Spatial transcriptomic landscape unveils immunoglobin-associated senescence as a hallmark of aging.

To systematically characterize the loss of tissue integrity and organ dysfunction resulting from aging, we produced an in-depth spatial transcriptomic profile of nine tissues in male mice during aging. We showed that senescence-sensitive spots (SSSs) colocalized with elevated entropy in organizational structure and that the aggregation of immunoglobulin-expressing cells is a characteristic feature of the microenvironment surrounding SSSs. Immunoglobulin G (IgG) accumulated across the aged tissues in both male and female mice, and a similar phenomenon was observed in human tissues, suggesting the potential of the abnormal elevation of immunoglobulins as an evolutionarily conserved feature in aging. Furthermore, we observed that IgG could induce a pro-senescent state in macrophages and microglia, thereby exacerbating tissue aging, and that targeted reduction of IgG mitigated aging across various tissues in male mice. This study provides a high-resolution spatial depiction of aging and indicates the pivotal role of immunoglobulin-associated senescence during the aging process.

Early Solar System instability triggered by dispersal of the gaseous disk.

The Solar System's orbital structure is thought to have been sculpted by an episode of dynamical instability among the giant planets1-4. However, the instability trigger and timing have not been clearly established5-9. Hydrodynamical modelling has shown that while the Sun's gaseous protoplanetary disk was present the giant planets migrated into a compact orbital configuration in a chain of resonances2,10. Here we use dynamical simulations to show that the giant planets' instability was probably triggered by the dispersal of the gaseous disk. As the disk evaporated from the inside out, its inner edge swept successively across and dynamically perturbed each planet's orbit in turn. The associated orbital shift caused a dynamical compression of the exterior part of the system, ultimately triggering instability. The final orbits of our simulated systems match those of the Solar System for a viable range of astrophysical parameters. The giant planet instability therefore took place as the gaseous disk dissipated, constrained by astronomical observations to be a few to ten million years after the birth of the Solar System11. Terrestrial planet formation would not complete until after such an early giant planet instability12,13; the growing terrestrial planets may even have been sculpted by its perturbations, explaining the small mass of Mars relative to Earth14.

The IFT81-IFT74 complex acts as an unconventional RabL2 GTPase-activating protein during intraflagellar transport.

Cilia are important cellular organelles for signaling and motility and are constructed via intraflagellar transport (IFT). RabL2 is a small GTPase that localizes to the basal body of cilia via an interaction with the centriolar protein CEP19 before downstream association with the IFT machinery, which is followed by initiation of IFT. We reconstituted and purified RabL2 with CEP19 or IFT proteins to show that a reconstituted pentameric IFT complex containing IFT81/74 enhances the GTP hydrolysis rate of RabL2. The binding site on IFT81/74 that promotes GTP hydrolysis in RabL2 was mapped to a 70-amino-acid-long coiled-coil region of IFT81/74. We present structural models for RabL2-containing IFT complexes that we validate in vitro and in cellulo and demonstrate that Chlamydomonas IFT81/74 enhances GTP hydrolysis of human RabL2, suggesting an ancient evolutionarily conserved activity. Our results provide an architectural understanding of how RabL2 is incorporated into the IFT complex and a molecular rationale for why RabL2 dissociates from anterograde IFT trains soon after departure from the ciliary base.

The anion channel SLAH3 interacts with potassium channels to regulate nitrogen-potassium homeostasis and the membrane potential in Arabidopsis.

Nitrogen (N) and potassium (K) are essential macronutrients for plants. Sufficient N and K uptake from the environment is required for successful growth and development. However, how N and K influence each other at the molecular level in plants is largely unknown. In this study, we found loss-of-function mutation in SLAH3 (SLAC1 HOMOLOGUE 3), encoding a NO3- efflux channel in Arabidopsis thaliana, enhanced tolerance to high KNO3 concentrations. Surprisingly, slah3 mutants were less sensitive to high K+ but not NO3-. Addition of NO3- led to reduced phenotypic difference between wild-type and slah3 plants, suggesting SLAH3 orchestrates NO3--K+ balance. Non-invasive Micro-test Technology analysis revealed reduced NO3- efflux and enhanced K+ efflux in slah3 mutants, demonstrating that SLAH3-mediated NO3- transport and SLAH3-affected K+ flux are critical in response to high K +. Further investigation showed that two K+ efflux channels, GORK (GATED OUTWARDLY-RECTIFYING K+ CHANNEL) and SKOR (STELAR K+ OUTWARD RECTIFIER), interacted with SLAH3 and played key roles in high K+ response. The gork and skor mutants were slightly more sensitive to high K+ conditions. Less depolarization occurred in slah3 mutants and enhanced depolarization was observed in gork and skor mutants upon K+ treatment, suggesting NO3-/K+ efflux-mediated membrane potential regulation is involved in high K+ response. Electrophysiological results showed that SLAH3 partially inhibited the activities of GORK and SKOR in Xenopus laevis oocytes. This study revealed that the anion channel SLAH3 interacts with the potassium channels GORK and SKOR to modulate membrane potential by coordinating N-K balance.

CD151 Maintains Endolysosomal Protein Quality to Inhibit Vascular Inflammation.

BACKGROUND: Tetraspanin CD151 is highly expressed in endothelia and reinforces cell adhesion, but its role in vascular inflammation remains largely unknown. METHODS: In vitro molecular and cellular biological analyses on genetically modified endothelial cells, in vivo vascular biological analyses on genetically engineered mouse models, and in silico systems biology and bioinformatics analyses on CD151-related events. RESULTS: Endothelial ablation of Cd151 leads to pulmonary and cardiac inflammation, severe sepsis, and perilous COVID-19, and endothelial CD151 becomes downregulated in inflammation. Mechanistically, CD151 restrains endothelial release of proinflammatory molecules for less leukocyte infiltration. At the subcellular level, CD151 determines the integrity of multivesicular bodies/lysosomes and confines the production of exosomes that carry cytokines such as ANGPT2 (angiopoietin-2) and proteases such as cathepsin-D. At the molecular level, CD151 docks VCP (valosin-containing protein)/p97, which controls protein quality via mediating deubiquitination for proteolytic degradation, onto endolysosomes to facilitate VCP/p97 function. At the endolysosome membrane, CD151 links VCP/p97 to (1) IFITM3 (interferon-induced transmembrane protein 3), which regulates multivesicular body functions, to restrain IFITM3-mediated exosomal sorting, and (2) V-ATPase, which dictates endolysosome pH, to support functional assembly of V-ATPase. CONCLUSIONS: Distinct from its canonical function in strengthening cell adhesion at cell surface, CD151 maintains endolysosome function by sustaining VCP/p97-mediated protein unfolding and turnover. By supporting protein quality control and protein degradation, CD151 prevents proteins from (1) buildup in endolysosomes and (2) discharge through exosomes, to limit vascular inflammation. Also, our study conceptualizes that balance between degradation and discharge of proteins in endothelial cells determines vascular information. Thus, the IFITM3/V-ATPase-tetraspanin-VCP/p97 complexes on endolysosome, as a protein quality control and inflammation-inhibitory machinery, could be beneficial for therapeutic intervention against vascular inflammation.

A small-molecule degrader of TET3 as treatment for anorexia nervosa in an animal model.

Anorexia nervosa (AN) is a psychiatric illness with the highest mortality. Current treatment options have been limited to psychotherapy and nutritional support, with low efficacy and high relapse rates. Hypothalamic AgRP (agouti-related peptide) neurons that coexpress AGRP and neuropeptide Y (NPY) play a critical role in driving feeding while also modulating other complex behaviors. We have previously reported that genetic ablation of Tet3, which encodes a member of the TET family dioxygenases, specifically in AgRP neurons in mice, activates these neurons and increases the expression of AGRP, NPY, and the vesicular GABA transporter (VGAT), leading to hyperphagia and anxiolytic effects. Bobcat339 is a synthetic small molecule predicted to bind to the catalytic pockets of TET proteins. Here, we report that Bobcat339 is effective in mitigating AN and anxiety/depressive-like behaviors using a well-established mouse model of activity-based anorexia (ABA). We show that treating mice with Bobcat339 decreases TET3 expression in AgRP neurons and activates these neurons leading to increased feeding, decreased compulsive running, and diminished lethality in the ABA model. Mechanistically, Bobcat339 induces TET3 protein degradation while simultaneously stimulating the expression of AGRP, NPY, and VGAT in a TET3-dependent manner both in mouse and human neuronal cells, demonstrating a conserved, previously unsuspected mode of action of Bobcat339. Our findings suggest that Bobcat339 may potentially be a therapeutic for anorexia nervosa and stress-related disorders.

Heritable changes of epialleles near genes in maize can be triggered in the absence of CHH methylation.

Trans-chromosomal interactions resulting in changes in DNA methylation during hybridization have been observed in several plant species. However, little is known about the causes or consequences of these interactions. Here, we compared DNA methylomes of F1 hybrids that are mutant for a small RNA biogenesis gene, Mop1 (Mediator of paramutation1), with that of their parents, wild-type siblings, and backcrossed progeny in maize (Zea mays). Our data show that hybridization triggers global changes in both trans-chromosomal methylation (TCM) and trans-chromosomal demethylation (TCdM), most of which involved changes in CHH methylation. In more than 60% of these TCM differentially methylated regions (DMRs) in which small RNAs are available, no significant changes in the quantity of small RNAs were observed. Methylation at the CHH TCM DMRs was largely lost in the mop1 mutant, although the effects of this mutant varied depending on the location of these DMRs. Interestingly, an increase in CHH at TCM DMRs was associated with enhanced expression of a subset of highly expressed genes and suppressed expression of a small number of lowly expressed genes. Examination of the methylation levels in backcrossed plants demonstrates that both TCM and TCdM can be maintained in the subsequent generation, but that TCdM is more stable than TCM. Surprisingly, although increased CHH methylation in most TCM DMRs in F1 plants required Mop1, initiation of a new epigenetic state of these DMRs did not require a functional copy of this gene, suggesting that initiation of these changes is independent of RNA-directed DNA methylation.

Two calcium sensor-activated kinases function in root hair growth.

Plant pollen tubes and root hairs typically polarized tip growth. It is well established that calcium ions (Ca2+) play essential roles in maintaining cell polarity and guiding cell growth orientation. Ca2+ signals are encoded by Ca2+ channels and transporters and are decoded by a variety of Ca2+-binding proteins often called Ca2+ sensors, in which calcineurin B-like protein (CBL) proteins function by interacting with and activating a group of kinases and activate CBL-interacting protein kinases (CIPKs). Some CBL-CIPK complexes, such as CBL2/3-CIPK12/19, act as crucial regulators of pollen tube growth. Whether these calcium decoding components regulate the growth of root hairs, another type of plant cell featuring Ca2+-regulated polarized growth, remains unknown. In this study, we identified CIPK13 and CIPK18 as genes specifically expressed in Arabidopsis (Arabidopsis thaliana) root hairs. The cipk13 cipk18 double mutants showed reduced root hair length and lower growth rates. The calcium oscillations at the root hair tip were attenuated in the cipk13 cipk18 mutants as compared to the wild-type plants. Through yeast 2-hybrid screens, CBL2 and CBL3 were identified as interacting with CIPK13 and CIPK18. cbl2 cbl3 displayed a shortened root hair phenotype similar to cipk13 cipk18. This genetic analysis, together with biochemical assays showing activation of CIPK13/18 by CBL2/3, supported the conclusion that CBL2/3 and CIPK13/18 may work as Ca2+-decoding modules in controlling root hair growth. Thus, the findings that CIPK12/19 and CIPK13/18 function in pollen tube and root hair growth, respectively, illustrate a molecular mechanism in which the same CBLs recruit distinct CIPKs in regulating polarized tip growth in different types of plant cells.

Tr1 Cells Emerge and Suppress Effector Th17 Cells in Glomerulonephritis.

T regulatory type 1 (Tr1) cells, which are defined by their regulatory function, lack of Foxp3, and high expression of IL-10, CD49b, and LAG-3, are known to be able to suppress Th1 and Th17 in the intestine. Th1 and Th17 cells are also the main drivers of crescentic glomerulonephritis (GN), the most severe form of renal autoimmune disease. However, whether Tr1 cells emerge in renal inflammation and, moreover, whether they exhibit regulatory function during GN have not been thoroughly investigated yet. To address these questions, we used a mouse model of experimental crescentic GN and double Foxp3mRFP IL-10eGFP reporter mice. We found that Foxp3neg IL-10-producing CD4+ T cells infiltrate the kidneys during GN progression. Using single-cell RNA sequencing, we could show that these cells express the core transcriptional factors characteristic of Tr1 cells. In line with this, Tr1 cells showed a strong suppressive activity ex vivo and were protective in experimental crescentic GN in vivo. Finally, we could also identify Tr1 cells in the kidneys of patients with antineutrophil cytoplasmic autoantibody-associated GN and define their transcriptional profile. Tr1 cells are currently used in several immune-mediated inflammatory diseases, such as T-cell therapy. Thus, our study provides proof of concept for Tr1 cell-based therapies in experimental GN.

Integrated 3D genome, epigenome and transcriptome analyses reveal transcriptional coordination of circadian rhythm in rice.

Photoperiods integrate with the circadian clock to coordinate gene expression rhythms and thus ensure plant fitness to the environment. Genome-wide characterization and comparison of rhythmic genes under different light conditions revealed delayed phase under constant darkness (DD) and reduced amplitude under constant light (LL) in rice. Interestingly, ChIP-seq and RNA-seq profiling of rhythmic genes exhibit synchronous circadian oscillation in H3K9ac modifications at their loci and long non-coding RNAs (lncRNAs) expression at proximal loci. To investigate how gene expression rhythm is regulated in rice, we profiled the open chromatin regions and transcription factor (TF) footprints by time-series ATAC-seq. Although open chromatin regions did not show circadian change, a significant number of TFs were identified to rhythmically associate with chromatin and drive gene expression in a time-dependent manner. Further transcriptional regulatory networks mapping uncovered significant correlation between core clock genes and transcription factors involved in light/temperature signaling. In situ Hi-C of ZT8-specific expressed genes displayed highly connected chromatin association at the same time, whereas this ZT8 chromatin connection network dissociates at ZT20, suggesting the circadian control of gene expression by dynamic spatial chromatin conformation. These findings together implicate the existence of a synchronization mechanism between circadian H3K9ac modifications, chromatin association of TF and gene expression, and provides insights into circadian dynamics of spatial chromatin conformation that associate with gene expression rhythms.

The Paf1 complex is required for RNA polymerase II removal in response to DNA damage.

Rpb1, the largest subunit of RNA polymerase II (RNAPII), is rapidly polyubiquitinated and degraded in response to DNA damage; this process is considered to be a "mechanism of last resort'' employed by cells. The underlying mechanism of this process remains elusive. Here, we uncovered a previously uncharacterized multistep pathway in which the polymerase-associated factor 1 (Paf1) complex (PAF1C, composed of the subunits Ctr9, Paf1, Leo1, Cdc73, and Rtf1) is involved in regulating the RNAPII pool by stimulating Elongin-Cullin E3 ligase complex-mediated Rpb1 polyubiquitination and subsequent degradation by the proteasome following DNA damage. Mechanistically, Spt5 is dephosphorylated following DNA damage, thereby weakening the interaction between the Rtf1 subunit and Spt5, which might be a key step in initiating Rpb1 degradation. Next, Rad26 is loaded onto stalled RNAPII to replace the Spt4/Spt5 complex in an RNAPII-dependent manner and, in turn, recruits more PAF1C to DNA lesions via the binding of Rad26 to the Leo1 subunit. Importantly, the PAF1C, assembled in a Ctr9-mediated manner, coordinates with Rad26 to localize the Elongin-Cullin complex on stalled RNAPII, thereby inducing RNAPII removal, in which the heterodimer Paf1/Leo1 and the subunit Cdc73 play important roles. Together, our results clearly revealed a new role of the intact PAF1C in regulating the RNAPII pool in response to DNA damage.

BRD4-directed super-enhancer organization of transcription repression programs links to chemotherapeutic efficacy in breast cancer.

BRD4 is well known for its role in super-enhancer organization and transcription activation of several prominent oncogenes including c-MYC and BCL2 As such, BRD4 inhibitors are being pursued as promising therapeutics for cancer treatment. However, drug resistance also occurs for BRD4-targeted therapies. Here, we report that BRD4 unexpectedly interacts with the LSD1/NuRD complex and colocalizes with this repressive complex on super-enhancers. Integrative genomic and epigenomic analyses indicate that the BRD4/LSD1/NuRD complex restricts the hyperactivation of a cluster of genes that are functionally linked to drug resistance. Intriguingly, treatment of breast cancer cells with a small-molecule inhibitor of BRD4, JQ1, results in no immediate activation of the drug-resistant genes, but long-time treatment or destabilization of LSD1 by PELI1 decommissions the BRD4/LSD1/NuRD complex, leading to resistance to JQ1 as well as to a broad spectrum of therapeutic compounds. Consistently, PELI1 is up-regulated in breast carcinomas, its level is negatively correlated with that of LSD1, and the expression level of the BRD4/LSD1/NuRD complex-restricted genes is strongly correlated with a worse overall survival of breast cancer patients. Together, our study uncovers a functional duality of BRD4 in super-enhancer organization of transcription activation and repression linking to oncogenesis and chemoresistance, respectively, supporting the pursuit of a combined targeting of BRD4 and PELI1 in effective treatment of breast cancer.

Skeletal muscle TET3 promotes insulin resistance through destabilisation of PGC-1α.

AIM/HYPOTHESIS: The peroxisome proliferator-activated receptor-γ coactivator α (PGC-1α) plays a critical role in the maintenance of glucose, lipid and energy homeostasis by orchestrating metabolic programs in multiple tissues in response to environmental cues. In skeletal muscles, PGC-1α dysregulation has been associated with insulin resistance and type 2 diabetes but the underlying mechanisms have remained elusive. This research aims to understand the role of TET3, a member of the ten-eleven translocation (TET) family dioxygenases, in PGC-1α dysregulation in skeletal muscles in obesity and diabetes. METHODS: TET expression levels in skeletal muscles were analysed in humans with or without type 2 diabetes, as well as in mouse models of high-fat diet (HFD)-induced or genetically induced (ob/ob) obesity/diabetes. Muscle-specific Tet3 knockout (mKD) mice were generated to study TET3's role in muscle insulin sensitivity. Genome-wide expression profiling (RNA-seq) of muscle tissues from wild-type (WT) and mKD mice was performed to mine deeper insights into TET3-mediated regulation of muscle insulin sensitivity. The correlation between PGC-1α and TET3 expression levels was investigated using muscle tissues and in vitro-derived myotubes. PGC-1α phosphorylation and degradation were analysed using in vitro assays. RESULTS: TET3 expression was elevated in skeletal muscles of humans with type 2 diabetes and in HFD-fed and ob/ob mice compared with healthy controls. mKD mice exhibited enhanced glucose tolerance, insulin sensitivity and resilience to HFD-induced insulin resistance. Pathway analysis of RNA-seq identified 'Mitochondrial Function' and 'PPARα Pathway' to be among the top biological processes regulated by TET3. We observed higher PGC-1α levels (~25%) in muscles of mKD mice vs WT mice, and lower PGC-1α protein levels (~25-60%) in HFD-fed or ob/ob mice compared with their control counterparts. In human and murine myotubes, increased PGC-1α levels following TET3 knockdown contributed to improved mitochondrial respiration and insulin sensitivity. TET3 formed a complex with PGC-1α and interfered with its phosphorylation, leading to its destabilisation. CONCLUSIONS/INTERPRETATION: Our results demonstrate an essential role for TET3 in the regulation of skeletal muscle insulin sensitivity and suggest that TET3 may be used as a potential therapeutic target for the metabolic syndrome. DATA AVAILABILITY: Sequences are available from the Gene Expression Omnibus ( https://www.ncbi.nlm.nih.gov/geo/ ) with accession number of GSE224042.

Fat mass and obesity-related protein contributes to the development and maintenance of bone cancer pain in rats by abrogating m6A methylation of RNA.

Effective prevention and treatment options for bone cancer-related pain (BCP) are lacking. In recent years, numerous studies have investigated the association between m6A epigenetic modifications and pain, revealing their significant role in pain initiation and maintenance. This study aimed to provide theoretical support for the treatment of BCP and to identify target drugs for future development. Specifically, we investigated the involvement of fat mass and obesity-related protein (FTO) in rat models of BCP by administering varying doses (1/5/10 mg/kg) of the FTO inhibitor meclofenamic acid (MA) and assessing changes in mechanical sensitivity through domain analysis, gait analysis, and open-field experiments. After successfully establishing the BCP model, we verified it by performing mechanical sensitivity assessments. We observed significantly increased expression levels of the demethylase FTO within the spinal dorsal horn accompanied by decreased m6A methylation levels in the model. Compared with untreated BCP rats, remarkably improved behavioral responses indicative of reduced pain were observed in the model rats after administration of 10 mg/kg MA, concomitant with decreased expression levels of FTO and increased m6A methylation levels. Compared with untreated BCP rats, the expression levels of p-ERK and pro-inflammatory cytokines were also significantly decreased after MA administration. Taken together, FTO can downregulate m6A methylation level and activate ERK/inflammatory cytokines signaling pathway to maintain BCP in rats.

Intradermal vaccination with Porcilis® Begonia can clinically protect against fatal PRV challenge with the highly virulent ZJ01 field strain.

Since pseudorabies (PR) re-emerged and rapidly spread in China at the end of 2011, researchers have focused on effective vaccine strategies to prevent and control pseudorabies virus (PRV) infection in pig herds. Due to the extensive application of an attenuated vaccine based on the Bartha-K61 strain isolated in Hungary in 1961 and the variation of the PRV strain, it has been suggested that traditional vaccines based on the Bartha-K61 strain offer only partial protection against variant strains. It was therefore evaluated whether the Porcilis® Begonia vaccine, which is based on the NIA-3 strain with deletions in the gE and TK genes, is efficacious against experimental infection with the virulent, contemporary Chinese PRV strain ZJ01. In this study, piglets were vaccinated with Porcilis® Begonia through either the intradermal (ID) route or the intramuscular (IM) route and subsequently challenged intranasally with strain ZJ01 at 4 weeks post-vaccination. An unvaccinated challenge group and an unvaccinated/nonchallenged group were also included in the study. All animals were monitored for 14 days after challenge. Vaccinated and negative control pigs stayed healthy during the study, while the unvaccinated control animals developed lesions associated with PRV ZJ01 challenge, and 44% of these pigs died before the end of the experiment. This study demonstrated that ID or IM vaccination of pigs with a vaccine based on the NIA-3 strain Porcilis® Begonia clinically protects against fatal PRV challenge with the ZJ01 strain.

Identification of Immune-Related Genes as Potential Biomarkers in Early Septic Shock.

INTRODUCTION: Septic shock, a severe manifestation of infection-induced systemic immune response, poses a critical threat resulting in life-threatening multi-organ failure. Early diagnosis and intervention are imperative due to the potential for irreversible organ damage. However, specific and sensitive detection tools for the diagnosis of septic shock are still lacking. METHODS: Gene expression files of early septic shock were obtained from the Gene Expression Omnibus (GEO) database. CIBERSORT analysis was used to evaluate immune cell infiltration. Genes related to immunity and disease progression were identified using weighted gene co-expression network analysis (WGCNA), followed by enrichment analysis. CytoHubba was then employed to identify hub genes, and their relationships with immune cells were explored through correlation analysis. Blood samples from healthy controls and patients with early septic shock were collected to validate the expression of hub genes, and an external dataset was used to validate their diagnostic efficacy. RESULTS: Twelve immune cells showed significant infiltration differences in early septic shock compared to control, such as neutrophils, M0 macrophages, and natural killer cells. The identified immune and disease-related genes were mainly enriched in immune, cell signaling, and metabolism pathways. In addition, six hub genes were identified (PECAM1, F11R, ITGAL, ICAM3, HK3, and MCEMP1), all significantly associated with M0 macrophages and exhibiting an area under curve of over 0.7. These genes exhibited abnormal expression in patients with early septic shock. External datasets and real-time qPCR validation supported the robustness of these findings. CONCLUSION: Six immune-related hub genes may be potential biomarkers for early septic shock.

Dietary branched-chain amino acids intake and new-onset hypertension: a nationwide prospective cohort study in China.

OBJECTIVE: This study aimed to investigate the relationship between dietary branched-chain amino acids (BCAAs) and the risk of developing hypertension. METHODS: A cohort study of 14,883 Chinese adults without hypertension at baseline with were followed for an average of 8.9 years. Dietary intakes of BCAAs, including Ile, Leu, and Val, were collected using 3-day 24-h meal recall and household condiment weighing. Cox proportional hazards regression, restricted cubic splines, interaction analysis, and sensitivity analysis were used to assess the relationship between dietary BCAAs and risk of developing self-reported hypertension, adjusting for age, gender, region, body mass index (BMI), smoking and drinking status, physical activity, energy intake, salt intake. RESULTS: Among 14,883 study subjects, 6386(42.9%) subjects aged ≥ 45 years at baseline, 2692 (18.1%) had new-onset hypertension during the study period, with a median age of 56 years. High levels of dietary BCAAs were associated with an increased risk of new-onset hypertension. Compared with the 41st-60th percentile, multivariable adjusted hazard ratio (HR) for new-onset hypertension was 1.16 (95% CI 1.01-1.32) for dietary BCAAs 61st-80th percentiles, 1.30 (1.13-1.50) for 81st-95th, 1.60 (1.32-1.95) for 96th-100th. The cut-off value of new-onset hypertension risk, total BCAAs, Ile, Leu, and Val were 15.7 g/day, 4.1 g/day, 6.9 g/day, 4.6 g/day, respectively, and the proportion of the population above these intake values were 13.9%, 13.1%, 15.4%, and 14.4%, respectively. Age, BMI, and salt intake had an interactive effect on this relationship (P < 0.001). CONCLUSION: There was a significant positive association between total dietary BCAAs, Ile, Leu, Val intake and the risk of developing hypertension, after adjustment for confounders. This relationship was influenced by age, BMI, and salt intake. Further research is needed to clarify the mechanism and potential role of BCAAs in the pathogenesis of hypertension.

A PSMA PET/CT-based risk model for prediction of concordance between targeted biopsy and combined biopsy in detecting prostate cancer.

PURPOSE: This study is to investigate the diagnostic value of 68Ga-PSMA-11 in improving the concordance between mpMRI-TB and combined biopsy (CB) in detecting PCa. METHODS: 115 consecutive men with 68Ga-PSMA-11 PET/CT prior to prostate biopsy were included for analysis. PSMA intensity, quantified as maximum standard uptake value (SUVmax), minimum apparent diffusion coefficient (ADCmin) and other clinical characteristics were evaluated relative to biopsy concordance using univariate and multivariate logistic regression analyses. A prediction model was developed based on the identified parameters, and a dynamic online diagnostic nomogram was constructed, with its discrimination evaluated through the area under the ROC curve (AUC) and consistency assessed using calibration plots. To assess its clinical applicability, a decision curve analysis (DCA) was performed, while internal validation was conducted using bootstrapping methods. RESULTS: Concordance between mpMRI-TB and CB occurred in 76.5% (88/115) of the patients. Multivariate logistic regression analyses performed that SUVmax (OR= 0.952; 95% CI 0.917-0.988; P= 0.010) and ADCmin (OR= 1.006; 95% CI 1.003-1.010; P= 0.001) were independent risk factors for biopsy concordance. The developed model showed a sensitivity, specificity, accuracy and AUC of 0.67, 0.78, 0.81 and 0.78 in the full sample. The calibration curve demonstrated that the nomogram's predicted outcomes closely resembled the ideal curve, indicating consistency between predicted and actual outcomes. Furthermore, the decision curve analysis (DCA) highlighted the clinical net benefit achievable across various risk thresholds. These findings were reinforced by internal validation. CONCLUSIONS: The developed prediction model based on SUVmax and ADCmin showed practical value in guiding the optimization of prostate biopsy pattern. Lower SUVmax and Higher ADCmin values are associated with greater confidence in implementing mono-TB and safely avoiding SB, effectively balancing benefits and risks.

Photochemistry of Imidazole-2-carbaldehyde in Droplets as a Potential Source of H2O2 and Its Oxidation of SO2.

Hydrogen peroxide (H2O2) plays a crucial role as an oxidizing agent within the tropospheric environment, making a substantial contribution to sulfate formation in hydrated aerosols and cloud and fog droplets. Field observations show that high levels of H2O2 are often observed in heavy haze events and polluted air. However, the source of H2O2 remains unclear. Here, using the droplets formed in situ by the deliquescence of hygroscopic compounds under a high relative humidity (RH), the formation of H2O2 by the photochemistry of imidazole-2-carbaldehyde (2-IC) under ultraviolet irradiation was explored. The results indicate that 2-IC produces IM-C•-OH and IM-C•═O radicals via H transfer itself to its excited triplet state and generates H2O2 and organic peroxides in the presence of O2, which has an evident oxidizing effect on SO2, suggesting the potential involvement of this pathway in the formation of atmospheric sulfate. H2O2 formation is limited in acidic droplets or droplets containing ammonium ions, and no H2O2 is detected in droplets containing nitrate, whereas droplets containing citric acid have an obvious promotion effect on H2O2 formation. These findings provide valuable insights into the behaviors of atmospheric photosensitizers, the source of H2O2, and the formation of sulfate in atmospheric droplets.

Sustainable Blue Foods from Rice-Animal Coculture Systems.

Global interest grows in blue foods as part of sustainable diets, but little is known about the potential and environmental performance of blue foods from rice-animal coculture systems. Here, we compiled a large experimental database and conducted a comprehensive life cycle assessment to estimate the impacts of scaling up rice-fish and rice-crayfish systems in China. We find that a large amount of protein can be produced from the coculture systems, equivalent to ∼20% of freshwater aquaculture and ∼70% of marine wild capture projected in 2030. Because of the ecological benefits created by the symbiotic relationships, cocultured fish and crayfish are estimated to be carbon-negative (-9.8 and -4.7 kg of CO2e per 100 g of protein, respectively). When promoted at scale to displace red meat, they can save up to ∼98 million tons of greenhouse gases and up to ∼13 million hectares of farmland, equivalent to ∼44% of China's total rice acreage. These results suggest that rice-animal coculture systems can be an important source of blue foods and contribute to a sustainable dietary shift, while reducing the environmental footprints of rice production. To harvest these benefits, robust policy supports are required to guide the sustainable development of coculture systems and promote healthy and sustainable dietary change.