SUSD2 suppresses CD8+ T cell antitumor immunity by targeting IL-2 receptor signaling.

Dysfunctional CD8+ T cells, which have defective production of antitumor effectors, represent a major mediator of immunosuppression in the tumor microenvironment. Here, we show that SUSD2 is a negative regulator of CD8+ T cell antitumor function. Susd2-/- effector CD8+ T cells showed enhanced production of antitumor molecules, which consequently blunted tumor growth in multiple syngeneic mouse tumor models. Through a quantitative mass spectrometry assay, we found that SUSD2 interacted with interleukin (IL)-2 receptor α through sushi domain-dependent protein interactions and that this interaction suppressed the binding of IL-2, an essential cytokine for the effector functions of CD8+ T cells, to IL-2 receptor α. SUSD2 was not expressed on regulatory CD4+ T cells and did not affect the inhibitory function of these cells. Adoptive transfer of Susd2-/- chimeric antigen receptor T cells induced a robust antitumor response in mice, highlighting the potential of SUSD2 as an immunotherapy target for cancer.

Neural networks of the mouse neocortex.

Numerous studies have examined the neuronal inputs and outputs of many areas within the mammalian cerebral cortex, but how these areas are organized into neural networks that communicate across the entire cortex is unclear. Over 600 labeled neuronal pathways acquired from tracer injections placed across the entire mouse neocortex enabled us to generate a cortical connectivity atlas. A total of 240 intracortical connections were manually reconstructed within a common neuroanatomic framework, forming a cortico-cortical connectivity map that facilitates comparison of connections from different cortical targets. Connectivity matrices were generated to provide an overview of all intracortical connections and subnetwork clusterings. The connectivity matrices and cortical map revealed that the entire cortex is organized into four somatic sensorimotor, two medial, and two lateral subnetworks that display unique topologies and can interact through select cortical areas. Together, these data provide a resource that can be used to further investigate cortical networks and their corresponding functions.

The mouse cortico-basal ganglia-thalamic network.

The cortico-basal ganglia-thalamo-cortical loop is one of the fundamental network motifs in the brain. Revealing its structural and functional organization is critical to understanding cognition, sensorimotor behaviour, and the natural history of many neurological and neuropsychiatric disorders. Classically, this network is conceptualized to contain three information channels: motor, limbic and associative1-4. Yet this three-channel view cannot explain the myriad functions of the basal ganglia. We previously subdivided the dorsal striatum into 29 functional domains on the basis of the topography of inputs from the entire cortex5. Here we map the multi-synaptic output pathways of these striatal domains through the globus pallidus external part (GPe), substantia nigra reticular part (SNr), thalamic nuclei and cortex. Accordingly, we identify 14 SNr and 36 GPe domains and a direct cortico-SNr projection. The striatonigral direct pathway displays a greater convergence of striatal inputs than the more parallel striatopallidal indirect pathway, although direct and indirect pathways originating from the same striatal domain ultimately converge onto the same postsynaptic SNr neurons. Following the SNr outputs, we delineate six domains in the parafascicular and ventromedial thalamic nuclei. Subsequently, we identify six parallel cortico-basal ganglia-thalamic subnetworks that sequentially transduce specific subsets of cortical information through every elemental node of the cortico-basal ganglia-thalamic loop. Thalamic domains relay this output back to the originating corticostriatal neurons of each subnetwork in a bona fide closed loop.

A guide to the BRAIN Initiative Cell Census Network data ecosystem.

Characterizing cellular diversity at different levels of biological organization and across data modalities is a prerequisite to understanding the function of cell types in the brain. Classification of neurons is also essential to manipulate cell types in controlled ways and to understand their variation and vulnerability in brain disorders. The BRAIN Initiative Cell Census Network (BICCN) is an integrated network of data-generating centers, data archives, and data standards developers, with the goal of systematic multimodal brain cell type profiling and characterization. Emphasis of the BICCN is on the whole mouse brain with demonstration of prototype feasibility for human and nonhuman primate (NHP) brains. Here, we provide a guide to the cellular and spatial approaches employed by the BICCN, and to accessing and using these data and extensive resources, including the BRAIN Cell Data Center (BCDC), which serves to manage and integrate data across the ecosystem. We illustrate the power of the BICCN data ecosystem through vignettes highlighting several BICCN analysis and visualization tools. Finally, we present emerging standards that have been developed or adopted toward Findable, Accessible, Interoperable, and Reusable (FAIR) neuroscience. The combined BICCN ecosystem provides a comprehensive resource for the exploration and analysis of cell types in the brain.

Mitochondrial calcium uniporter promotes phagocytosis-dependent activation of the NLRP3 inflammasome.

Mitochondria, a highly metabolically active organelle, have been shown to play an essential role in regulating innate immune function. Mitochondrial Ca2+ uptake via the mitochondrial Ca2+ uniporter (MCU) is an essential process regulating mitochondrial metabolism by targeting key enzymes involved in the tricarboxylic acid cycle (TCA). Accumulative evidence suggests MCU-dependent mitochondrial Ca2+ signaling may bridge the metabolic reprogramming and regulation of immune cell function. However, the mechanism by which MCU regulates inflammation and its related disease remains elusive. Here we report a critical role of MCU in promoting phagocytosis-dependent activation of NLRP3 (nucleotide-binding domain, leucine-rich repeat containing family, pyrin domain-containing 3) inflammasome by inhibiting phagolysosomal membrane repair. Myeloid deletion of MCU (McuΔmye) resulted in an attenuated phagolysosomal rupture, leading to decreased caspase-1 cleavage and interleukin (IL)-1ß release, in response to silica or alum challenge. In contrast, other inflammasome agonists such as adenosine triphosphate (ATP), nigericin, poly(dA:dT), and flagellin induced normal IL-1ß release in McuΔmye macrophages. Mechanistically, we demonstrated that decreased NLRP3 inflammasome activation in McuΔmye macrophages was caused by improved phagolysosomal membrane repair mediated by ESCRT (endosomal sorting complex required for transport)-III complex. Furthermore, McuΔmye mice showed a pronounced decrease in immune cell recruitment and IL-1ß production in alum-induced peritonitis, a typical IL-1-dependent inflammation model. In sum, our results identify a function of MCU in promoting phagocytosis-dependent NLRP3 inflammatory response via an ESCRT-mediated phagolysosomal membrane repair mechanism.

Whole-genome resequencing provides insights into the diversity and adaptation to desert environment in Xinjiang Mongolian cattle.

BACKGROUND: Xinjiang Mongolian cattle is an indigenous breed that inhabits the Taklimakan Desert and is characterized by its small body size. However, the genomic diversity, origin, and genetic basis underlying the adaptation to the desert environment have been poorly studied. RESULTS: We analyzed patterns of Xinjiang Mongolian cattle genetic variation by sequencing 20 genomes together with seven previously sequenced genomes and comparing them to the 134 genomes of nine representative breeds worldwide. Among the breeds of Bos taurus, we found the highest nucleotide diversity (0.0024) associated with the lower inbreeding coefficient (2.0110-6), the lowest linkage disequilibrium (r2 = 0.3889 at distance of 10 kb), and the highest effective population size (181 at 20 generations ago) in Xinjiang Mongolian cattle. The genomic diversity pattern could be explained by a limited introgression of Bos indicus genes. More importantly, similarly to desert-adapted camel and same-habitat sheep, we also identified signatures of selection including genes, GO terms, and/or KEGG pathways controlling water reabsorption and osmoregulation, metabolic regulation and energy balance, as well as small body size in Xinjiang Mongolian cattle. CONCLUSIONS: Our results imply that Xinjiang Mongolian cattle might have acquired distinct genomic diversity by virtue of the introgression of Bos indicus, which helps understand the demographic history. The identification of selection signatures can provide novel insights into the genomic basis underlying the adaptation of Xinjiang Mongolian cattle to the desert environment.

Complement system is overactivated in patients with IgA nephropathy after COVID-19.

IgA nephropathy (IgAN), which has been confirmed as a complement mediated autoimmune disease, is also one form of glomerulonephritis associated with COVID-19. Here, we aim to investigate the clinical and immunological characteristics of patients with IgAN after COVID-19. The level of plasma level of C5a (p < 0.001), soluble C5b-9 (p = 0.018), FHR5 (p < 0.001) were all significantly higher in Group CoV (33 patients with renal biopsy-proven IgAN experienced COVID-19) compared with Group non-CoV (44 patients with IgAN without COVID-19), respectively. Compared with Group non-CoV, the intensity of glomerular C4d (p = 0.017) and MAC deposition (p < 0.001) and Gd-IgA1 deposition (p = 0.005) were much stronger in Group CoV. Our finding revealed that for IgAN after COVID-19, mucosal immune responses to SARS-CoV-2 infection may result in the overactivation of systemic and renal local complement system, and increased glomerular deposition of Gd-IgA1, which may lead to renal dysfunction and promote renal progression in IgAN patients.

Electronic structures and quantum capacitance of twisted bilayer graphene with defects based on three-band tight-binding model.

Twisted bilayer graphene (tBLG) with C vacancies would greatly improve the density of states (DOS) around the Fermi level (EF) and quantum capacitance; however, the single-band tight-binding model only considering pz orbitals cannot accurately capture the low-energy physics of tBLG with C vacancies. In this work, a three-band tight-binding model containing three p orbitals of C atoms is proposed to explore the modulation mechanism of C vacancies on the DOS and quantum capacitance of tBLG. We first obtain the hopping integral parameters of the three-band tight-binding model, and then explore the electronic structures and the quantum capacitance of tBLG at a twisting angle of θ = 1.47° under different C vacancy concentrations. The impurity states contributed by C atoms with dangling bonds located around the EF and the interlayer hopping interaction could induce band splitting of the impurity states. Therefore, compared with the quantum capacitance of pristine tBLG (∼18.82 µF cm-2) at zero bias, the quantum capacitance is improved to ∼172.76 µF cm-2 at zero bias, and the working window with relatively large quantum capacitance in the low-voltage range is broadened in tBLG with C vacancies due to the enhanced DOS around the EF. Moreover, the quantum capacitance of tBLG is further increased at zero bias with an increase of the C vacancy concentration induced by more impurity states. These findings not only provide a suitable multi-band tight-binding model to describe tBLG with C vacancies but also offer theoretical insight for designing electrode candidates for low-power consumption devices with improved quantum capacitance.

Synthesis of narrow-spectrum anti-mycobacterial molecules without effect on the diversity of gut microbiota in mice based on the structure of rifampicin.

Rifampicin (RIF) is a broad-spectrum antimicrobial agent that is also a first-line drug for treating tuberculosis (TB). Based on the naphthyl ring structure of RIF this study synthesized 16 narrow-spectrum antimicrobial molecules that were specifically anti-Mycobacterium tuberculosis (Mtb). The most potent candidate was 2-((6-hydroxynaphthalen-2-yl) methylene) hydrazine-1-carbothioamide (compound 3c) with minimum inhibitory concentration (MIC) of 1 µg/mL against Mtb. Synergistic anti-Mtb test indicated that none of the combinations of 3c with the major anti-TB drugs are antagonistic. Consistent with RIF, compound 3c induced large amounts of reactive oxygen radicals (ROS) in the cells of Mtb. The killing kinetics of compound 3c and RIF are very similar. Furthermore, molecular docking showed that compound 3c was able to access the RIF binding pocket of the ß subunit of Mtb RNA polymerase (RNAP). Experiments in mice showed that compound 3c increased the variety of intestinal flora in mice, while RIF significantly decreased the diversity of intestinal flora in mice. In addition, compound 3c is non-toxic to animal cells with a selection index (SI) much more than 10. The evidence from this study suggests that the further development of 3c could contribute to the development of novel drug for TB treatment.

Piezo1 channel activation facilitates baroreflex afferent neurotransmission with subsequent blood pressure reduction in control and hypertension rats.

Mechanosensitive cation channels such as Piezo1 and Piezo2 are activated by mechanical force like a starched wall of the aorta while blood pressure (BP) rising, which helps to elucidate the underlying mechanism of mechanotransduction of baroreceptor endings. In this study we investigated how Piezo1 channel activation-mediated gender- and afferent-specific BP regulation in rats. We established high-fat diet and fructose drink-induced hypertension model rats (HFD-HTN) and deoxycorticosterone (DOCA)-sensitive hypertension model rats. We showed that the expression levels of Piezo1 and Piezo2 were significantly up-regulated in left ventricle of HFD and DOCA hypertensive rats, whereas the down-regulation of Piezo1 was likely to be compensated by Piezo2 up-regulation in the aorta. Likewise, down-regulated Piezo1 was observed in the nodose ganglion (NG), while up-regulated Piezo2 was found in the nucleus tractus solitarius (NTS), which might synergistically reduce the excitatory neurotransmitter release from the presynaptic membrane. Notably, microinjection of Yoda1 (0.025-2.5 mg/ml) into the NG concentration-dependently reduced BP in both hypertensive rat models as well as in control rats with similar EC50; the effect of Yoda1 was abolished by microinjection of a Piezo1 antagonist GsMTx4 (1.0 µM). Functional analysis in an in vitro aortic arch preparation showed that instantaneous firing frequency of single Ah-fiber of aortic depressor nerve was dramatically increased by Yoda1 (0.03-1.0 µM) and blocked by GsMTx4 (1.0 µM). Moreover, spontaneous synaptic currents recorded from identified 2nd-order Ah-type baroreceptive neurons in the NTS was also facilitated over 100% by Yoda1 (1.0 µM) and completely blocked by GsMTx4 (3.0 µM). These results demonstrate that Piezo1 expressed on Ah-type baroreceptor and baroreceptive neurons in the NG and NTS plays a key role in a sexual-dimorphic BP regulation under physiological and hypertensive condition through facilitation of baroreflex afferent neurotransmission, which is presumably collaborated by Piezo2 expression at different level of baroreflex afferent pathway via compensatory and synergistic mechanisms.

Exploring testicular miRNA profiles during developmental stages in Dezhou donkeys: A preliminary insight.

Testicular development and spermatogenesis are complex phenomena controlled by various genetic factors, including miRNA-based post-transcriptional gene expression regulation. Exploring the miRNA expression patterns during testicular development in Dezhou donkeys would enhance our understanding of equine fertility and spermatogenesis. In this investigation, we examined the testicular miRNA profiles at various stages of development. The experimental animals were divided into three groups based on their developmental stages: 2 months old (juvenile: n = 3), 12 months old (adolescent; n = 3) and 24 months old (adult; n = 3) donkeys. Total RNA was extracted from dissected testicles for miRNA sequencing and analysis. In total, 586 miRNAs, including 451 known miRNAs and 135 novel miRNAs, were identified. Among identified miRNAs, 315 displayed age-dependent expression differences. The levels of miRNA expression in the juvenile group were significantly higher than in the adolescent or adult groups. The MiR-483 exhibited the maximum fold change between juvenile and adolescent groups. Several screened genes, including SLC45A4 and TFCP2L1, have been linked to male reproductive pathways in donkeys. In addition, miR-744 was predicted to regulate SPIN2B, a gene implicated in spermatocyte cell cycle progression and genomic integrity of spermatozoa. These results contribute to our comprehension of microRNA regulation during testicular development and spermatogenesis in Dezhou donkeys. The identified microRNAs and their target genes have the potential to serve as biomarkers for evaluating the reproductive capacity of stud donkeys.

[Content of secondary metabolites and antioxidant activities of Lonicera japonica flowers at different developmental stages from Shandong province].

This study established an ultrasound-assisted extraction-high performance liquid chromatography method for simulta-neously determinining the content of 11 bioactive compounds including iridoids, phenolic acids, and flavonoids in Lonicera japonica flowers. The flowers at six stages from the rice bud stage(ML) to the golden flower stage(JH) of L. japonica varieties 'Sijuhua' and 'Beihua No.1' in two planting bases in Shandong province were collected. The established method was employed to determine the content of 11 target compounds, on the basis of which the dynamics of active components in L. japonica sampels during different development stages was investigated. The correlation analysis was carried out to reveal the correlations of the content of iridoids, phenolic acids, and flavonoids. Furthermore, the antioxidant activities of samples at different developmental stages were determined, and the relationship between antioxidant activity and chemical components was analyzed by the correlation analysis. The results showed that the total content of the 11 components in 'Sijihua' changed in a "W" pattern from the ML to JH, being the highest at the ML and the second at the slight white stage(EB). The total content of 11 compounds in 'Beihua No.1' was the highest at the ML and decreased gra-dually from the ML to JH. The samples of 'Sijihua' had higher content of iridoids and lower content of phenolic acids than those of 'Beihua No.1'. The content of flavonoids and phenolic acids showed a positive correlation(R~2=0.90, P<0.05) in 'Sijihua' but no obvious correlation in 'Beihua No.1'. The antioxidant activity and phenolic acid content showed positive correlations, with the determination coefficients(R~2) of 0.84(P<0.05) in 'Beihua No.1' and 0.73(P<0.05) in 'Sijihua'. The antioxidant activity of both varieties was the strongest at the ML and the second at the EB. This study revealed that the content dynamics of iridoids, phenolic acids, and flavonoids in 'Sijihua' and 'Beihua No.1' cultivated in Shandong province during different developmental stages. The results indicated that the antioxidant activity of L. japonica flowers was significantly correlated with the content of phenolic acids at different deve-lopmental stages, which provided a basis for determining the optimum harvest time of L. japonica flowers.

[Role of NLRP3 inflammasome in prevention and treatment of cognitive impairment-related diseases and traditional Chinese medicine intervention: a review].

Alzheimer's disease(AD), vascular dementia(VD), and traumatic brain injury(TBI) are more common cognitive impairment diseases characterized by high disability and mortality rates, imposing a heavy burden on individuals and their families. Although AD, VD, and TBI have different specific mechanisms, their pathogenesis is closely related to the nucleotide-binding oligome-rization domain-like receptor protein 3(NLRP3). The NLRP3 inflammasome is involved in neuroinflammatory responses, mediating microglial polarization, regulating the reduction of amyloid ß-protein(Aß) deposition, neurofibrillary tangles(NFTs) formation, autophagy regulation, and maintaining brain homeostasis, and synaptic stability, thereby contributing to the development of AD, VD, and TBI. Previous studies have shown that traditional Chinese medicine(TCM) can alleviate neuroinflammation, promote microglial polarization towards the M2 phenotype, reduce Aß deposition and NFTs formation, regulate autophagy, and maintain brain homeostasis by intervening in NLRP3 inflammasome, hence exerting a role in preventing and treating cognitive impairment-related diseases, reducing psychological and economic pressure on patients, and improving their quality of life. Therefore, this article elucidated the role of NLRP3 inflammasome in AD, VS, and TBI, and provided a detailed summary of the latest research results on TCM intervention in NLRP3 inflammasome for the prevention and treatment of these diseases, aiming to inherit the essence of TCM and provide references and foundations for clinical prevention and treatment of cognitive impairment-related diseases with TCM. Meanwhile, this also offers insights and directions for further research in TCM for the prevention and treatment of cognitive impairment-related diseases.

RNA-seq and microRNA association analysis to explore the pathogenic mechanism of DHAV-1 infection with DEHs.

Duck hepatitis A virus 1 (DHAV-1) is one of the main contagious pathogens that causes rapid death of ducklings. To illuminate the potential of DHAV-1-infected underlying mechanisms, we analyzed the mRNA and microRNA (miRNA) expression profiles of duck embryonic hepatocytes (DEHs) in response to DHAV-1. We found 3410 differentially expressed genes (DEGs) and 142 differentially expressed miRNAs (DEMs) at 36 h after DHAV-1 infection. Additionally, DEGs and the target genes of miRNA expression were analyzed and enriched utilizing GO and KEGG, which may be crucial for immune responses, viral resistance, and mitophagy. For instance, the dysregulation of DDX58, DHX58, IRF7, IFIH1, STING1, TRAF3, CALCOCO2, OPTN, PINK1, and MFN2 in DHAV-1-infected DEHs was verified by RT-qPCR. Then, the association analysis of mRNAs and miRNAs was constructed utilizing the protein-protein interaction (PPI) networks, and the expressions of main miRNAs were confirmed, including miR-132c-3p, miR-6542-3p, and novel-mir163. These findings reveal a synthetic characterization of the mRNA and miRNA in DHAV-1-infected DEHs and advance the understanding of molecular mechanism in DHAV-1 infection, which may provide a hint for the interactions of virus and host.

An In Situ Assembled Trapping Gel Repairs Spinal Cord Injury by Capturing Glutamate and Free Calcium Ions.

Spinal cord injury (SCI) can lead to devastating autonomic dysfunction. One of the most challenging issues for functional repair in SCI is the secondary damage caused by the increased release of glutamate and free Ca2+ from injured cells. Here, an in situ assembled trapping gel (PF-SA-GAD) is developed to sweep glutamate and Ca2+ , promoting SCI repair. The hydrogel solution is a mixture of recombinant glutamate decarboxylase 67 (rGAD67) protein, sodium alginate (SA), and pluronic F-127 (PF-127). After intrathecal administration, temperature-sensitive PF-127 promoted in situ gelation. Glutamate (Glu) is captured and decarboxylated by rGAD67 into γ-aminobutyric acid (GABA). SA reacted with the free Ca2+ to generate gellable calcium alginate. Thereby, this in situ trapping gel retarded secondary neuron injury caused by Glu and free Ca2+ during SCI. In rat models of SCI, PF-SA-GAD reduces the lesion volume and inflammatory response after SCI, restores the motor function of rats with SCI. Together, the in situ assembled trapping gel is a long-term effective and minimally invasive sweeper for the direct elimination of glutamate and Ca2+ from injury lesions and can be a novel strategy for SCI repair by preventing secondary injury.

Novel Gene Clusters for Natural Product Synthesis Are Abundant in the Mangrove Swamp Microbiome.

Natural microbial communities produce a diverse array of secondary metabolites with ecologically and biotechnologically relevant activities. Some of them have been used clinically as drugs, and their production pathways have been identified in a few culturable microorganisms. However, since the vast majority of microorganisms in nature have not been cultured, identifying the synthetic pathways of these metabolites and tracking their hosts remain a challenge. The microbial biosynthetic potential of mangrove swamps remains largely unknown. Here, we examined the diversity and novelty of biosynthetic gene clusters in dominant microbial populations in mangrove wetlands by mining 809 newly reconstructed draft genomes and probing the activities and products of these clusters by using metatranscriptomic and metabolomic techniques. A total of 3,740 biosynthetic gene clusters were identified from these genomes, including 1,065 polyketide and nonribosomal peptide gene clusters, 86% of which showed no similarity to known clusters in the Minimum Information about a Biosynthetic Gene Cluster (MIBiG) repository. Of these gene clusters, 59% were harbored by new species or lineages of Desulfobacterota-related phyla and Chloroflexota, whose members are highly abundant in mangrove wetlands and for which few synthetic natural products have been reported. Metatranscriptomics revealed that most of the identified gene clusters were active in field and microcosm samples. Untargeted metabolomics was also used to identify metabolites from the sediment enrichments, and 98% of the mass spectra generated were unrecognizable, further supporting the novelty of these biosynthetic gene clusters. Our study taps into a corner of the microbial metabolite reservoir in mangrove swamps, providing clues for the discovery of new compounds with valuable activities. IMPORTANCE At present, the majority of known clinical drugs originated from cultivated species of a few bacterial lineages. It is vital for the development of new pharmaceuticals to explore the biosynthetic potential of naturally uncultivable microorganisms using new techniques. Based on the large numbers of genomes reconstructed from mangrove wetlands, we identified abundant and diverse biosynthetic gene clusters in previously unsuspected phylogenetic groups. These gene clusters exhibited a variety of organizational architectures, especially for nonribosomal peptide synthetase (NRPS) and polyketide synthase (PKS), implying the presence of new compounds with valuable activities in the mangrove swamp microbiome.

Hemolymph Node - An Immunomorphlogical Organ: Modeling the Hemolymph Node by Allografting Renal Tissue in the Rat.

There is no authoritative characterization of the attributes of the hemolymph node (HLN) since Gibbes' first description in 1884. Early reports showed that HLN are found near the kidney in human and animals with the feature of numerous erythrocytes in sinuses. Subsequent studies mainly focused on anatomy and histology, such as the source, distribution, and quantity of erythrocytes in sinuses. Recent articles mentioned that the emergence of HLN was related to immunity, but there was no strong evidence to support this hypothesis. Therefore, it is still uncertain whether the HLN is an organ of anatomy, histology, or immunology. It has been found that the development of HLN could be elicited in the parathymic area by stimuli such as Escherichia coli, allogeneic breast cancer cells, and renal tissue that were injected/transplanted into the tail of rats in our pilot studies. In this study, the model of the HLN was established by transferring allogeneic renal tissue in the rat. Intrasinusoidal erythrocytes of the node were the component for producing a red macroscopic appearance, while macrophage-erythrocyte-lymphocyte rosettes were the major immunomorphological changes, reflecting the immune activity against the invasion of the allogeneic tissue within the node. Therefore, the HLN is an immunomorphological organ.

Melatonin ameliorates bleomycin-induced pulmonary fibrosis via activating NRF2 and inhibiting galectin-3 expression.

Pulmonary fibrosis (PF) is a chronic interstitial lung disease with no effective therapies. Galectin-3 (Gal-3), a marker of oxidative stress, plays a key role in the pathogenesis of PF. Fibroblast-myofibroblast differentiation (FMD) is an important source of fibrotic cells in PF. Previous studies showed that melatonin (MT) exerted anti-fibrotic effect in many diseases including PF through its antioxidant activity. In the present study we investigated the relationships among Gal-3, NRF2, ROS in FMD and their regulation by MT. We established an in vitro model of FMD in TGF-ß1-treated human fetal lung fibroblast1 (HFL1) cells and a PF mouse model via bleomycin (BLM) intratracheal instillation. We found that Gal-3 expression was significantly increased both in vitro and in vivo. Knockdown of Gal-3 in HFL1 cells markedly attenuated TGF-ß1-induced FMD process and ROS accumulation. In TGF-ß1-treated HFL1 cells, pretreatment with NRF2-specific inhibitor ML385 (5 µM) significantly increased the levels of Gal-3, α-SMA and ROS, suggesting that the expression of Gal-3 was regulated by NRF2. Treatment with NRF2-activator MT (250 µM) blocked α-SMA and ROS accumulation accompanied by reduced Gal-3 expression. In BLM-induced PF model, administration of MT (5 mg·kg-1·d-1, ip for 14 or 28 days) significantly attenuated the progression of lung fibrosis through up-regulating NRF2 and down-regulating Gal-3 expression in lung tissues. These results suggest that Gal-3 regulates TGF-ß1-induced pro-fibrogenic responses and ROS production in FMD, and MT activates NRF2 to block FMD process by down-regulating Gal-3 expression. This study provides a useful clue for a clinical strategy to prevent PF. Graphic abstract of the mechanisms. MT attenuated BLM-induced PF via activating NRF2 and inhibiting Gal-3 expression.

Cohort Profile: Guangzhou Nutrition and Health Study (GNHS): A Population-Based Multi-Omics Study.

BACKGROUND: The Guangzhou Nutrition and Health Study (GNHS) aims to assess the determinants of metabolic disease in nutritional aspects, as well as other environmental and genetic factors, and explore possible biomarkers and mechanisms with multi-omics integration. METHODS: The population-based sample of adults in Guangzhou, China (baseline: 40-83 years old; n = 5118) was followed up about every 3 years. All will be tracked via on-site follow-up and health information systems. We assessed detailed information on lifestyle factors, physical activities, dietary assessments, psychological health, cognitive function, body measurements, and muscle function. Instrument tests included dual-energy X-ray absorptiometry scanning, carotid artery and liver ultrasonography evaluations, vascular endothelial function evaluation, upper-abdomen and brain magnetic resonance imaging, and 14-d real-time continuous glucose monitoring tests. We also measured multi-omics, including host genome-wide genotyping, serum metabolome and proteome, gut microbiome (16S rRNA sequencing, metagenome, and internal transcribed spacer 2 sequencing), and fecal metabolome and proteome. RESULTS: The baseline surveys were conducted from 2008 to 2015. Now, we have completed 3 waves. The 3rd and 4th follow-ups have started but have yet to end. A total of 5118 participants aged 40-83 took part in the study. The median age at baseline was approximately 59.0 years and the proportion of female participants was about 69.4%. Among all the participants, 3628 (71%) completed at least one on-site follow-up with a median duration of 9.48 years. CONCLUSION: The cohort will provide data that have been influential in establishing the role of nutrition in metabolic diseases with multi-omics.

Association between interpregnancy interval and maternal and neonatal adverse outcomes in women with a cesarean delivery: a population-based study.

BACKGROUND: Interpregnancy interval (IPI) has been linked with several maternal and neonatal adverse events in the general population. However, the association between IPI and maternal and neonatal outcomes in women whose first delivery was by cesarean delivery is unclear. We aimed to investigate the association between IPI after cesarean delivery and the risk of maternal and neonatal adverse events. METHODS: Women (aged ≥ 18 years) whose first delivery was cesarean delivery with 2 consecutive singleton pregnancies from the National Vital Statistics System (NVSS) database between 2017 and 2019 were included in this retrospective cohort study. In this post-hoc analysis, logistic regression analyses were used to examine IPI (≤ 11, 12-17, 18-23 [reference], 24-35, 36-59, and ≥ 60 months) in relation to the risk of repeat cesarean delivery, maternal adverse events (maternal transfusion, ruptured uterus, unplanned hysterectomy, and admission to an intensive care unit), and neonatal adverse events (low birthweight, premature birth, Apgar score at 5 min < 7, and abnormal conditions of the newborn). Stratified analysis based on age (< 35 and ≥ 35 years) and previous preterm birth. RESULTS: We included 792,094 maternities, 704,244 (88.91%) of which underwent a repeat cesarean delivery, 5,246 (0.66%) women had adverse events, and 144,423 (18.23%) neonates had adverse events. After adjusting for confounders, compared to an IPI of 18-23 months, the IPI of ≤ 11 months [odds ratio (OR) = 1.55, 95% confidence interval (CI): 1.44-1.66], 12-17 months (OR = 1.38, 95%CI: 1.33-1.43), 36-59 months (OR = 1.12, 95%CI: 1.10-1.15), and ≥ 60 months (OR = 1.19, 95%CI: 1.16-1.22) were associated with an increased risk of repeat cesarean delivery. In terms of maternal adverse events, only IPI of ≥ 60 months (OR = 0.85, 95%CI: 0.76-0.95) was observed to be associated with decreased risk of maternal adverse events in women aged < 35 years. In analysis of neonatal adverse events, IPI of ≤ 11 months (OR = 1.14, 95%CI: 1.07-1.21), 12-17 months (OR = 1.07, 95%CI: 1.03-1.10), and ≥ 60 months (OR = 1.05, 95%CI: 1.02-1.08) were related to an increased risk of neonatal adverse events. CONCLUSION: Both short and long IPI were associated with an increased risk of repeat cesarean delivery and neonatal adverse events, and women < 35 years may benefit from a longer IPI.