNF609 is a moderate predictor for AKI in heart disease patients. Overexpression of circ-ZNF609 can activate AKT3/mTOR signaling and induce autophagy flux impairment and cell apoptosis while inhibiting proliferation in HK-2 cells, which is blocked by silencing circ-ZNF609. Mechanistically, circ-ZNF609 encodes a functional protein consisting of 250 amino acids (aa), termed ZNF609-250aa, the overexpression of which can activate AKT3/mTOR signaling and induce autophagy flux impairment and cell apoptosis in HK-2 cells in vitro and in AKI kidneys in vivo. The blockade of AKT and mTOR signaling with pharmacological inhibitors is capable of reversing ZNF609-250aa-induced autophagy flux impairment and cell apoptosis in HK-2 cells. The present study demonstrates that highly expressed circ-ZNF609-encoded ZNF609-250aa induces cell apoptosis and AKI by impairing the autophagy flux via an AKT/mTOR-dependent mechanism. These findings imply that targeting circ-ZNF609 may be a novel therapy for ischemic AKI.

Targeting inflammatory macrophages rebuilds therapeutic efficacy of DOT1L inhibition in hepatocellular carcinoma.

Epigenetic reprogramming is a promising therapeutic strategy for aggressive cancers, but its limitations in vivo remain unclear. Here, we showed, in detailed studies of data regarding 410 patients with human hepatocellular carcinoma (HCC), that increased histone methyltransferase DOT1L triggered epithelial-mesenchymal transition-mediated metastasis and served as a therapeutic target for human HCC. Unexpectedly, although targeting DOT1L in vitro abrogated the invasive potential of hepatoma cells, abrogation of DOT1L signals hardly affected the metastasis of hepatoma in vivo. Macrophages, which constitute the major cellular component of the stroma, abrogated the anti-metastatic effect of DOT1L targeting. Mechanistically, NF-κB signal elicited by macrophage inflammatory response operated via a non-epigenetic machinery to eliminate the therapeutic efficacy of DOT1L targeting. Importantly, therapeutic strategy combining DOT1L-targeted therapy with macrophage depletion or NF-κB inhibition in vivo effectively and successfully elicited cancer regression. Moreover, we found that the densities of macrophages in HCC determined malignant cell DOT1L-associated clinical outcome of the patients. Our results provide insight into the crosstalk between epigenetic reprogramming and cancer microenvironments and suggest that strategies to influence the functional activities of inflammatory cells may benefit epigenetic reprogramming therapy.

Evaluating AAPM-TG-218 recommendations: Gamma index tolerance and action limits in IMRT and VMAT quality assurance using SunCHECK.

PURPOSE: This study aimed to improve the safety and accuracy of radiotherapy by establishing tolerance (TL) and action (AL) limits for the gamma index in patient-specific quality assurance (PSQA) for intensity-modulated radiation therapy (IMRT) and volumetric-modulated arc therapy (VMAT) using SunCHECK software, as per AAPM TG-218 report recommendations. METHODS: The study included 125 patients divided into six groups by treatment regions (H&N, thoracic and pelvic) and techniques (VMAT, IMRT). SunCHECK was used to calculate the gamma passing rate (%GP) and dose error (%DE) for each patient, for the planning target volume and organs at risk (OARs). The TL and AL were then determined for each group according to TG-218 recommendations. We conducted a comprehensive analysis to compare %DE among different groups and examined the relationship between %GP and %DE. RESULTS: The TL and AL of all groups were more stringent than the common standard as defined by the TG218 report. The TL and AL values of the groups differed significantly, and the values for the thoracic groups were lower for both VMAT and IMRT. The %DE of the parameters D95%, D90%, and Dmean in the planning target volume, and Dmean and Dmax in OARs were significantly different. The dose deviation of VMAT was larger than IMRT, especially in the thoracic group. A %GP and %DE correlation analysis showed a strong correlation for the planning target volume, but a weak correlation for the OARs. Additionally, a significant correlation existed between %GP of SunCHECK and Delta4. CONCLUSION: The study established TL and AL values tailored to various anatomical regions and treatment techniques at our institution. Establishing PSQA workflows for VMAT and IMRT offers valuable clinical insights and guidance. We also suggest developing a standard combining clinically relevant metrics with %GP to evaluate PSQA results comprehensively.

Adaptive and Ultrahigh-Affinity Recognition in Water by Sulfated Conjugated Corral[5]arene.

The pursuit of synthetic receptors with high binding affinities has long been a central focus in supramolecular chemistry, driven by their significant practical relevance in various fields. Despite the numerous synthetic receptors that have been developed, most exhibit binding affinities in the micromolar range or lower. Only a few exceptional receptors achieve binding affinities exceeding 109  M-1 , and their substrate scopes remain rather limited. In this context, we introduce SC[5]A, a conjugated corral-shaped macrocycle functionalized with ten sulfate groups. Owing to its deep one-dimensional confined hydrophobic cavity and multiple sulfate groups, SC[5]A displays an extraordinarily high binding strength of up to 1011  M-1 towards several size-matched, rod-shaped organic dications in water. Besides, its conformation exhibits good adaptability, allowing it to encapsulate a wide range of other guests with diverse molecular sizes, shapes, and functionalities, exhibiting relatively strong affinities (Ka =106 -108  M-1 ). Additionally, we've explored the preliminary application of SC[5]A in alleviating blood coagulation induced by hexadimethrine bromide in vitro and in vivo. Therefore, the combination of ultrahigh binding affinities (towards complementary guests) and adaptive recognition capability (towards a wide range of functional guests) of SC[5]A positions it as exceptionally valuable for numerous practical applications.

African Suid Genomes Provide Insights into the Local Adaptation to Diverse African Environments.

African wild suids consist of several endemic species that represent ancient members of the family Suidae and have colonized diverse habitats on the African continent. However, limited genomic resources for African wild suids hinder our understanding of their evolution and genetic diversity. In this study, we assembled high-quality genomes of a common warthog (Phacochoerus africanus), a red river hog (Potamochoerus porcus), as well as an East Asian Diannan small-ear pig (Sus scrofa). Phylogenetic analysis showed that common warthog and red river hog diverged from their common ancestor around the Miocene/Pliocene boundary, putatively predating their entry into Africa. We detected species-specific selective signals associated with sensory perception and interferon signaling pathways in common warthog and red river hog, respectively, which contributed to their local adaptation to savannah and tropical rainforest environments, respectively. The structural variation and evolving signals in genes involved in T-cell immunity, viral infection, and lymphoid development were identified in their ancestral lineage. Our results provide new insights into the evolutionary histories and divergent genetic adaptations of African suids.

Exploring Plant Meiosis: Insights from the Kinetochore Perspective.

The central player for chromosome segregation in both mitosis and meiosis is the macromolecular kinetochore structure, which is assembled by >100 structural and regulatory proteins on centromere DNA. Kinetochores play a crucial role in cell division by connecting chromosomal DNA and microtubule polymers. This connection helps in the proper segregation and alignment of chromosomes. Additionally, kinetochores can act as a signaling hub, regulating the start of anaphase through the spindle assembly checkpoint, and controlling the movement of chromosomes during anaphase. However, the role of various kinetochore proteins in plant meiosis has only been recently elucidated, and these proteins differ in their functionality from those found in animals. In this review, our current knowledge of the functioning of plant kinetochore proteins in meiosis will be summarized. In addition, the functional similarities and differences of core kinetochore proteins in meiosis between plants and other species are discussed, and the potential applications of manipulating certain kinetochore genes in meiosis for breeding purposes are explored.

Fecal Signatures of Streptococcus anginosus and Streptococcus constellatus for Noninvasive Screening and Early Warning of Gastric Cancer.

BACKGROUND & AIMS: Most patients with gastric cancer (GCa) are diagnosed at an advanced stage. We aimed to investigate novel fecal signatures for clinical application in early diagnosis of GCa. METHODS: This was an observational study that included 1043 patients from 10 hospitals in China. In the discovery cohort, 16S ribosomal RNA gene analysis was performed in paired samples (tissues and feces) from patients with GCa and chronic gastritis (ChG) to determine differential abundant microbes. Their relative abundances were detected using quantitative real-time polymerase chain reaction to test them as bacterial candidates in the training cohort. Their diagnostic efficacy was validated in the validation cohort. RESULTS: Significant enrichments of Streptococcus anginosus (Sa) and Streptococcus constellatus (Sc) in GCa tumor tissues (P < .05) and feces (P < .0001) were observed in patients with intraepithelial neoplasia, early and advanced GCa. Either the signature parallel test Sa∪Sc or single signature Sa/Sc demonstrated superior sensitivity (Sa: 75.6% vs 72.1%, P < .05; Sc: 84.4% vs 64.0%, P < .001; and Sa∪Sc: 91.1% vs 81.4%, P < .01) in detecting early GCa compared with advanced GCa (specificity: Sa: 84.0% vs 83.9%, Sc: 70.4% vs 82.3%, and Sa∪Sc: 64.0% vs 73.4%). Fecal signature Sa∪Sc outperformed Sa∪CEA/Sc∪CEA in the discrimination of advanced GCa (sensitivity: 81.4% vs 74.2% and 81.4% vs 72.3%, P < .01; specificity: 73.4% vs 81.0 % and 73.4% vs 81.0%). The performance of Sa∪Sc in the diagnosis of both early and advanced GCa was verified in the validation cohort. CONCLUSION: Fecal Sa and Sc are noninvasive, accurate, and sensitive signatures for early warning in GCa. (ClinicalTrials.gov, Number: NCT04638959).

BACH1 promotes intervertebral disc degeneration by regulating HMOX1/GPX4 to mediate oxidative stress, ferroptosis, and lipid metabolism in nucleus pulposus cells.

BACKGROUND: Intervertebral disc degeneration (IDD) is a primary health problem worldwide that involves oxidative stress, ferroptosis, and lipid metabolism. However, the underlying mechanism remains unclear. We investigated whether the transcription factor BTB and CNC homology 1 (BACH1) affected IDD progression by regulating HMOX1/GPX4-mediated ferroptosis and lipid metabolism in nucleus pulposus cells (NPCs). METHODS: A rat IDD model was created to detect BACH1 expression in intervertebral disc tissues. Next, rat NPCs were isolated and treated with tert-butyl hydroperoxide (TBHP). BACH1, HMOX1, and GPX4 were knocked down, and oxidative stress and ferroptosis-related marker levels were examined. The binding of BACH1 to HMOX1 and of BACH1 to GPX4 was verified using chromatin immunoprecipitation (ChIP). Finally, untargeted lipid metabolism analysis was performed. RESULTS: An IDD model was successfully created, and BACH1 activity was found to be enhanced in the rat IDD tissues. BACH1 inhibited TBHP-induced oxidative stress and oxidative stress-induced ferroptosis in NPCs. Simultaneously, ChIP verified that BACH1 protein bound to HMOX1 and targeted the HMOX1 transcription inhibition to affect oxidative stress in NPCs. ChIP also verified that BACH1 bound to GPX4 and targeted the GPX4 inhibition to affect ferroptosis in NPCs. Finally, BACH1 inhibition in vivo improved IDD and affected lipid metabolism. CONCLUSIONS: The transcription factor BACH1 promoted IDD by regulating HMOX1/GPX4 to mediate oxidative stress, ferroptosis, and lipid metabolism in NPCs.

Heterogeneity in the immune microenvironment of bone metastasis in driver-positive non-small cell lung cancer.

Mutations in epidermal growth factor receptor and anaplastic lymphoma kinase are common driver events in non-small cell lung cancer (NSCLC), which are associated with a high frequency of bone metastases (BMs). While the bone marrow represents a specialized immune microenvironment, the immune repertoire of BMs remains unknown. Considering the higher incidence of BMs in driver gene-positive NSCLCs, and the unique biology of the bone, herein, we assessed the infiltrating immune cells and T cell receptor (TCR) profile of BMs in driver-positive NSCLCs. Immune profile of BMs in driver gene-positive NSCLC were assessed in 10 patients, where 6 had driver gene-positive mutation. TCR and bulk RNA sequencing were performed on malignant bone samples. The diversity and clonality of the TCR repertoire were analyzed. The cellular components were inferred from bulk gene expression profiles computationally by CIBERSORT. Although BMs were generally regarded as immune-cold tumors, immune cell composition analyses showed co-existence of cytotoxic and suppressor immune cells in driver-positive BM samples, as compared to primary lung. Analysis of the TCR repertoire indicated a trend of higher diversity and similar clonality in the driver-positive compared with the driver-negative subsets. In addition, we identified two cases that showed the opposite response to immune checkpoint blockade. A comparison of these two patients' BM samples showed more highly amplified clones, fewer M2 macrophages and more activated natural killer cells in the responder. In summary, BMs in NSCLC are heterogeneous in their immune microenvironment, which might be related to differential clinical outcomes to immune checkpoint blockade.

Physical adsorption and oxidation of ultra-thin MoS2crystals: insights into surface engineering for 2D electronics and beyond.

The oxidation mechanism of atomically thin molybdenum disulfide (MoS2) plays a critical role in its nanoelectronics, optoelectronics, and catalytic applications, where devices often operate in an elevated thermal environment. In this study, we systematically investigate the oxidation of mono- and few-layer MoS2flakes in the air at temperatures ranging from 23 °C to 525 °C and relative humidities of 10%-60% by using atomic force microscopy (AFM), Raman spectroscopy and x-ray photoelectron spectroscopy. Our study reveals the formation of a uniform nanometer-thick physical adsorption layer on the surface of MoS2, which is attributed to the adsorption of ambient moisture. This physical adsorption layer acts as a thermal shield of the underlying MoS2lattice to enhance its thermal stability and can be effectively removed by an AFM tip scanning in contact mode or annealing at 400 °C. Our study shows that high-temperature thermal annealing and AFM tip-based cleaning result in chemical adsorption on sulfur vacancies in MoS2, leading to p-type doping. Our study highlights the importance of humidity control in ensuring reliable and optimal performance for MoS2-based electronic and electrochemical devices and provides crucial insights into the surface engineering of MoS2, which are relevant to the study of other two-dimensional transition metal dichalcogenide materials and their applications.